Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23][CH2:24]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:31]1([C:37]2([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23][CH2:24][N:40]3[CH2:39][CH2:38][C:37]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41]3)[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(c1ccc(Cl)cc1)N1CCC(CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: NC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3ccc(Cl)cc3)C2)CC1

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.72 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1>CC(N(C)C)=O>[N:9]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Clc1ccc(Br)cn1
Reactant: C1CNC1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: Brc1ccc(N2CCC2)nc1
Temperature: 170 °C

Procedure:
A mixture of 5-bromo-2-chloropyridine (Sigma-Aldrich, Buchs, Switzerland, 196 mg, 1.018 mmol), azetidine (Sigma-Aldrich, Buchs, Switzerland, 0.213 ml, 3.06 mmol) and pyridine (0.124 ml, 1.528 mmol) in DMA (2.5 ml) was heated under microwave irradiation at 150° C. for 10 min and 170° C. for 10 min. The reaction was not completed. Again azetidine (0.106 ml) was added and the RM was heated under microwave irradiation at 170° C. for 1 h. Then the RM was quenched with saturated aqueous NaHCO3 (50 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried over Na2SO4, filtered and evaporated to dryness to give the title compound as an off-white solid. (HPLC: tR 1.97 min (Method A); M+H=213, 215 (Br-pattern) MS-ES. 1H-NMR (d6-DMSO, 400 MHz) 8.12 (s, 1H), 7.70-7.60 (m, 1H), 6.37-6.29 (m, 1H), 3.96-3.86 (m, 4H), 2.34-2.24 (m, 2H))
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C([O-])(O)=O.[Na+].C(O[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)C>>[C:19]([O:8][C:7]([C@H:2]1[NH:1][C:5](=[O:6])[CH2:4][CH2:3]1)=[O:9])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of L-pyroglutamic acid (2.00 g, 15.49 mmol) in t-butyl acetate was added 70% HClO4 (0.46 mL, 17.04 mmol). The suspension was stirred at rt in a tightly closed flask overnight. The resulting solution was poured slowly into a sat. solution of NaHCO3 and extracted twice with EtOAc. The organic phase was dried over MgSO4 and concentrated to provide (S)-pyrrolidin-2-one-5-carboxylic acid t-butyl ester. (2.04 g, 85%) as a white solid 1H NMR (CDCl3) δ 1.48 (s, 9H), 2.16-2.48 (m, 4H), 4.14 (m, 1H), 5.97 (bs, 1H). MS calcd for C9H15NO3 +H 186, found 186.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>>[ClH:3].[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:25][C:17]1[CH:18]=[CH:19][C:20]2[NH:21][C:22]3[N:23]=[C:7]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=4)[CH2:14][CH2:15][C:16]=1[CH:24]=2)[N:6]=[CH:5][C:4]=3[Cl:3])=[O:31]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)c1ccccc1Cl
Yield: 24 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride and 2-chlorobenzoyl chloride as the starting materials in 24% yield. LCMS for C25H20Cl2N5O (M+H)+: m/z=476.2.
Reaction SMILES: [N+]([O-])([O-])=O.[O-2].[Bi+3:6].[CH2:7]([N:18]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][C:20]([OH:22])=[O:21])[CH2:8][N:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12]>O>[Bi:6].[CH2:8]([N:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])[CH2:7][N:18]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][C:20]([OH:22])=[O:21]
Reactant: [Bi+3]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [O-2]
Solvent: O
Product: [Bi]

Procedure:
A mixture of bismuth oxynitrate (20.09 g) and N,N'-1,2-ethanediylbis[N-(carboxymethyl)glycine] (EDTA; 17.57 g) in water (100 ml) was heated at 90°-95° for 2 h. The hot suspension was filtered and the residue re-heated at 90°-95° with water (4×70 ml) until almost all the solid had dissolved. On each extraction, the suspension was filtered and the strongly acidic filtrates evaporated in vacuo to approximately 70 ml. The mixture from the extractions was cooled to 18° and the precipitated solid filtered off and washed free of nitric acid with cold water, then ethanol and ether, and dried to give the title compound (18.52 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([O:25]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:10]([OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (±)-cis-4-benzyloxycarbonylamino-3-(4-nitro-benzoyloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.63 mmol, 0.315 g) in THF (5 mL) at 0° C. was added LiOH (0.16 g) dissolved in water (1.5 mL) and continued stirring at 0° C. for 30 min followed by 2 h at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (10 mL) and extracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to provide (±)-cis-4-benzyloxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:41])[CH:38]([CH3:40])[CH3:39]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:41])[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)=CCC(OC(=O)C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 88 mg (1 mmole) of isobutanoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 161 mg (Yield: 45%) of the title compound having the following structure as a red oil.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7]1([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[CH:27]=[N:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[O:17])[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1>>[CH:1]1([NH:6][C:21]([C:20]2[CH:24]=[CH:25][N:26]=[CH:27][C:19]=2[NH:18][C:16]([C:14]2[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=[C:10]([CH:7]3[CH2:9][CH2:8]3)[N:15]=2)=[O:17])=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C(NC1CCCC1)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 18 %

