Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[CH:33]([CH3:37])[C:34](=O)[CH3:35]>C(#N)C>[CH3:37][C:33]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:14]4=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]4[CH:12]=3)=[O:10])[CH:5]=[CH:4][N:3]2[C:34]=1[CH3:35]
Reactant: CC(=O)C(C)Br
Reactant: Nc1cc(NC(=O)c2cc3cc(C(F)(F)F)cnc3n2Cc2cccc(F)c2)ccn1
Solvent: CC#N
Product: Cc1nc2cc(NC(=O)c3cc4cc(C(F)(F)F)cnc4n3Cc3cccc(F)c3)ccn2c1C
Yield: 33.4 %

Procedure:
Compound 16 was prepared according to a process similar to that described in step 15.3, by reacting 0.12 g (0.28 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 15.2, with 0.084 g (0.56 mmol) of 3-bromobutan-2-one in 5 mL of acetonitrile. 45 mg of the expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:6].[CH2:19]([O:21][C:22](=[O:33])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[C:26]([CH3:32])[CH:25]=1)[CH3:20]>CO>[CH2:19]([O:21][C:22](=[O:33])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=4)[CH:15]=[CH:16][C:17]=3[N:18]=2)=[C:26]([CH3:32])[CH:25]=1)[CH3:20]
Reactant: CCOC(=O)Nc1ccc(C=O)c(C)c1
Reactant: Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1N
Solvent: CO
Product: CCOC(=O)Nc1ccc(-c2nc3ccc(C(=O)Nc4cccc(Cl)c4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-diamino-N-(3-chloro-phenyl)-benzamide (0.4 mL in 0.2 M DMSO solution), (4-formyl-3-methyl-phenyl)-carbamic acid ethyl ester (0.4 mL in 0.2 M toluene solution) and FeCl3 (0.2 mL in 0.02M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give {4-[6-(3-Chloro-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-3-methyl-phenyl}-carbamic acid ethyl ester: MS (m/z) 449 (M+1).
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]2[N:21]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)=[O:26])[CH2:22][CH2:23][N:24]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:69]([SH:72])(=[O:71])[CH3:70]>O1CCCC1.C(OCC)(=O)C>[C:69]([S:72][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]2[N:21]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=3)=[O:26])[CH2:22][CH2:23][N:24]=2)[CH2:3]1)(=[O:71])[CH3:70]
Reactant: CC(=O)S
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN=C1[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1C[C@@H](C2=NCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
(2S, 4R) -4-Hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl)-2-imidazolin-2-yl]-pyrrolidine (655 mg) and triphenylphosphine (0.51 g) were dissolved in tetrahydrofuran (20 ml) at 0° C. To this solution was added dropwise a solution of diethyl azodicarboxylate (0.30 ml) in tetrahydrofuran (5 ml) with stirring for 30 minutes, followed by addition of a solution of thioacetic S-acid (0.14 ml). Stirring was continued at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The obtained oily residue was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and acetone (20:1, V/V) to give (2S, 4S )-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl)-2-imidazolin-2 -yl]-pyrrolidine (1.2 g).
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[CH3:7].[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:7]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCOCn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccn1COCC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
1.6 M n-BuLi (12.0 mL, 19.2 mmol) is slowly added to a solution of 1-ethoxymethyl-1H-imidazole [available via the procedure outlined in Tang, C. C.; Davalian, D.; Huang, P.; Breslow, R. J. Am. Chem. Soc. 1978, 100, 3918] (2.20 g, 17.4 mmol) in THF (30 mL) at −78° C. under N2. The reaction mixture is stirred at −78° C. for 20 minutes whereupon tributyl tin chloride (5.7 mL, 20.9 mmol) is added slowly. The reaction mixture is stirred at −78° C. for 10 minutes and then warmed to room temperature. After stirring at room temperature for 1.5 hours, the reaction mixture is concentrated in vacuo. The residue is triturated with hexanes and filtered, and the filtrate is concentrated in vacuo. The residue is again triturated with hexanes and filtered, and the filtrate concentrated in vacuo. The 1H NMR of the resulting oil indicates a 2:1 mixture of 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole: 1-ethoxymethyl-1H-imidazole. This material is used in the next reaction (Example 5) without further purification. Selected 1H NMR resonances (400 MHz, CDCl3) δ 7.21 (s, 1H), 7.14 (s, 1H), 5.24 (s, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:50][C:51]1[C:66]([F:67])=[CH:65][C:54]2[NH:55][C:56]([CH2:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][NH:60]3)=[N:57][C:53]=2[CH:52]=1>CN(C=O)C>[F:50][C:51]1[C:66]([F:67])=[CH:65][C:54]2[NH:55][C:56]([CH2:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][N:60]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:16])=[N:57][C:53]=2[CH:52]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: Fc1cc2nc(CC3CCCCN3)[nH]c2cc1F
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: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)c(-c2ccc(F)cc2)s1
Reaction time: 16 h
Yield: 97 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (700 mg, 3.0 mmol), HATU (1.12 g, 3.0 mmol) and N,N-diisopropylethylamine (1.54 ml, 9.0 mmol) in DMF (20 ml) was stirred at room temperature under argon for 2 min. The mixture was then treated with (RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D18 (742 mg, 3.0 mmol) and stirring was continued for 16 h. The solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-5% methanol-ethyl acetate) afforded the title compound as a pale yellow solid (1.35 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5](I)=[CH:4][N:3]=1.[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=1)#[CH:15].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=3)[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]=2[CH:7]=1
Reactant: C#Cc1cnn(C(=O)OC(C)(C)C)c1
Reactant: CS(=O)(=O)Nc1cc(Cl)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Cl)cc3n2S(C)(=O)=O)cn1
Temperature: 60 °C
Yield: 49.2 %

