Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]([F:49])([F:48])[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][CH2:40][C:39]([F:48])([F:49])[F:38])[CH2:47][CH2:46]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: FC(F)(F)CCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC(F)(F)F)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(3,3,3-trifluoro-propyl)-piperazine (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C36H43Cl2F3N5O2 [(M+H)+] 704.2741, observed 704.274.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)C1CC1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)C4CC4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 62.6 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.00 g, 3.10 mmol) and cyclopropanecarbonyl chloride (0.32 g, 3.10 mmol) in THF (35 mL), was added triethylamine (0.88 mL, 6.20 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 6 h then cooled to rt. The mixture was filtered and the filtrate diluted with EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (100 mL), water (2×75 mL), dried (MgSO4) and concentrated in vacuo to give cyclopropanecarboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.69 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 2.96 min (98.96%); mp: 163-165° C.; 1H NMR (DMSO-d6) δ 0.62-0.78 (m, 4H), 1.63 (m, 1H), 1.95-2.17 (m, 1H), 2.53-2.67 (m, 2H), 2.79-3.00 (m, 1H), 4.46 (d, J=6.0 Hz, 2H), 5.15 (dd, J=5.4, 12.9 Hz, 1H), 7.67-7.79 (m, 2H), 7.89 (d, J=7.6 Hz, 1H), 8.77 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 6.44, 13.57, 21.99, 30.93, 42.05, 48.99, 121.83, 123.54, 129.74, 131.60, 133.35, 147.77, 166.99, 167.13, 169.82, 172.73, 172.94; Anal Calcd for C18H17N3O5+0.2H2O: C, 60.23; H, 4.89; N, 11.71. Found: C, 60.16; H, 4.54; N, 11.70.
Reaction SMILES: [CH:1]1([CH2:7][C:8](Cl)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2([CH:23]([NH2:25])[CH3:24])[CH2:22][CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>CCOCC>[CH:1]1([CH2:7][CH2:8][NH:25][CH:23]([C:19]2([C:14]3[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=3)[CH2:20][CH2:21][CH2:22]2)[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(NCCC1CCCCC1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 3 h

Procedure:
Cyclohexylacetyl chloride (3.21 g) in dry ether (100 ml) was added over 30 minutes to a stirred mixture of 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine (4.88 g), triethylamine (2.5 g) and dry ether (100 ml) at 0°-6° C. After stirring for a further 3 hours the mixture was filtered and the residue was washed with dry ether. The filtrate and washings were combined, dried and evaporated. The residue was dissolved in tetrahydrofuran (50 ml) and the solution heated under reflux in an atmosphere of nitrogen. Borane-methyl sulphide complex (3 ml) was added from a syringe. The resulting mixture was heated under reflux for 12 hours after which it was cooled and ice-water and then 5N hydrochloric acid were added. The organic solvent was removed by evaporation and the residue was cooled, basified with 5N sodium hydroxide solution and extracted with ether. The extracts were washed with water, dried and the ether removed by evaporation. From the residue N-(2-cyclohexylethyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine was obtained by distillation (b.p. 170° C./0.5 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[CH2:4][O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[F:21][C:22]([F:43])([F:42])[C:23]1[CH:41]=[CH:40][C:26]([O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH:33]([CH3:37])[C:34](Cl)=[O:35])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:21][C:22]([F:42])([F:43])[C:23]1[CH:41]=[CH:40][C:26]([O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH:33]([CH3:37])[C:34]([O:8][CH2:7][CH2:6][O:5][CH2:4][C:3]3[C:2]([Cl:1])=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:13])=[O:35])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1
Reactant: OCCOCc1c(Cl)cccc1Cl
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCCOCc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
22.1 g of 2-(2,6-dichlorobenzyloxy)ethanol and 10.1 g of triethylamine were dissolved in 200 ml of toluene, then cooled to 0° C. To this solution was dropwise added a solution of 34.5 g of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride in 50 ml of toluene at 0° to 10° C. After the dropwise addition, the reaction mixture was gradually heated and, at 40° C., it was stirred for one hour to complete the reaction. After cooling the reaction solution to room temperature, it was washed successively with 1% strength by weight sodium hydroxide aqueous solution and water, then dehydrated. After distilling off toluene under reduced pressure, the resulting colorless, viscous, oily product was allowed to stand for about 1 month to obtain 49.2 g of crystalline 2-(2,6-dichlorobenzyloxy)ethyl 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionate. m.p. 51° to 53° C.
