Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:23](OCC)=[O:24].[SH:28][C:29]1[NH:30][CH:31]=[CH:32][N:33]=1.O>CN1CCCC1=O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]1[C:23](=[O:24])[N:30]3[CH:31]=[CH:32][N:33]=[C:29]3[S:28][C:2]2=1)=[O:22]
Reactant: Sc1ncc[nH]1
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1cccc2c1ncc1c(=O)n3ccnc3sc12)c1c(Cl)cccc1Cl
Temperature: 65 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 4-chloro-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (251 mg) in N-methylpyrrolidone (2 ml) was added 2-mercaptoimidazole (89 mg), and the mixture was stirred for 1 hour at 65° C. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol to give 4-(2,6-dichlorobenzoylamino)-7H-imidazo[2',1':2,3][1,3]thiazino-[5,6-c]quinolin-7-one (248.2 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH3:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(Br)c1ccc(Br)cc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
The product from Example 44A (995 mg, 3.77 mmol) was reacted with 4-chloro-3-nitro-phenol (650 mg, 3.77 mmol) in 15 mL of DMF with K2CO3 (10.4 g, 3.77 mmol) at 80° C. for 3 h. Cooled to room temperature and diluted with water. Extracted with CH2Cl2, washed four times with water. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (1.24 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(CC)CC)C.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)(Cl)Cl>[CH2:29]([NH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: CCCCCCCCCCCCBr
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 33.4 %

Procedure:
In a 100-ml round-bottomed flask were placed 2,4-dichlorobenzylamine (3.5 g (20 mmol)), triethylamine (4.0 g (40 mmol)), and chloroform (10 ml) under nitrogen. While stirring, laurylbromide (4.9 g (20 mmol)) in chloroform (5 ml) was added dropwise at 50°-60° C. The mixture was stirred for 6 hours. The reaction mixture was cooled to room temperature and concentrated. The resultant concentrate was dissolved in ethyl acetate, washed with water, and purified via silica gel column chromatography (chloroform:methanol=10:1), thereby obtaining 2.3 g of N-lauryl-2,4-dichlorobenzylamine as pale yellow crystals (yield: 34%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].CS(O[CH:30]([O:32][CH2:33][CH3:34])[CH3:31])(=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:31][CH2:30][O:32][CH2:33][CH3:34])[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3ccccc3[nH]2)CC1
Reactant: CCOC(C)OS(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOCCn1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Yield: 91.5 %

Procedure:
In a reaction vessel, 4-(1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g) prepared in the Example 10, toluene (10 mL) and potassium hydroxide (0.8 g) were introduced, and temperature of the mixture was controlled to 50° C. or more. To the mixture, ethoxyethanol methane sulfonate (1.3 g) was added, and then, it was stirred at the same temperature until the reaction was completed. After the reaction was completed, distilled water (10 mL) was added to separate layers, and then an organic layer was condensed to obtain 4-[1-(2-ethoxyethyl)-1H-benzoimidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.7 g, 91%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:3]=1.[O:21]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C>C(O)C>[O:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]3)[CH:3]=2)=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ncn2)C1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
To a stirring solution of tert-butyl 3-(6-chloropyrimidin-4-ylamino)pyrrolidin-1-carboxylate (0.5 g, 1.6 mmol) and 4-phenoxy aniline (0.309 g, 1.6 mmol) in ethanol (4 mL) was added acetic acid (0.1 mL) and the reaction mixture was heated at 100° C. for 36 h. The reaction mixture was cooled, ethanol was removed under reduced pressure and the residue was taken in ethyl acetate (10 mL). It was washed with NaHCO3 solution (2 mL), brine (2 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was further purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to yield tert-butyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyrrolidine-1-carboxylate (0.3 g, 42.8%) as a white solid.
Reaction SMILES: C[O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=O.[C:40]1([CH2:46]C(Cl)=O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:24]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:23]([N:20]1[CH2:21][CH2:22][CH:6]2[N:5]([C:3](=[O:2])[CH2:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:9][CH:8]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH:7]12)=[O:39])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)Cc1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 66.4 %

