Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:4][N:3]=[CH:2]1.O.NN.Cl.N1(CCCCCCN)C=CN=C1.N1(CCCCCCCN)C=CN=C1.N1(CCCCCCCCN)C=CN=C1>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1
Agent: Cl
Agent: NCCCCCCCCn1ccnc1
Agent: NCCCCCCCn1ccnc1
Solvent: CCO
Solvent: O
Product: NCCCCn1ccnc1

Procedure:
A mixture of 0.2 mole of 2-[4-(1H-imidazol-1-yl)butyl]-1H-isoindole-1,3(2H)-dione, 0.22 mole of hydrazine hydrate and 400 ml of ethanol was heated on a steam bath for 3 hours and then treated with 400 ml of 3N hydrochloric acid and heated at reflux for an additional 2 hours. The insoluble material was filtered off and the mother liquor was concentrated to a low volume and again filtered. The remainder of the volatile material was distilled off and the residue was treated with saturated potassium carbonate solution. The 1H-imidazole-1-butanamine was extracted into methylene chloride and further purified by distillation on a Kugelrohr apparatus. In like manner from the appropriate 2-[ω-(1H-imidazol-1-yl)alkyl]-1H-isoindole-1,3(2H)-dione were prepared 1H-imidazole-1-pentanamine; 1H-imidazole-1-hexanamine; 1H- imidazole-1-heptanamine; and 1H-imidazole-1-octanamine.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[C:9]([Cl:20])[CH:10]=[C:11]([C:15]([O:17]CC)=[O:16])[C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1)[CH3:2].[OH-].[K+].C(O)C>O>[CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[C:9]([Cl:20])[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(SCC)CCS2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCSC1CCSc2c(Cl)cc(C(=O)O)c(C)c21
Temperature: 60 °C
Yield: 143.6 %

Procedure:
0.75 Gram (2.3 mmol) of 4-ethylthio-5-methyl-6-ethoxycarbonyl-8-chlorothiochroman, 0.47 g (7.1 mmol) of potassium hydroxide, 5 ml of ethanol and 2 ml of water were mixed, and the mixture was stirred under heat at 60° C. for 2 hours. After the completion of the reaction, the solvent was distilled off, 5 ml of water was added, and then 2N hydrochloric acid was added to adjust a pH of 1. Then, the mixture was extracted with ethyl acetate twice. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 1.0 g (yield 100%) of 4-ethylthio-5-methyl-6-carboxy-8-chlorothiochroman.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C@:16]12[CH2:33][CH2:32][C@H:31]3[C@@H:21]([CH2:22][CH2:23][C:24]4[C@:29]3([CH3:30])[CH2:28][CH2:27][C:26](=[O:34])[CH:25]=4)[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[C:35](O)=[O:36].C(N(CC)CC)C.FC(F)(F)S(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][C:35]([C@H:17]2[CH2:18][CH2:19][C@H:20]3[C@H:21]4[C@H:31]([CH2:32][CH2:33][C@:16]23[CH3:15])[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH2:27][CH2:28]2)[CH2:23][CH2:22]4)=[O:36])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 89 %

Procedure:
0.108 ml of benzhydrylamine was added to a solution of 100 mg of androsta-4-ene-3-one-17β-carboxylic acid, a catalytic amount of 4-dimethylaminopyridine and 0.132 ml of triethylamine in 4 ml of methylene chloride. 0.050 ml of trifluoromethanesulfonyl chloride was divided into three portions and added to this reaction mixture at intervals of 30 minutes at room temperature, whilst stirring. One hour after finishing the addition of trifluoromethanesulfonyl chloride, the reaction mixture was diluted with methylene chloride, washed with 1 N aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was crystallized from acetone to give 135.2 mg (yield 89%) of the title compound, having the same properties as the product of Preparation 17.
Reaction SMILES: [ClH:1].Cl.C[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]([CH3:22])[C:13]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[N:12]2)=[CH:7][CH:6]=1.C([O-])(=O)/C=C/C([O-])=O.B(Br)(Br)Br.Cl>C(Cl)Cl>[ClH:1].[ClH:1].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]([CH3:22])[C:13]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)=[N:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(C2N=C(CCc3ccncc3)N(C)Cc3ccccc32)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: ClCCl
Product: CN1Cc2ccccc2C(c2ccc(O)cc2)N=C1CCc1ccncc1
Reaction time: 3 h
Yield: 83 %