Procedure:
Bis(triphenylphosphine)palladium dichloride (15.53 mg, 0.022 mmol) was added to a solution of N-(2-chloro-5-iodopyridin-4-yl)methanesulfonamide (14) (184.0 mg, 0.553 mmol), tert-butyl 4-ethynyl-1H-pyrazole-1-carboxylate (4) (160.0 mg, 0.830 mmol), triethylamine (347 μL, 2.49 mmol) and copper iodide (6.32 mg, 0.033 mmol) in anhydrous DMF (2.0 mL). The reaction mixture was heated at 60° C. for 1 h under microwave irradiation, then partitioned between water (60 mL) and EtOAc (60 mL). The aqueous layer was extracted with more EtOAc (2×60 mL), the combined extracts were washed with brine (2×40 mL), dried (Na2SO4) and concentrated in vacuo. The resulting residue was absorbed on silica gel (2.0 g) and the free-running powder was placed on a 20 g isolute silica column. Elution with dichloromethane and 1% ethanol in dichloromethane afforded the title compound (108 mg, 49%). 1H-NMR (500 MHz, DMSO-d6) 1.61 (s, 9H), 3.48 (s, 3H), 7.12 (d, J=0.6 Hz, 1H), 7.91 (br t, J=0.5 Hz, 1H), 8.07 (d, J=0.5 Hz, 1H), 8.61 (d, J=0.5 Hz, 1H), 8.78 (d, J=0.7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[CH:13]1[CH:18]=[C:17]([CH:19]=[O:20])[CH:16]=[C:15]([CH:21]=O)[CH:14]=1.C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2](/[CH:1]=[CH:21]/[C:15]1[CH:16]=[C:17]([CH:18]=[CH:13][CH:14]=1)[CH:19]=[O:20])[CH:11]=[CH:10]2
Reactant: O=Cc1cccc(C=O)c1
Reactant: Cc1ccc2cc(F)ccc2n1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: O=Cc1cccc(/C=C/c2ccc3cc(F)ccc3n2)c1
Yield: 50.7 %