Procedure:
A solution containing amine 50 (296 mg, 0.61 mmol) in DCM (8 mL) was cooled to 0° C. TEA (145 mg, 1.43 mmol) was added followed by phenylacetyl chloride (105 mg, 0.68 mmol) and the reaction mixture was warmed to ambient temperature. After 40 min, the reaction mixture was diluted with DCM and the resulting organic solution was washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc to 1:2 hexanes/EtOAc) to afford 244 mg (66%) of 56 as an off-white-colored foam. 1H NMR (300 MHz, CDCl3), mixture of amide rotamers: δ8.27 (s, 0.7H), 8.20 (s, 0.3H), 8.02 (dd, J=5.1, 8.4 Hz, 0.7H), 7.35-7.27 (m, 5H), 6.96-6.89 (m, 2H), 6.53 (s, 0.3H), 6.14 (s, 0.7H), 5.34 (d, J=9.3 Hz, 0.7H), 4.77 (d, J=5.1 Hz, 0.3H), 4.51-4.38 (m, 2H), 4.34-4.28 (m, 1H), 4.12 (app q, J=6.9 Hz, 1H), 4.04-3.89 (m, 2H), 3.77 (s, 1H), 3.51-3.42 (m, 0.7H), 3.30-3.20 (m, 0.3H), 2.60-2.53 (m, 1H), 1.76-1.63 (m, 6H), 1.44 (s, 9H), 1.19-1.05 (m, 5H) ppm. Mass spectrum, m/z [603.4] (M+H)+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].[CH3:8][N:9]([CH3:22])[CH:10]=[N:11][C:12]1[S:13][C:14]([CH:20]=O)=[C:15](Cl)[C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[CH3:22][N:9]([CH3:8])[CH:10]=[N:11][C:12]1[S:13][C:14]2[CH:20]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[S:3][C:15]=2[C:16]=1[C:17]#[N:18]
Reactant: CN(C)C=Nc1sc(C=O)c(Cl)c1C#N
Reactant: CCOC(=O)CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2sc(N=CN(C)C)c(C#N)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
120 parts of ethyl thioglycolate were added to a mixture of 241.5 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-5-formylthien-2-yl)formamidine, 138 parts of potassium carbonate and 1,400 parts of N,N-dimethylformamide. After the slightly exothermic reaction had died down, the reaction mixture was stirred at 50° C. for 2 hours. 1,000 parts of ice, 1,000 parts of water and 150 parts of concentrated hydrochloric acid were then added. The precipitate was filtered off with suction, washed with water and dried. This gave 284 parts (93% of theory) of N,N-dimethyl-N'-(3-cyano-5-ethoxycarbonylthieno[3,2-b]thien-2-yl)formamidine.
Reaction SMILES: [CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[CH:13]=1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:28]=[C:29]([CH3:30])[C:22]=12.ClCCl>BrC1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[N:27]([CH2:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[N:28]=[C:29]([CH3:30])[C:22]=23)=[C:14]([F:19])[CH:13]=1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Reactant: CC(=O)N(Cc1ccccc1)c1ccc(O)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Brc1ccccc1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N(Cc5ccccc5)C(C)=O)cc4F)ccnc32)cc1
Temperature: 150 °C
Yield: 74.4 %