Procedure:
To a mixture of 4,5-dihydro-1-(4-methoxyphenyl)-4-methyl-3-[2-(4-pyridyl)ethyl]-1H-2,4-benzodiazepine dihydrochloride (3.81 g, 8.6 mmol, prepared from the fumarate of Example 398 by standard procedures) in CH2Cl2 (40 mL) in an ice-bath under N2 was added boron tribromide (17.2 mL, 1M in CH2Cl2). The mixture was stirred for 3 hours, 2N HCl was added and the mixture was stirred for 1/2 hour. The layers were separated, the aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with 2N HCl. The organic layer was treated with saturated Na2CO3 and the product which precipitates was collected by filtration to afford 3.06 g (83%) of 4,5-dihydro-1-(4-hydroxyphenyl)-4-methyl-3-[2-(4-pyridyl)ethyl]-1H-2,4-benzodiazepine dihydrochloride, m.p. 258°-259° C. after recrystallization from methanol/ether.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:13][NH2:14]>C(O)(=O)C>[CH2:10]([C:9]1[NH:14][N:13]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1)[CH3:11]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A solution of ethyl 2,4-dioxohexanoate (˜0.464 mol), prepared as described in Part A of Example 10, in glacial acetic acid (300 mL) was cooled to 0° C. Hydrazine (8.91 g, 0.278 mol) was added dropwise. The reaction was allowed to warm to ambient temperature, stirred overnight, and concentrated under reduced pressure. The residue was adjusted to pH 10 with the addition of 2 M aqueous sodium carbonate. The mixture was extracted with chloroform (3×250 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 27.0 g of ethyl 5-ethyl-1H-pyrazole-3-carboxylate, which was used without purification.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:11]3[CH:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=2)[CH2:2]1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)Cl>[CH3:21][N:22]([CH3:26])[C:23]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[C:11]3[CH:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=2)[CH2:2]1)=[O:24]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)c1cc(OC2CNC2)c2cc(C)oc2c1
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC2CN(C(=O)N(C)C)C2)c2cc(C)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a solution of ethyl 4-(azetidin-3-yloxy)-2-methyl-1-benzofuran-6-carboxylate (200 mg, 0.73 mmol) in dissolved in DCM with containing TEA (0.4 mL, 2.9 mmol) was added dimethylcarbamic chloride (0.1 mL, 1.09 mmol). The mixture solution was stirred at room temperature for 2 hrs. The reaction was diluted with DCM, washed with NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified via gradient silica gel chromatography using EtOAc/Hexanes (20/80 to 60/40) to provide the product (138 mg, 55%) as a colorless oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36-1.54 (m, 3 H) 2.49 (s, 3 H) 2.88 (s, 6 H) 4.06-4.20 (m, 2 H) 4.33-4.53 (m, 4 H) 5.04-5.18 (m, 1 H) 6.52 (s, 1 H) 7.01 (s, 1 H) 7.80 (s, 1 H); MS (ESI, pos): 347.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:8](=O)[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])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26]>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:8](=[S:26])[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])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)CN(C)C(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Solvent: c1ccccc1
Product: CCOC(=O)CN(C)C(=S)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 60 °C
Yield: 35.2 %

Procedure:
To benzene (10 ml) was added N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-methylglycine ethyl ester (610 mg, 1.7 mmol) obtained in Example 3-ii) and phosphorus pentasulfide (378 mg, 1.7 mmol) and the mixture was heated at 60° C. for 3 hours. The organic phase was decanted and the residue was extracted with ether. All the organic phases were combined, washed with water, dried and evaporated to yield a residue, which was crystallized from hexane-isopropyl ether to give N-[3-(4,5,7-trifluorobenzothiazol-2-yl)-1-thioxopropyl]N-methylglycine ethyl ester (225 mg, 35%) as colorless crystals.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[C:10]([Cl:16])[CH:9]=1.[BH4-].[Na+].[OH2:22]>O1CCCC1.[OH-].[Na+]>[CH3:19][Si:2]([CH3:1])([CH3:18])[CH2:3][CH2:4][O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:22])[CH3:15])=[C:10]([Cl:16])[CH:9]=1
Reactant: O
Reactant: C=Cc1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(O)c1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl
Reaction time: 15 h