Reaction SMILES: [CH2:1]([Si:3]1([CH2:19][CH3:20])[Si:6]([CH2:9][CH3:10])([CH2:7][CH3:8])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:4]1([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:2].[C:21]1([Si:27]([Li])([CH3:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:9]([Si:6]([CH2:7][CH3:8])([Si:3]([CH2:1][CH3:2])([CH2:19][CH3:20])[Si:4]([CH2:15][CH3:16])([CH2:17][CH3:18])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:27]([CH3:29])([CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[Si:27]([CH3:29])([CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:10]
Reactant: [Li][Si](C)(C)c1ccccc1
Reactant: CC[Si]1(CC)[Si](CC)(CC)[Si](CC)(CC)[Si]1(CC)CC
Solvent: C1CCOC1
Product: CC[Si](CC)([Si](C)(C)c1ccccc1)[Si](CC)(CC)[Si](CC)(CC)[Si](CC)(CC)[Si](C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an argon atmosphere, to a tetrahydrofuran solution (1 ml) of 52 mg (0.15 mmol) of octaethylcyclotetrasilane was added 0.58 ml (0.15 mmol) of a tetrahydrofuran solution (0.27M) of phenyldimethylsilyllithium, and stirred at 0° C. for 15 minutes. Then, tetrahydrofuran was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 1). A dichloromethane solution (1 ml) of 49 mg (0.05 mmol) of undecasilane (8) obtained in Example 8 was treated with 7.5 mg (0.05 mmol) of trifluoromethanesulfonic acid at room temperature for 30 minutes to afford 1-(trifluoromethanesulfonyloxy)undecasilane. Then, dichloromethane was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 2). The Solution 1 was added to the Solution 2 at -78° C. and stirred for 15 minutes. Methanol (0.1 ml) and triethylamine (0.1 ml) were added, then saturated aqueous sodium bicarbonate solution (2 ml) was added, stirred, the hexane layer was separated, and dried with magnesium sulfate. The resulting crude product was purified by a silica gel column chromatography (hexane) to give 36 mg (41% yield) of hexadecasilane (9) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:29](O)=[O:30])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:42][CH2:43][CH3:44])[C@H:34]([OH:41])[C:35]([NH:37][CH:38]1[CH2:40][CH2:39]1)=[O:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:29]([NH:32][C@@H:33]([CH2:42][CH2:43][CH3:44])[C:34](=[O:41])[C:35]([NH:37][CH:38]3[CH2:40][CH2:39]3)=[O:36])=[O:30])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Cl)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Cl)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2,4-dichlorophenylsulfonyl)pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide in step 1. MS (m/e)=670.11 [M+H+].
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:16]=[CH:15][N:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[CH3:19][O:20][CH2:21]Cl>O1CCCC1>[CH3:19][O:20][CH2:21][O:1][C:2]1[C:3]2[CH:16]=[CH:15][N:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Oc1c(-c2ccccc2)sc2cnccc12
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c(-c2ccccc2)sc2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
A solution of 1.1 g (4.8 mmol) 3-hydroxy-2-phenyl-6-azabenzo[b]thiophene and 0.116 g (4.8 mmol) of sodium hydride in 15 mL of tetrahydrofuran was stirred at room temperature for 15 minutes. Then 0.37 mL (5.0 mmol) of chloromethyl methyl ether was added and the solution was stirred at room temperature for 2 hours. The solution was partitioned between ether and water and the ether extract was concentrated to afford 1.2 g (92%) of white crystalline material, m.p. 55°-56° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.S(C1C=CC(C)=CC=1)(O[CH2:22][CH:23]1[O:25][CH2:24]1)(=O)=O>CN(C)C=O>[O:25]1[CH2:24][CH:23]1[CH2:22][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: Oc1cccc2ncccc12
Reactant: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1cc(OCC2CO2)c2cccnc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
297 g of cesium carbonate was added to 600 ml of dimethylformamide. Further, 83.5 g of 5-hydroxyquinoline was added. The mixture was stirred at 25°-30° C. for 30 minutes. To the reaction mixture was slowly added 109 g of glycidyl tosylate. The resulting mixture was stirred at 25°-30° C. for 15 hours. The reaction mixture was poured into 3 liters of ice water, followed by stirring and extraction with 2 liters of ethyl acetate. The aqueous layer was subjected to extraction with 2 liters of ethyl acetate. The organic layers were combined and washed twice with 2 liters of water. The ethyl acetate layer was dried over anhydrous Glauber's salt and subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 76.8 g (yield: 66%) of intended 5-(2,3-epoxypropoxy)quinoline as a light yellow powder.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:22][O:23][C:24](=[O:43])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1>>[CH3:22][O:23][C:24](=[O:43])[CH2:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=2[CH2:4][N:5]2[C@@H:9]([CH3:10])[C@@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[C:29]([O:32][CH3:33])=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1ccccc1Br