Procedure:
Using the procedure of Preparation I1, 5.04 g of 2-methyl-6-fluoroquinoline, 4.20 g of isophthaldehyde and 8.86 ml of acetic anhydride in 100 ml of xylene gave 4.40 g of the titled product as a pale yellow solid, m.p. 110°-111° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]=[C:9]=[S:10].[C:11]([NH:14][NH2:15])(=[O:13])[CH3:12]>O1CCOCC1.CCOCC>[C:11]([NH:14][NH:15][C:9](=[S:10])[NH:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[Br:1])(=[O:13])[CH3:12]
Reactant: S=C=Nc1ccncc1Br
Reactant: CC(=O)NN
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)NNC(=S)Nc1ccncc1Br
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 90.6 %

Procedure:
3-bromo-4-isothiocyanato-pyridine (1 g, 4.650 mmol) and acetylhydrazine (344.5 mg, 4.650 mmol) were dissolved in dry 1,4-dioxane (10 mL) and stirred at 80° C. for 0.75 hrs. The orange suspension was allowed to cool to RT. The viscous suspension was diluted with ether and the solid was collected by filtration and washed with ether (3×5 mL) to give 2-acetyl-N-(3-bromopyridin-4-yl)hydrazinecarbothioamide as a salmon-pink solid (1.2187 g, 91% Yield). MS (ES−) 288.9.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: NC1CCOCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc2c(c(NC3CCOCC3)n1)SCC2
Temperature: 130 °C

Procedure:
0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine followed by 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated at 130° C. until there is no further reaction and after cooling evaporated down. The product is treated with water in the ultrasound bath, suction filtered and dried. 0.66 g (III-5) are obtained as a solid.
Reaction SMILES: Cl.[CH:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.Cl.Cl.[N:16]12[CH2:23][C@H:20]([CH2:21][CH2:22]1)[CH2:19][C@@H:18]([NH2:24])[CH2:17]2>>[N:16]12[CH2:23][C@H:20]([CH2:21][CH2:22]1)[CH2:19][C@@H:18]([NH:24][C:8]([C:6]1[N:7]=[CH:2][C:3]3[N:4]([CH:11]=[CH:12][CH:13]=3)[CH:5]=1)=[O:10])[CH2:17]2
Reactant: N[C@@H]1C[C@H]2CCN(C1)C2
Reactant: O=C(O)c1cn2cccc2cn1
Agent: Cl
Product: O=C(N[C@@H]1C[C@H]2CCN(C2)C1)c1cn2cccc2cn1
Yield: 83 %

Procedure:
Example 15 is prepared from pyrrolo[1,2-a]pyrazine-3-carboxylic acid hydrochloride and (3R,5R)-1-azabicyclo[3.2.1]octan-3-amine dihydrochloride using Procedure C to give a mixture purified by silica gel chromatography (9% MeOH/1%NH3OH/CHCl3 as the eluent) salted with fumaric acid, and crystallized from acetone to give a white solid. Yield 83%. HRMS (FAB) calcd for C15H18N4O MH+271.1559, found 271.1550.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2[C:30]([NH:31][C:32](=[S:41])[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=3O)=[CH:29][CH:28]=[CH:27][N:26]=2)=[O:24])=[N:20][CH:21]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:34]2[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:33]=2[C:32]([NH:31][C:30]2[C:25]([C:23]([NH:22][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][N:20]=3)=[O:24])=[N:26][CH:27]=[CH:28][CH:29]=2)=[S:41])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Product: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCC2CCN(C(=O)OC(C)(C)C)C2)c1

Procedure:
Using a procedure analogous to Example 38-D, 1-t-butoxycarbonylpyrrolidin-3-ylmethanol (Isomer II), from the prior example, and N-(5-chloropyridin-2-yl)-3-[2-hydroxy-4-methylthiobenzoylamino]pyridine-2-carboxamide gave the title compound as a white solid (1.0 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+]>O.CCOCC>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NCC(=O)O
Reactant: CCCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCC(=O)NCC(=O)O
Yield: 79.5 %

