Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][N:6]([C:8](=[O:23])[CH2:9][CH2:10][C:11]1[S:12][C:13]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:14]=2[N:15]=1)[CH3:7])C.[OH-].[Na+]>CO.O>[F:22][C:16]1[C:14]2[N:15]=[C:11]([CH2:10][CH2:9][C:8]([N:6]([CH3:7])[CH2:5][C:4]([OH:24])=[O:3])=[O:23])[S:12][C:13]=2[C:19]([F:20])=[CH:18][C:17]=1[F:21]
Reactant: CCOC(=O)CN(C)C(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CC(=O)O)C(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-methylglycine ethyl ester (290 mg, 0.8 mmol) in methanol (2 ml) was added 2N sodium hydroxide (0.5 ml, 1 mmol) and the mixture was stirred for 30 min. at room temperature. The reaction mixture was diluted with water and then washed with ether. The aqueous layer was acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, then dried and evaporated to yield a residue, which was recrystallized from ethanol-isopropyl ether to give N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-methylglycine (185 mg, 70%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[CH:22]=3)[C:17]([OH:19])=O)=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[S:55][CH:56]=[C:57]([CH3:59])[N:58]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[CH:22]=3)[C:17]([NH:53][C:54]3[S:55][CH:56]=[C:57]([CH3:59])[N:58]=3)=[O:19])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@H]2CCOC2)c1
Reactant: Cc1csc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@H]3CCOC3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
3-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (200 mg, 0.52 mmol), HATU (475 mg, 1.25 mmol) and 2-amino-4-methylthiazole (119 mg, 1.04 mmol) were suspended in DMF (2 mL). DIPEA (0.220 mL, 1.26 mmol) was then added and the reaction mixture stirred at RT for 16 hours. The DMF was removed in vacuo and water (15 mL) added. The mixture was extracted with ethyl acetate (3×20 mL) and the extracts combined, washed with water (15 mL), 1N hydrochloric acid (10 mL), water (10 mL), a saturated aqueous solution of sodium bicarbonate (10 mL), brine (10 mL), dried (MgSO4), filtered, and evaporated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 60-100% ethyl acetate in isohexane, to give the desired compound (70 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5]1.C1OCCOCCOCCOCCOCCOC1.[C-:47]#[N:48].[K+]>CS(C)=O.O>[CH3:1][O:2][CH2:3][C@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:7][C@@H:6]([C:47]#[N:48])[CH2:5]1
Reactant: COC[C@H]1C[C@H](S(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC[C@@H]1C[C@H](C#N)CN1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
5 (13.76 g, 0.034 mol) was dissolved in DMSO (17 mL). 18-Crown-6 (5 eq) and finely ground KCN (5 eq) were added and the reaction mixture was stirred for 6 h at 80° C. The reaction solution was diluted with H2O (17 mL) and then extracted with ethyl acetate. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with hexanes/ethyl acetate (4/1, v/v) to afford 13.76 g (69% yield) of the desired product 6 as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:15][C:16]1[C:21]([C:22](O)=[O:23])=[CH:20][N:19]=[CH:18][CH:17]=1>>[CH3:15][C:16]1[C:21]([C:22]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]3[CH3:11])=[CH:4][CH:3]=2)=[O:23])=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: Cc1ccncc1C(=O)O
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Product: Cc1ccncc1C(=O)Nc1ccc2c(c1)N(C)C(=O)C2(C)C

Procedure:
Prepared in analogy to example 1b from 6-amino-1,3,3-trimethylindolin-2-one and 4-methylnicotinic acid. The title compound was obtained as red oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:25]([O:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30])[CH3:26].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:16]2[N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:30][C:29]5[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=5[O:27][CH2:25][CH3:26])[S:3][C:4]=4[CH:10]=3)[CH:13]=[N:14][C:15]=2[CH:20]=1
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Reactant: CCOc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOc1ccccc1Nc1nc2ccc(Cn3cnc4cc(OC)c(OC)cc43)cc2s1
Temperature: 110 °C
Yield: 22 %