Procedure:
To a stirred solution of N-benzyl-N-(3-fluoro-4-hydroxyphenyl)acetamide (34 mg, 0.13 mmol) and 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (29 mg, 0.1 mmol) (prepared in Example 43, step E) in 400 μL bromobenzene in a capped reaction vial was added DMAP (25 mg, 0.20 mmol). The solution was heated to 150° C. overnight. The reaction was cooled to ambient temperature and loaded onto a Biotage 12S column with dichloromethane and eluted with ethyl acetate to provide the desired product as a tan solid (38 mg, 74% yield).
Reaction SMILES: [CH3:1][C:2]([NH:37]C(=O)OC(C)(C)C)([CH3:36])[C:3]([NH:5][C@H:6]([CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]([N:9]1[CH2:26][CH2:25][CH2:24][C@:11]2([C:15](=[O:16])[N:14]([CH3:17])[CH2:13][C@H:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)=[O:8])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:2]([CH3:36])([CH3:1])[C:3]([NH:5][C@H:6]([CH2:27][CH2:28][O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:7]([N:9]1[CH2:26][CH2:25][CH2:24][C@:11]2([C:15](=[O:16])[N:14]([CH3:17])[CH2:13][C@H:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10]1)=[O:8])=[O:4]
Reactant: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@@H](CCOc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@@H](CCOc3ccccc3)NC(=O)C(C)(C)N)C2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl 2-methyl-1-((R)-1-((4S,5R)-2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxo-4-phenoxybutan-2-ylamino)-1-oxopropan-2-ylcarbamate (38.7 mg; 0.064 mmol) was solubilised in DCM (0.5 ml). TFA (0.125 ml; 1.622 mmol) was added and the solution stirred at RT for 20 minutes before being concentrated in vacuo. The residual oil was dissolved in methanol (1 ml) and passed through a 1 g SCX-2 cartridge eluting with 2M NH3 in methanol (4 ml. Evaporation gave the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11](=[O:14])(O)[O-:12].[Na+]>C(OCC)(=O)C.O>[C:4]([O:12][C:11](=[O:14])[NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[Br:2])([CH3:7])([CH3:5])[CH3:3]
Reactant: NCc1ccccc1Br
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 2-bromobenzylamine hydrochloride (5.00 g) and di-tert-butoxycarbonyl (5.39 g) in ethyl acetate (30 ml) was added saturated sodium bicarbonate solution (30 ml), and stirred at room temperature for 16 hours. The obtained reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as a colorless liquid (6.48 g, 95%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]P(=O)(OCC)OCC.[Li]CCCC.[CH:25]([C:27]1[N:28]=[C:29]2[C:34]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:33][CH:32]=[N:31][N:30]2[C:41]=1[C:42]1[CH:54]=[CH:53][C:45]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:44][CH:43]=1)=O.[NH4+].[Cl-]>C1COCC1.O>[O:38]1[CH2:37][CH2:36][N:35]([C:34]2[C:29]3[N:30]([C:41]([C:42]4[CH:54]=[CH:53][C:45]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])=[CH:44][CH:43]=4)=[C:27](/[CH:25]=[CH:11]/[C:2]4[CH:3]=[CH:4][C:5]5[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=5[N:1]=4)[N:28]=3)[N:31]=[CH:32][CH:33]=2)[CH2:40][CH2:39]1
Reactant: CCOP(=O)(Cc1ccc2ccccc2n1)OCC
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of compound 58a (125 mg, 0.441 mmol) in 2.5 mL of THF at RT was added n-BuLi (275 μL, 0.441 mmol, 1.6M in hexane) dropwise. After stirring at rt for 15 min, the mixture was added slowly to a suspension of compound 5f (150 mg, 0.367 mmol) in 2.5 mL of THF. The resulting mixture was stirred at rt for 30 min, then 2 mL of saturated NH4Cl was added. The mixture was diluted with 10 mL of water, then extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (15 mL) and dried with Na2SO4, filtered and concentrated. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (0:1-1:4 EtOAc/DCM) to afford compound 60a as a pale yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 8.16 (d, J=8.1 Hz, 2H), 7.98 (d, J=5.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 2H), 7.73 (d, J=15.7 Hz, 1H), 7.50-7.58 (m, 1H), 7.29-7.35 (m, 1H), 7.21-7.26 (m, 1H), 6.11 (d, J=5.6 Hz, 1H), 4.02-4.09 (m, 4H), 3.93-4.02 (m, 4H), 2.93 (t, J=6.3 Hz, 2H), 2.77 (t, J=6.1 Hz, 2H), 1.86-1.95 (m, 2H), 1.77-1.86 (m, 2H), 1.63 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C32H35N5O3, 538.1 (M+H). found 538.0.
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]3[O:39][CH2:38]3)[C:32]([O:34]C)=[O:33])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]([OH:39])[CH2:38][S:1][C:2]3[NH:11][C:10](=[O:12])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)[C:32]([OH:34])=[O:33])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: O=c1[nH]c(S)nc2ccccc12
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc4ccccc4c(=O)[nH]3)C(=O)O)cc2)cc1

Procedure:
Example 24 is prepared from 2-mercapto-4(3H)-quinazolinone and 1d using the procedure described for compound 20.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:35])[C:12]2[C:13](=[O:34])[C:14]3[C:19]([O:20][C:21]=2[C:22]=1[CH2:23][CH:24]=[CH2:25])=[C:18]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:17]=[CH:16][CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:38]I.CO>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:35][CH3:38])[C:12]2[C:13](=[O:34])[C:14]3[C:19]([O:20][C:21]=2[C:22]=1[CH2:23][CH:24]=[CH2:25])=[C:18]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:17]=[CH:16][CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCc1c(OCc2ccccc2)cc(O)c2c(=O)c3cccc(OCc4ccccc4)c3oc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C=CCc1c(OCc2ccccc2)cc(OC)c2c(=O)c3cccc(OCc4ccccc4)c3oc12
Temperature: 50 °C
Yield: 85.2 %

Procedure:
To a solution of xanthone 6 (63 g, 135 mmol) in dry DMF (300 mL) was added sodium hydride (9 g 60% in oil, 225 mmol) portionwise at room temperature. Methyl Iodide (180 g, 1.28 mol) was added and the mixture was heated to 50° C. for 90 minutes. The reaction was then chilled with an ice bath and methanol was added dropwise (20 mL) until the remaining sodium hydride was consumed. The reaction mixture was diluted with ethyl acetate (1.2L) and washed with brine (3×500 mL), dried over magnesium sulfate, filtered over a pad of silica gel (60×100 mm) and the solvent was removed in vacuo to afford the xanthone 7 as a solid (55 g, 115 mmol, 85%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Br[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)[C:11](O)=[O:12].[OH-].[Na+]>>[Br:20][C:16]1[CH:15]=[C:14]([CH:10]2[NH:8][C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:7][C:11]2=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)C(Br)c1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2ccccc2NC1c1cccc(Br)c1
Temperature: 60 °C