Product: COC(=O)Cc1ccc(OC)c(-c2ccccc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4S,5R)-3-(2-bromo-benzyl)-4-methyl-5-phenyl-oxazolidin-2-one and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][NH:3]1.[OH-].[Na+].[CH2:11](I)[CH2:12][CH2:13][CH3:14].C(O)(=O)C>O>[CH2:11]([S:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCI
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCCSc1nccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thioxo-2,3-dihydro-1H-pyrimidin-4-one (12.8 g) was added to a solution of NaOH (8.0 g) in water (70 mL). After complete dissolution of the solids butyl iodide (12.4 mL) was added to the solution and the resulting mixture was stirred at RT overnight. A second aliquot of butyl iodide (1.2 mL) was then added and the reaction mixture was stirred for 24 h. A third aliquot of butyl iodide (1.2 mL) was added and the resulting mixture was stirred for 6 days. Glacial acetic acid (5.5 mL) was added and the reaction mixture was stirred for 30 min, it was then stored at 4° C. overnight. The precipitate formed was collected by filtration and dried under reduced pressure to give 12.3 g of 2-butylsulfanyl-3H-pyrimidin-4-one.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([C:15](Cl)=[O:16])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23]2.N1C=CC=CC=1>C(Cl)Cl>[OH:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:19][NH:18][C:15]([C:10]1[CH:9]=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=1[CH2:12][CH2:13][CH3:14])=[O:16])[CH:29]=[CH:28]2
Reactant: NCc1ccc2cc(O)ccc2c1
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1c(C(=O)NCc2ccc3cc(O)ccc3c2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
A solution of 1-phenyl-5-propyl-1H-pyrazole-4-carbonyl chloride (2.0 g, 8 mmol) in 20 mL of methylene chloride was added dropwise under nitrogen to a mixture of 6-aminomethyl-naphthalen-2-ol (1.63 g, 9.42 mmol), prepared in step 1 of Example 8, and 75 mL of anhydrous pyridine. The reaction stirred at room temperature for 17 h (overnight). The reaction was diluted with methylene chloride and extracted with 1N HCl. The aqueous layer was separated and extracted with methylene chloride. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give a brown solid. The solid was recrystallized from ethyl acetate and then again from isopropanol. The crystals were collected by filtration and dried under reduced pressure to give 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (0.767 g, 25%) as a tan solid, mp 189-190° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:16])[C:9]([CH2:12][C:13]([OH:15])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:29]([NH2:32])[CH2:30][CH3:31]>C(Cl)(Cl)Cl>[CH2:29]([NH:32][C:13](=[O:15])[CH2:12][C:9]1[C:8](=[O:16])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)[CH2:30][CH3:31]
Reactant: CCCN
Reactant: Cc1cccc2ncc(CC(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)Cc1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
A mixture containing 2.18 g (0.01 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-acetic acid and 1.55 ml (0.011 mol) of triethylamine in 60 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 0.945 g (0.01 mol) of methyl chloroformate in 5 ml of chloroform is dropped to the above mixture at -12° C. during 7 minutes. After stirring for 5 minutes, 0.65 g (0.011 mol) of propylamine dissolved in 10 ml of chloroform is dropped to the above solution at -15° C. during 10 minutes. The reaction mixture is stirred at -15° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 40 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 40 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. Alter thoroughly triturating the residue with cold ethyl acetate, 0.8 g (30.9%) of the named compound is obtained, m.p.: 96°-98° C. after recrystallization from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH3:28]>C(#N)C.ClCCl>[CH3:26][CH:27]([N:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14]1)[CH3:28]
Reactant: COc1cc(N2CCCNCC2)ccc1[N+](=O)[O-]
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(N2CCCN(C(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 60 h
Yield: 83.5 %

Procedure:
1-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (580 mg, 2.3 mmol) was dissolved in acetonitrile (10 mL). Potassium carbonate (952 mg, 6.9 mmol) and 1-iodopropane (0.344 mL, 3.45 mmol) were added. Reaction was stirred at it for 60 h. At this time the reaction mixture was diluted with dichloromethane and washed with a saturated sodium bicarbonate solution, water and a saturated sodium chloride solution, dried over Na2SO4 and filtered. Solvents were removed under reduced pressure and purified by SiO2 chromatography to afford 1-(1-methylethyl)-4-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (0.565 g, 1.92 mmol). ESIMS (M+H)+=295.