Procedure:
To a suspension of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (60 mg, 0.15 mmol) from Example 2 and 2-ethoxyaniline (61 mg, 0.46 mmol) in anhydrous DMA (600 μL) at rt was added DIEA (155 μL, 0.90 mmol). The mixture was heated in a sealed tube at 110° C. for 72 h. After cooling to rt, the resulting reaction solution was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(2-ethoxyphenyl)benzo[d]thiazol-2-amine (15.2 mg, 22%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.31-8.44 (m, 1H), 8.18 (s, 1H), 7.76 (d, J=1.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.29 (dd, J=1.5, 8.3 Hz, 1H), 7.19 (d, J=2.4 Hz, 2H), 6.91-7.07 (m, 3H), 5.47 (s, 2H), 4.12 (q, J=6.8 Hz, 2H), 3.76 (s, 6H), 1.37 (t, J=7.0 Hz, 3H). LCMS (ESI) m/z 461 (M+H)+.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][OH:12])[CH3:7].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([O:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:13][CH3:14])[CH2:6][CH3:7])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]
Reactant: CCN(CC)CCCO
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
MsCl (6.0 mmol) was added dropwise at 0° C. to a stirred solution of 3-diethylamino-1-propanol (6.0 mmol), TEA (6.0 mmol) in anhydrous DCM (6 mL), and the mixture was stirred at the same temperature for 10 min, and at room temperature for additional 1 h. After the removal of the solvent in vacuo, the solid residue was mixed with 4-chloro-3-nitrophenol (5.0 mmol), and K2CO3 (10 mmol) in anhydrous DMF (10 mL), following the general procedure III (Step A). The crude product is purified using silica gel column chromatography 5% MeOH/DCM as eluent to yield 2-chloro-5-(3-diethylamino-1-propoxy)nitrobenzene (1.3 g).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10]CC)=[O:9].[OH-].[Na+]>C(O)C>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1ccccc1-c1nn[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccccc1-c1nn[nH]n1
Yield: 0.1 %

Procedure:
Methyl 2-cyanobenzoate (0.124 moles, 20.0 g) was dissolved in 55 g tributyltinazide and heated at 85° C. for 72 hours. The solution was allowed to cool. Methanol (200 mi) and water (50 mi) were added. The solution was stirred for 1hour. Ethyl acetate and brine were added. The organic layer was dried and evaporated. The residue was triturated 3 times with large volumes of hexane, dissolved in chloroform, and precipitated with hexane. The precipitate was filtered to yield 10.0 g of ethyl 2-(2H-tetrazol-5-yl)benzoate. The ester (6.8 moles, 1.4 g) was dissolved in 5 ml ethanol and 10 ml of 2N NaOH added and heated on a steam bath for 1 hour. The solvent was removed under vacuum. The residue was dissolved in water. The pH was adjusted to 2.0 using 2N HCl. The intermediate was extracted with ethyl acetate to yield 0.8 g of 2-(2-H-tetrazol-5-yl)benzoic acid.
Reaction SMILES: OS(O)(=O)=O.C(=O)=O.[C:9]([C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15])([CH3:12])([CH3:11])[CH3:10].[N+:20]([O-])([O-:22])=[O:21].[K+]>>[C:9]([C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH2:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccccc1N
Reactant: O=[N+]([O-])[O-]
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Concentrated H2SO4 (1 L) was cooled to −10° C. with a dry ice IpOH bath in a 2 L 3-neck round bottom flask fitted with a mechanical stirrer and temperature probe. 2-t-Butylaniline (109 g, 730 mmol) was added, giving a clumpy solid. Once the temperature of the mixture was stabilized at −10° C., KNO3 (101 g, 1001 mmol) was added portion-wise, as the solid, over 4 h, maintaining the temperature between −20 and −5° C. Once all of the KNO3 was added, the reaction was stirred overnight with gradual warming to RT. The reaction was quenched by diluting it with H2O and extracting it 3× with EtOAc. The EtOAc extracts were washed multiple times with saturated NaHCO3(aq), until gas evolution ceased, then with brine. The EtOAc extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure giving a black oil. The oil was eluted through a 36×7 cm column of silica gel with a 5%; 10%; 15%; 25%; and 50% EtOAc:Hexanes step gradient (2 L each step) giving 2-tert-butyl-5-nitro-phenylamine as a red solid.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.O.[NH2:11][NH2:12]>>[NH:11]([C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[NH2:12]
Reactant: NN
Reactant: Cc1cnc(C)c(Cl)n1
Solvent: O
Product: Cc1cnc(C)c(NN)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 3-chloro-2,5-dimethylpyrazine (26.0 g, 0.182 mol) placed in a round bottom flask was added hydrazine hydrate (75 mL). The reaction mixture was refluxed for 3 h, cooled to ambient temperature, and then kept in a refrigerator for 24 h. The precipitate was collected and washed with hexanes and diethyl ether to afford the title compound as dark colored solid. The compound was used in the next step without further purification. LC/MS 138.9 (M+1); 1H-NMR (500 MHz, CDCl3): δ 2.33 (s, 3H), 2.41 (s, 3H), 4.10 (br S, 2H), 5.75 (br s, 1H), 7.70 (s, 1H).
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][C@H:22]([NH2:27])[C:23]([O:25][CH3:26])=[O:24])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].FC(F)(F)C(O)=O>C(#N)C>[I:1][C:16]1[CH:17]=[C:18]([O:19][CH3:20])[C:13]([O:12][CH3:11])=[CH:14][C:15]=1[CH2:21][C@H:22]([NH2:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Reactant: NC(=O)CCC(=O)NI
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1cc(OC)c(OC)cc1I
Yield: 84.3 %