Procedure:
(3-Chloro-4-vinyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (2.6 g) is added to a solution of mercuric acetate (3.48 g) in water (7 mL) and tetrahydrofuran (5.25 mL) and the mixture is stirred for approximately 15 hours. 3N Aqueous sodium hydroxide (8.7 mL) and a 0.5 M solution of sodium borohydride in 3N aqueous sodium hydroxide (8.7 mL) are then added and stirring is continued for 6 hours. The solution is then saturated with sodium chloride and extracted with ethyl acetate. These organic extracta are then washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12](C(OC(C)(C)C)=O)[CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:37].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:37]
Reactant: COC(=O)COc1ccc(N(Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C(=O)OC(C)(C)C)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)COc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 22.7 %

Procedure:
A solution of crude (4-{tert-butoxycarbonyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2-methyl-phenoxy)-acetic acid methyl ester (2.1 g containing 1.83 g, 3.32 mmol) in CH2Cl2 (33 ml) was treated at 0° C. with TFA (12.7 ml) and stirred at RT for 45 min. The reaction was evaporated, treated with chilled aqueous saturated NaHCO3 solution/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash chromatography with a gradient of n-heptane:EtOAc 95:5 to 4:1 yielded 0.34 g of (2-methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester as an light yellow solid, MS: 451.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[NH:19][CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[C:23](O)(=[O:25])[CH3:24]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[N:19]([C:23](=[O:25])[CH3:24])[CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC(=O)O
Reactant: CC1c2cc[nH]c2CCN1C(=O)c1cc2ncc(Br)cn2n1
Product: CC(=O)n1ccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-5-yl)-methanone is reacted with acetic acid to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C1CCCCO1)[N:6]=[C:5]2[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH2:24]2)[N:18]=1.[CH3:37][O:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:44]=1.C([O-])([O-])=O.[Na+].[Na+].Cl.CC(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.O1CCOCC1.O>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([N:23]3[CH2:24][CH2:25][CH:26]([NH2:29])[CH2:27][CH2:28]3)[N:18]=2)[CH:42]=[N:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nccc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)CC1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1cncc(-c2ccc3[nH]nc(-c4ccnc(N5CCC(N)CC5)n4)c3c2)c1
Temperature: 145 °C

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 1-(4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-yl)piperidin-4-ylcarbamate (0.305 g, 0.547 mmol), 3-methoxypyridine-5-boronic acid pinacol ester (0.232 g, 0.987 mmol, Frontier Scientific), Na2CO3 (0.356 g, 3.36 mmol) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.056 g, 0.080 mmol). Water (2 mL) and dioxane (5 mL) were added and the reaction mixture was sealed under argon and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 145° C. for 20 min. The reaction mixture was partitioned between DCM/brine and the aqueous layer was extracted with DCM (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, (40 gram)) eluting with 2M NH3 in MeOH:DCM (0:1→1:39) to give a white amorphous solid. The material was heated at 50° C. for 5 h in the presence of HCl, 5-6N in IPA (10 mL, 50.0 mmol). The mixture was cooled to RT and the solvent was removed in vacuo. The residue was dissolved in DMSO and purified by reverse-phase HPLC (Gilson; Gemini-NX 10μ C18 110 A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O:0.1% TFA ACN (9:1→1:9). The fractions containing the desired product were combined and concentrated in vacuo to give an off-white amorphous solid. m/z: 402.2 [M+1].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)[C:15]2=[O:20].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][N:14]([CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:15]3=[O:20])=[O:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2Cc3c(N)cccc3C2=O)CC1
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CCN2Cc3c(NC(=O)c4ccc(Cl)s4)cccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 0.97 g (5.35 mmol) of 5-chlorothiophene-2-carbonyl chloride is added dropwise to a suspension of 1.48 g (4.12 mmol) of tert-butyl 4-[2-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-piperidinecarboxylate, 1.7 ml (20.6 mmol) of pyridine and 25 mg (0.206 mmol) of 4-DMAP in 21 ml of absolute THF. The mixture is slowly warmed to room temperature and stirred overnight. The reaction 10 mixture is concentrated and then separated by chromatography on silica gel (dichloromethane/methanol 97:3).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:22][CH3:23])=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Br:19])=[CH:14][C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:29]>ClCCl.CO>[C:1]([O:4][C:5]1[C:6]([O:22][CH3:23])=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16](=[O:29])[C:17]=2[C:18]=1[Br:19])=[CH:14][C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)Sc1c(cc(OC)c(OC(C)=O)c1Br)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)S(=O)c1c(cc(OC)c(OC(C)=O)c1Br)N2
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 3-acetoxy-4-bromo-2,7-dimethoxy-10H-phenothiazine (10.0 g) in dichloromethane (125 ml) and methanol (125 ml) there was added at room temperature 85% m-chloro peroxybenzoic acid (4.36 g). The mixture was stirred for one hour and the solid was filtered and washed with ether. This crude product was stirred at room temperature in dichloromethane (50 ml) overnight and filtered again to afford pure title product (7.7g). m.p.: 243°-247° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17]3)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccc(C)cc3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C(=O)O)[nH]c23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
To a mixed solution of ethyl 7-{[(4-methylphenyl)sulfonyl]amino}-1H-indole-2-carboxylate (356 mg) in tetrahydrofuran (6 mL)-methanol (6 mL) was added aqueous solution (3 mL) of 85% potassium hydroxide (450 mg), and the mixture was stirred at room temperature for 18 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (312 mg, yield 95%) as pale-yellow crystals. melting point 268-269° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][Cl:29])=[CH:21][CH:20]=1)=[O:18].O>CN(C)C=O>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][Cl:29])=[CH:21][CH:20]=1)=[O:18])[CH3:12]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: O=C(CBr)c1ccc(OCCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1ccc(OCCCCl)cc1)c1ccccn1
Reaction time: 14 h