Procedure:
Glycine (20 mmol) was reacted with nonanoyl chloride (22 ml) in the presence of NaOH (40 mmol) in a mixture of water and ether as described in Example 1 Part A. The crude crystalline product (4.25 g) was recrystallized from ethyl acetate (40-50 ml) to give the title compound (3.42 g, 79.5%), m.p. 106°-109° C.
Reaction SMILES: ClS(O)(=O)=O.[Sb](F)(F)(F)(F)F.Cl[CH2:13][C:14](O)=O.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[C:17]1([S:23]([C:14]2[CH:13]=[CH:19][CH:18]=[CH:17][CH:22]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)CCl
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: F[Sb](F)(F)(F)F
Agent: O=S(=O)(O)Cl
Solvent: c1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into a mixture of 6.6 ml of chlorosulfonic acid, 6 ml of antimony pentafluoride and 10 ml of monochloroacetic acid, was added 8.9 ml of benzene at 25° C., and the mixture was stirred for 3 hours. The reaction mixture was transferred into ice water and the precipitated product was extracted with benzene. From the results of analysis, it was confirmed that benzene-sulfonyl chloride and diphenylsulfone were formed in yields of 50% and 20%, respectively, based on benzene.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[N:27]=[C:28]=[O:29]>O1CCOCC1>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([N:2]([CH3:1])[C:28]([NH:27][C:21]3[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:26])=[O:29])[CH:4]=2)=[CH:15][CH:14]=1)(=[O:18])[CH3:17]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CNc1cc(Nc2ccc(C(C)=O)cc2)ncn1
Solvent: C1COCCO1
Product: CC(=O)c1ccc(Nc2cc(N(C)C(=O)Nc3c(Cl)cccc3Cl)ncn2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 1-[4-(6-methylamino-pyrimidin-4-ylamino)-phenyl]-ethanone (3.77 g, 15.56 mmol), 2,6-dichlorophenyl isocyanate (3.22 g, 17.12 mmol) in dry dioxane (30 mL) is shaken for 16 h at 80° C. After evaporation of the solvent in vacuo, the residue is distributed between ethyl acetate and half-saturated K2CO3 solution. The precipitate is filtered off and washed with H2O and ethyl acetate. The solid residue is suspended in methanol, heated to reflux for several h and the hot yellow suspension filtered. This procedure is repeated once. The residue obtained after the second filtration is washed with CH3OH and dried in vacuo to afford the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C[Al](C)C.[C:22](OCC)(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1(C)C=CC=CC=1>[C:23]1([C:22]2[N:4]([CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:3][CH2:2][N:1]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCN)CC1
Reactant: CCOC(=O)c1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCN=C2c2ccccc2)CC1
Temperature: -10 °C

Procedure:
To tert-butyl 4-[(2-aminoethyl)amino]piperidine-1-carboxylate (6 g) taken in dry toluene (50 ml) cooled to −10° C., trimethylaluminium was added slowly in dry toluene under nitrogen atmosphere. Reaction mixture was allowed to warm to r.t. and a second lot of solution of tert-butyl 4-[(2-aminoethyl)amino]piperidine-1-carboxylate (6 g in 50 ml of toluene) was added very slowly to it. The combined mixture was heated up to 55° C. for 30 minutes. A solution of ethyl benzoate (7.4 g in 50 ml of dry toluene) was added very-very slowly to the reaction mixture at 55° C. over a period of 40 minutes. After the completion of addition, the reaction mixture was refluxed for over night. Reaction mixture was cooled to 0° C. and water (3×50 ml) was added. The combined mixture was filtered through celite pad. The filtrate was concentrated under reduced pressure and the resulting oil was purified by column chromatography to afford tert-butyl 4-(2-phenyl-4,5-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate as a pure product.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][C:16]([NH2:18])=[S:17])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.C(O)C.Br.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=O.C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C=O>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]1[N:18]=[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:7]3[S:6][C:5]4[N:4]=[CH:3][CH:2]=[N:1][C:10]=4[NH:9][C:8]=3[CH:11]=2)[S:17][CH:24]=1
Reactant: NC(=S)Cc1ccc2c(c1)Nc1nccnc1S2
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: c1ccc(-c2csc(Cc3ccc4c(c3)Nc3nccnc3S4)n2)nc1
Temperature: 65 °C
Yield: 56.1 %