Procedure:
To a solution of N-iodosuccinamide (8.3 g, 37 mmol) in 80 mL of dry acetonitrile were added (S)-3-(3,4-dimethoxyphenyl)1-methoxy-1-oxopropan-2-amine hydrochloride (4.63 g, 16.8 mmol) and trifluoroacetic acid (2.7 mL, 37 mmol) with stirring. The reaction mixture was stirred at room temperature in a 250 mL round bottom flask protected from light for 2 and half hours. The acetonitrile was removed and the remaining solid was taken up into water. The water solution was treated with saturated sodium bisulfite aqueous solution until the purple color disappeared. The pH was adjusted to 8 using saturated sodium bicarbonate solution. The neutralized aqueous solution was extracted with dichloromethane (3×50 mL) The organic layers were combined and dried over sodium sulfate. The solvent was evaporated to yield (S)-3-(2-Iodo-4,5-dimethoxyphenyl)-1-methoxy-1-oxopropan-2-amine (5.17 g, 98%) as a pale yellow oil. The crude product was dried over dynamic vacuum overnight and was sufficiently pure for subsequent steps.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[SH:10].Cl.Cl[CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=1.[OH-].[Na+]>O>[CH3:22][O:21][C:18]1[C:17]([CH3:23])=[CH:16][N:15]=[C:14]([CH2:13][S:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:19]=1[CH3:20]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COc1c(C)cnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cnc(CSc2nc3ccccc3[nH]2)c1C