Reaction SMILES: S1C2C=C(NC(=O)C3C=C([N+]([O-])=O)C(F)=CC=3Cl)C=CC=2N=C1.[NH4+].[OH-].[NH2:26][C:27]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][C:30]([C:31]([NH:33][C:34]2[CH:42]=[CH:41][C:37]3[N:38]=[CH:39][S:40][C:36]=3[CH:35]=2)=[O:32])=[C:29](Cl)[CH:28]=1.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>O1CCOCC1>[NH2:26][C:27]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][C:30]([C:31]([NH:33][C:34]2[CH:42]=[CH:41][C:37]3[N:38]=[CH:39][S:40][C:36]=3[CH:35]=2)=[O:32])=[C:29]([N:53]2[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]2)[CH:28]=1
Reactant: CN1CCNCC1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3ncsc3c2)cc1[N+](=O)[O-]
Agent: O=C(Nc1ccc2ncsc2c1)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1CCN(c2cc(N)c([N+](=O)[O-])cc2C(=O)Nc2ccc3ncsc3c2)CC1
Temperature: 25 °C

Procedure:
A solution of N-benzothiazol-6-yl-2-chloro-4-fluoro-5-nitrobenzamide (2 mmol) in dioxane (4 mL) was reacted with aqueous NH4OH using the conditions described in Example 115. After the formation of 4-amino-N-benzothiazol-6-yl-2-chloro-5-nitrobenzamide was complete, the reaction mixture was charged with N-methylpiperazine (12 mmol). The contents were heated at reflux for 10 h, and the reaction mixture was cooled to RT. The contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-N-benzothiazol-6-yl-2-(4-methyl-piperazin-1-yl)-5-nitrobenzamide as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH3:24])=[O:4].[Br:25]N1C(C)(C)C(=O)N(Br)C1=O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH2:24][Br:25])=[O:4]
Reactant: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(Cl)cc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.8 %

Procedure:
A mixture of 1-benzenesulfonyl-5-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (16.9 g, 46.2 mmol), 1,3-dibromo-5,5-dimethylhydantoin (13.21 g, 46.2 mmol) and 1,1-azobis(cyclohexanecarbonitrile) (1.52 g, 9.3 mmol) in 1,2-dichloroethane (200 mL) was heated under reflux for 90 minutes then stirred at ambient temperature for 16 hours. The reaction mixture was washed with saturated aqueous sodium thiosulfate solution. The organic layer was dried (Na2SO4) then filtered. The filtrate was stirred with flash silica gel, filtered and the filtrate evaporated under reduced pressure. The resultant residue was triturated with diethyl ether/pentane (1:1) to afford the title compound as white solid (13.7 g, 61%). LCMS (Method B): RT=4.35 min, M+H+=443/445/447. 1H NMR (400 MHz, CDCl3): 8.46-8.46 (m, 2H), 8.39 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 7.64-7.64 (m, 1H), 7.55-7.52 (m, 2H), 5.67 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:13][CH3:14])[CH2:10][CH2:9][CH:8]=[C:7]([Br:11])[C:6]1=[O:12].[CH2:16]([Mg]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.[Br-].[Zn+2].[Br-]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:13][CH3:14])[CH2:10][CH2:9][CH:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]([Br:11])[C:6]1=[O:12]
Reactant: CCC1(CC(=O)OC)CCC=C(Br)C1=O
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC)CCC(Cc2ccccc2)C(Br)C1=O
Reaction time: 0.08 h

Procedure:
A solution of 3-bromo-1-ethyl-2-oxocyclohex-3-eneacetic acid methyl ester (10 g, 36.3 mmol, as prepared in Example 1) and copper (I) bromide-dimethyl sulfide complex (3.63 mmol, 746 mg) in 107 mL of dry tetrahydrofuran was stirred at 0° C. under nitrogen and treated with anhydrous zinc bromide (36.3 mmol, 8.17 g). After 5 minutes, the mixture was treated dropwise with 36.3 mmol of benzylmagnesium chloride (18.2 mL of 2M in THF). After 45 minutes, another 8 mmol of benzylmagnesium chloride were added followed by 350 mg of copper (I) bromide-dimethyl sulfide complex and then another 16 mmol of benzylmagnesium chloride. The reaction was quenched with 150 mL of 1M HCl and extracted with 4×50 mL of ether. The extracts were conbined, dried over magnesium sulfate, and concentrated affording 3-bromo-1-ethyl-2-oxo-4-(phenylmethyl)cyclohexaneacetic acid methyl ester. This was then stirred in a solution of 74 mL of N,N-dimethylformamide and 35 mL of water and treated with 109 mmol (18.96 g) of sodium dithionite. The mixture was heated at 55° C. under nitrogen for 20 minutes, poured into 200 mL of water and extracted with 4×100 mL of 1:1 ether-petroleum ether. The extracts were combined, washed with 100 mL of water and 100 mL of saturated sodium bicarbonate (aq), dried over magnesium sulfate, and concentrated affording 10.48 g (36.3 mmol, 100% crude yield) of product as a pale yellow oil. Analysis by capillary GC demonstrated a 4.41:1 ratio of diastereomers, with the cis isomer predominating. The reduction of the intermediate 3-bromo-1-ethyl- 2-oxo-4-(phenylmethyl)cyclohexaneacetic acid methyl ester to the title compound can also be carried out as described in Example 3.