Procedure:
Ortho-phenylenediamine is treated with a suitably substituted bromoacetic acid derivative, such as 2-bromo-2-(3-bromophenyl)acetic acid, in basic medium, such as aqueous sodium hydroxide, which upon warming to 60° C. and then maintaining at this temperature for 30 minutes, affords the product 3-(3-bromophenyl)-1,2,3,4-tetrahydro-2-quinoxalinone as a precipitate.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[OH:22][N:23]=[C:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.FC(F)(F)C([O-])=O.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]2[CH2:28][CH2:29][C:24](=[N:23][OH:22])[CH2:25][CH2:26]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: ON=C1CCNCC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(N2CCC(=NO)CC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 38.2 %

Procedure:
298 mg (1 mmol) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in 5 ml of dimethyl sulfoxide, and 570 mg (2.5 mmol) of 4-hydroxyiminopiperidine-trifluoroacetate and 404 mg (4 mmol) of triethylamine were added thereto. The mixture was stirred at 80° C. for 6 hours. After cooling, the precipitate thereby formed was collected by filtration and washed with water, isopropanol and diethyl ether to give 150 mg of the desired product as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=[C:6]([Cl:14])[C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:5][CH2:4][C:3]1[C:6]([Cl:14])=[CH:7][CH:8]=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:2]=1[Cl:1])(=[O:25])=[O:24]
Reactant: CC(C)Oc1ccc(Cl)c(CO)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Temperature: 5 °C
Yield: 94.2 %

Procedure:
To a mixture of 2,6-dichloro-3-isopropoxybenzyl alcohol (1.65 g) and triethylamine (808 mg) in dichloromethane was added methanesulfonyl chloride (884 mg) in a few minutes at 5° C. After stirring for half an hour at 5° C., the mixture was washed with diluted hydrochloric acid and then with aqueous sodium bicarbonate solution, dried, and concentrated in vacuo. The residue was crystallized from n-hexane to give 2,6-dichloro-3-isopropoxybenzyl methanesulfonate (2.07 g).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[CH2:21]([SH:24])[CH2:22][SH:23]>>[SH:23][CH2:22][CH2:21][S:24][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: SCCS
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Product: CC1(c2ccccc2)OC(CC(SCCS)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 1,2-ethanedithiol to provide 5-[2-[(2-mercaptoethyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (CDCl3) δ1.63 (m, 1H) and overlapping 1.65 and 1.68 (singlets, 3H), 2.47-2.80 (m, 4H), 3.07-3.25 (m, 2H), 4.47 (m, 1H), 5.37 and 5.39 (singlets, 1H), 7.05-7.18 (m, 2H), 7.25-7.45 (m, 6H); MS (HR-EI) m/z 376.0605 (M+ calcd. for C19H20O2S3 376.0626).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].O>C(Cl)Cl>[NH2:13][CH2:12][CH2:11][NH:14][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: NCCN
Solvent: ClCCl
Solvent: O
Product: NCCNS(=O)(=O)c1ccc(Br)s1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A mixture of 5-bromothiophene-2-sulfonyl chloride (2.5 g, 9.6 mmol, 1.0 eq) in CH2Cl2 (100 mL) was stirred at 0° C., ethane-1, 2-diamine (2.3 g, 38.24 mmol, 4 eq) was added drop-wise. Then, the mixture was stirred at 0° C. for 0.5 h. Water was added and extracted with EA (6×80 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated to give N-(2-aminoethyl)-5-bromothiophene-2-sulfonamide (2.51 g, 92.0%). LC-MS (m/z)=284.1 [M+H]+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1.Br[CH2:33][CH2:34][OH:35].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[OH:35][CH2:34][CH2:33][N:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@@H]3CCNC3)ccc21
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@@H]3CCN(CCO)C3)ccc21
Temperature: 50 °C

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [(R)-1-(2-hydroxy-ethyl)-pyrrolidin-3-yl]amide (25 mg) was prepared starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (R)-pyrrolidin-3-ylamide dihydrochloride (200 mg), 2-bromo-ethanol (50 uL) and Cs2CO3 (300 mg) in DMF (1 mL). The reaction was heated to 50° C. for 8 h. The reaction was filtered and purified with silica gel chromatography using DCM:10% methanol in DCM (100:0 to 0:100) as an eluent system to give pure product. LC/MS: m/z 470.6.