Procedure:
In a 500 mL round bottom flask ethyl 2-pyridylacetate (2.0 g, 12.1 mmol), and 60% sodium hydride (508 mg, 12.7 mmol) in dimethylformamide (50 mL) was stirred 1 h. 2-Bromo-1-[4-(3-chloro-propoxy)-phenyl]-ethanone (3.53 g, 12.1 mmol) was then added in dimethylformamide (50 mL) via dropping funnel. The reaction was stirred 14 h. Water (300 mL) was added and the organics were extracted three times with ethyl acetate, and then dried over MgSO4. Purification with silica gel chromatography eluting with hexanes/ethyl acetate (3:1) produced 2.8 g (62%). MS m/z 376 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:28]I>C1COCC1.CCOCC>[C:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][N:23]([S:24]([CH3:27])(=[O:26])=[O:25])[CH3:28])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CNS(C)(=O)=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a stirred suspension of sodium hydride (60% in oil, 113 mg, 2.82 mmol) in THF (20 mL) at 0° C. under nitrogen was added a solution of 1-Boc-4-[2-(methanesulfonylamino-methyl)-phenyl]-piperazine (0.99 g, 2.68 mmol) in THF (5 mL). The mixture was stirred for about 1 hour at room temperature. It then was cooled back to 0° C. and treated with methyl iodide (0.184 mL, 2.95 mmol). After stirring for about 20 hours, the reaction mixture was diluted with ether (150 mL) and then quenched by addition of saturated aqueous ammonium chloride (50 mL). The organic phase was separated, washed with water (50 mL) and brine (50 mL) and then dried over magnesium sulfate. Concentration under reduced pressure followed by silica gel chromatography (30% ethyl acetate in hexanes) afforded the title compound (0.96 g, 94%) as a clear oil.
Reaction SMILES: [N:1]1[C:2](=[O:10])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[CH3:11][N:12]([CH3:25])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15][CH:14]=1>N1CCCCC1.C(O)C>[CH3:11][N:12]([CH3:25])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:15][CH:14]=1
Reactant: O=C1C=c2ccccc2=N1
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)c1ccc(C=C2C(=O)Nc3ccccc32)c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 1.33 g of indole-2-one (10 mmol), 1.99 g of 4-dimethylamino-1-naphthaldehyde (10 mmol) and 3 drops of piperidine are refluxed in 40 ml of ethanol for 5 hours. The desired product precipitates as an orange solid during the reaction. After cooling to room temperature, the product is filtered off, washed with ethanol and dried in vacuo. Yield 2.67 g (85%).