Procedure:
64.8 g of 2-benzimidazolethiol are suspended in 400 ml of alcohol and treated with 95.9 g of 2-chloromethyl-4-methoxy-3.5-dimethylpyridine hyrochloride while cooling with ice. Thereafter, a solution of 34.5 g of sodium hydroxide in 1.5 l of water is added dropwise thereto, the mixture is left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue is dissolved in 2.0 l of methylene chloride. The solution is washed firstly with 600 ml of 1.5N sodium hydroxide solution and then 3× with 2.2 l of water, dried over sodium sulphate and evaporated in vacuo. The crude product is purified on 1300 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gives 2-[[(4-methoxy-3,5 -dimethyl-2-pyridyl)methyl]thio]benzimidazole of melting point 129°-131°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:25])=[C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:12](O)=[O:13])[CH:9]=1)(=[O:3])[NH2:2].Cl.[CH:27]([S:30]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:44])[N:41]([CH3:43])[CH3:42])=[CH:35][C:34]=1[C@H:45]1[CH2:49][CH2:48][CH2:47][NH:46]1)(=[O:32])=[O:31])([CH3:29])[CH3:28]>>[CH3:43][N:41]([CH3:42])[C:40](=[O:44])[NH:39][C:36]1[CH:37]=[CH:38][C:33]([S:30]([CH:27]([CH3:28])[CH3:29])(=[O:32])=[O:31])=[C:34]([C@H:45]2[CH2:49][CH2:48][CH2:47][N:46]2[C:12](=[O:13])[C@H:11]([NH:10][C:8]2[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=2[F:25])[C:1]([NH2:2])=[O:3])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[CH:35]=1
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)N(C)C)cc1[C@H]1CCCN1
Reactant: CCOc1cc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)ccc1F
Agent: Cl
Product: CCOc1cc([C@@H](Nc2cc(C(N)=O)ccc2F)C(=O)N2CCC[C@@H]2c2cc(NC(=O)N(C)C)ccc2S(=O)(=O)C(C)C)ccc1F

Procedure:
Example 33 was prepared according to the general coupling condition using 29A and 31A. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.19 (d, J=6.59 Hz, 3 H) 1.31 (t, J=7.03 Hz, 3H) 1.44 (d, J=6.59 Hz, 3H) 1.68-1.81 (m, 1H) 1.99-2.09 (m, 1H) 2.08-2.19 (m, 1H) 2.40-2.57 (m, 1H) 3.00 (s, 6H) 3.69-3.78 (m, 1H) 3.79-3.89 (m, 1H) 3.90-4.02 (m, 2H) 4.11-4.20 (m, 1H) 5.44 (s, 1H) 5.65 (dd, J=8.35, 5.27 Hz, 1H) 6.80 (d, J=2.20 Hz, 1H) 6.96-7.05 (m, 4H) 7.10-7.19 (m, 1 H) 7.30 (d, J=8.79 Hz, 2H) 7.71 (d, J=8.35 Hz, 1H), LCMS: 672 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([NH:28][C:29]2[N:38]=[CH:37][C:36]3[N:35]([CH3:39])[C:34](=[O:40])[CH2:33][N:32]([CH:41]([CH3:43])[CH3:42])[C:31]=3[N:30]=2)[CH:21]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14](=[O:16])[NH:17][C:18]2[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[C:20]([NH:28][C:29]3[N:38]=[CH:37][C:36]4[N:35]([CH3:39])[C:34](=[O:40])[CH2:33][N:32]([CH:41]([CH3:43])[CH3:42])[C:31]=4[N:30]=3)[CH:19]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)C4CN(C(=O)OC(C)(C)C)CCO4)cc(S(C)(=O)=O)c3)nc21
Yield: 57 %

Procedure:
Starting from morpholine-2,4-dicarboxylic acid 4-tert-butyl ester (70 mg; 0.307 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (80 md; 0.205 mmol), 70 mg (0.116 mmol; 57% yield) of the desired compound were obtained.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([NH:16][CH3:17])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[ClH:18]>O>[ClH:18].[NH:5]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([NH:16][CH3:17])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[NH2:1]
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CNS(=O)(=O)Cc1ccc(NN)cc1
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (13.72 g) in water (160 ml) was added slowly to a cooled stirred mixture of 4-Amino-N-methylbenzene methanesulphonamide (39.3 g), water (240 ml) and conc. hydrochloric acid (400 ml) such that the temperature did not exceed 0°. After stirring for 15 min this mixture was added slowly to a cold solution of stannous chloride dihydrate (221.1 g) in conc. hydrochloric acid (400 ml) again keeping the temperature below 0°. Once the addition was complete the mixture was allowed to warm to room temperature (1 h). The solid was collected by filtration, washed well with diethyl ether (4×250 ml) and dried at 45° to give the title compound as a white powder (31.6 g). An assay by periodate titration showed this to be 91.3% pure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[CH2:10]([S:17](Cl)(=[O:19])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([S:17]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=[O:19])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cn1cccc1CCN
Product: Cn1cccc1CCNS(=O)(=O)Cc1ccccc1