Procedure:
To a solution of 550 mg of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)thioacetamide in a solvent mixture of ethanol (10 ml) with N,N-dimethylformamide (10 ml) was added 560 mg of (2-bromoacetyl)pyridine hydrobromide and the resulting mixture was heated to 60 to 70° C. for 2 hours. Then the reaction mixture was brought back to room temperature and distributed into dichloromethane and an aqueous solution of sodium bicarbonate. After extracting the organic layer, the extract was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the crystals thus precipitated were washed successively with ethyl acetate and diethyl ether to thereby give 420 mg of the title compound as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:3]=1[O:14][CH2:15][CH3:16].C([Li])(C)(C)C.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([F:31])=[C:27]([CH:30]=1)[CH:28]=[O:29].[Cl-].[NH4+]>COCCOC>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([F:31])=[C:27]([CH:28]([C:2]2[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:3]=2[O:14][CH2:15][CH3:16])[OH:29])[CH:30]=1
Reactant: CCOc1c(Br)cc(C(C)C)cc1C(C)C
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: COCCOC
Product: CCOc1c(C(C)C)cc(C(C)C)cc1C(O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Bromo-2-ethoxy-3,5-diisopropyl-benzene (2.0 g, 7.01 mmol) was dissolved in ethylene glycol dimethyl ether (20 ml) and the mixture cooled to −78° C. t-Butyl lithium (8.66 ml, 1.7M, 14.7 mmol) dropwise to the mixture over 30 min., then the reaction was stirred for an additional 30 min. before 5-bromo-2-fluorobenzaldehyde (1.57 g, 7.71 mmol) was added in one portion. The reaction was allowed to warm to ambient temperature, then stirred overnight The mixture was poured into saturated ammonium chloride solution (100 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified flash column (5% ethyl acetate in hexanes) to give (5-bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanol, as a pale yellow oil (1.88 g, 66%). 1H NMR (250 MHz, CDCl3): δ 7.73 (dd, 1H, J=1.2, J=7.5), 7.42 (m, 1H), 7.11 (d, 1H, J=1.2), 6.95 (t, 1H, J=7.5), 6.85 (d, 1H, J=1.2), 6.35 (d, 1H, J=6.2), 3.84 (q, 2H, J=6.9), 3.30 (m, 1H), 3.07 (d, 1H, J=6.2), 2.85 (m, 1H), 1.47 (t, 3H, J=6.9), 1.25 (s, 6H), 1.20 (s, 6H). MS [EI+] 431, 433 (M+Na)+.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:8]1=[S:26])C.O.[OH-].[Li+].O.Cl>O1CCOCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:9]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[CH:11][N:7]([CH2:6][CH2:5][C:4]([OH:27])=[O:3])[C:8]2=[S:26])=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCn1cc(-c2ccc(F)cc2)n(-c2ccc(Cl)cc2)c1=S
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCn1cc(-c2ccc(F)cc2)n(-c2ccc(Cl)cc2)c1=S
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(1-(4-chlorophenyl)-5-(4-fluorophenyl)-1,2-dihydro-2-thioxoimidazol-3-yl)propionic acid ethyl ester (1 eq) and lithium hydroxide hydrate (1.2 eq) is dissolved in 1,4-dioxane:water (4/1:v/v) and allowed to stir at room temperature for 3 hours. The reaction mixture is neutralized with aqueous 2N HCl and extracted with ethyl acetate. The organics are dried and concentrated under vacuum to give 3-(1-(4-chlorophenyl)-5-(4-fluorophenyl)-1,2-dihydro-2-thioxoimidazol-3-yl)propionic acid.