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and benzylsulphonyl chloride analogously to Example A.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10](C3C=CC(Cl)=CC=3)=[C:9]([O:18][CH3:19])[C:8]([CH3:20])=[CH:7][C:5]=2[N:6]=1.[CH3:21][NH:22][CH3:23].C1COCC1>CN(C=O)C>[CH3:19][O:18][C:9]1[C:8]([CH3:20])=[CH:7][C:5]2[N:6]=[C:2]([N:22]([CH3:23])[CH3:21])[S:3][C:4]=2[CH:10]=1
Reactant: COc1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2sc(N(C)C)nc2cc1C
Temperature: 80 °C

Procedure:
To a solution of 2-bromo-7-(4-chlorophenyl)-6-methoxy-5-methylbenzo[d]thiazole (8C) (135 mg, 0.37 mmol) in DMF (2 ml), was added dimethylamine in THF (2M, 0.46 ml, 0.92 mmol). The reaction mixture was stirred at 80° C. After the reaction finished, the reaction was cooled and concentrated. The residue was purified by silica gel column, eluting by 0-100% EtOAc in hexanes. LCMS-ESI+: calc'd for C17H17ClN2OS: 333.1 (M+H+). Found: 333.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: CN1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCN(C)CC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (2 g, 8.23 mmol) and 1-methylpiperidin-4-one (1.86 g, 16.46 mmol) in methanol (20 mL), acetic acid (0.5 g, 8.23 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.622 g, 9.87 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the desired compound (0.9 g, 33%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[C:6]1([S:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Reactant: ClCC1CO1
Product: O=S(=O)(c1ccccc1)N1CCN(CC(O)CCl)CC1
Yield: 98.7 %

Procedure:
Epichlorohydrin (0.5 g) and 3.7 g of 1-benzenesulfonylpiperazine were reacted and worked up in the same way as in Referential Example 1 to give 1.7 g of 1-benzenesulfonyl-4-(3-chloro-2-hydroxypropyl)piperazine as a colorless powdery crystal having a melting point of 136 to 137° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=[O:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH2:19][Br:21])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c(CBr)c(C#N)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile (1.00 g, 3.48 mmol), N-bromosuccinimide (0.650 g, 3.65 mmol), and benzoyl peroxide (0.0421 g, 0.174 mmol) in carbon tetrachloride (10 mL) was heated at reflux overnight. After cooling to room temperature, the mixture was diluted with dichloromethane and washed with water. The organic layers were dried over magnesium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to give the desired product (0.57 g, 45%). LCMS calculated for C16H11BrClFNO (M+H)+: m/z=366.0; Found: 366.0.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8]1)=[O:6])[CH3:3].[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23].[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:23])[CH:16]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: CC(C)NC(=O)C1OC1c1ccccc1
Reactant: Cc1cccc(O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cccc(OC(c2ccccc2)C(O)C(=O)NC(C)C)c1

Procedure:
This compound was prepared as in Example 12 from N-(1-methylethyl)-3-phenyl-2-oxiranecarboxamide (6.16 g.), m-cresol (3.3 g.), sodium hydride (50% oil dispersion, 1.5 g.), 18-crown-6 (0.9 g.), and acetonitrile (250 ml.). The product which was recrystallized from ether melted at 158°-159°, and weighed 3.2 g.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br:20]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:20])[N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrBr
Reactant: COc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
6-Amino-9-benzyl-2-methoxypurine (118 mg, 0.46 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (90 mg, yield 58%).