Procedure:
According to the general method described in step 3 of example 53, reaction of cyclopentylamine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (18%) as amorphous yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH:14](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:14]=[N:8][N:7]=2)[CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12]
Reactant: CCOC(OCC)OCC
Reactant: NNC(=O)c1cc(Cl)c(O)c(Cl)c1
Product: Oc1c(Cl)cc(-c2nnco2)cc1Cl

Procedure:
A mixture of 8.9 g 3,5-dichloro-4-hydroxybenzoic acid hydrazide and 500 ml triethyl orthoformate was stirred and heated at reflux for 4 hrs. The solvent was removed in vacuo to afford the product (9.9 g) as a yellow solid, used directly in the next reaction.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH:2]12.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([Mg]Br)[CH:12]=[CH:13][CH:14]=1.C(OCC)(=O)C.Cl>O1CCCC1.[Cu]Cl>[OH:1][CH:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[CH:14]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: C1CC2OC2C1
Agent: Cl[Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C2CCCC2O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of a mixture of 1,2-epoxycyclopentane (7.0 g) and copper(I) chloride (260 mg) in tetrahydrofuran (70 ml) was added 3-methoxyphenylmagnesium bromide (53.5 m mol) in tetrahydrofuran (60 ml) at -78° C. under N2. The mixture was stirred for 1 hour at 0° C. The reaction mixture was poured into a mixture of ethyl acetate and 1N-hydrochloric acid and then the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine. The combined organic extracts were concentrated and the residue was purified by column chromatography on silica gel to give 1-hydroxy-2-(3-methoxyphenyl)-cyclopentane (13 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][Cl:27].O>CN(C=O)C.C(OCC)(=O)C>[Cl:27][CH2:26][CH2:25][CH2:24][N:7]1[C:8]2[C:13](=[CH:12][C:11]([CH2:15][N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: ClCCCBr
Reactant: CCOC(=O)c1cc2cc(Cn3ccnc3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(Cn3ccnc3)ccc2n1CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Ethoxycarbonyl-5-(1H-imidazol-1-ylmethyl)-1H-indole (1.00 g) was dissolved in DMF (10 ml), and thereto was added sodium hydride (156 mg, purity 60%) under ice-cooling, followed by stirring at room temperature for 1 hour. Thereto was added 1-bromo-3-chloropropane (0.39 ml ), and the mixture was stirred for 1.5 hours. 1-Bromo-3-chloropropane (0.20 ml) was added again, and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture for extraction, followed by washing with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (Daisogel 15 g, elution; CHCl3 --CHCl3 /MeOH=50/1-30/1) to give 1.26 g of an oily substance (1). IR (Neat, νcm-1) 1710, 1700, 1520, 1470 1H-NMR (CDCl3, δ ppm) 1.40 (3H, t, J=6.6 Hz, CH2CH3 ), 2.29 (2H, m, CH2CH2Cl), 3.63 (2H, t, J=6.0 Hz, CH2Cl), 4.38 (2H, quart, J=6.6 Hz, CH2CH3), 4.72 (2H, t, J=6.0 Hz, NCH2), 5.20 (2H, s, C5--CH2), 6.70-7.85 (7H, indole H, imidazole H)
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].C(Cl)(C([Cl:24])=O)=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[C:3]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([Cl:24])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1sc2ccc(-c3ccccc3)cc2c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1sc2ccc(-c3ccccc3)cc2c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 52d (136.2 mg, 0.5 mmol) in CH2Cl2 (5 mL) at room temperature was added (COCl)2 (0.064 mL, 0.75 mmol), followed by DMF (0.01 mL, 0.125 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 52e (light pink powder), which was used in the next reaction without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)(=O)=O.[C:22]([B-](F)(F)F)([CH3:24])=[CH2:23].[K+].C(Cl)Cl.C(N(CC)CC)C>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:22]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)([CH3:24])=[CH2:23]
Reactant: CC(C)(c1ccc(OS(=O)(=O)C(F)(F)F)cc1)C(F)(F)F
Reactant: C=C(C)[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCO
Product: C=C(C)c1ccc(C(C)(C)C(F)(F)F)cc1
Yield: 69.2 %

Procedure:
The procedure described in Example 10B was followed using a mixture of 4-(2,2,2-trifluoro-1,1-dimethylethyl)phenyl trifluoromethanesulfonate (13.3 g, 40 mmol), potassium isopropenyltrifluoroborate (7.0 g, 47.6 mmol), PdCl2(dppf).CH2Cl2 (1.6 g, 1.98 mmol) and triethylamine (5.5 ml, 40 mmol) in n-propanol (400 ml). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and EtOAc (100/1) to afford 6.32 g (70% yield) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][C:22]1[N:26]([CH3:27])[N:25]=[N:24][N:23]=1.[OH:28][CH2:29][CH2:30][S:31][C:32]1[C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[N:43][S:44]([C:47]2[S:48][CH:49]=[CH:50][CH:51]=2)(=[O:46])=[O:45])[CH:33]=1>>[OH:42][C:41]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([NH:43][S:44]([C:47]2[S:48][CH:49]=[CH:50][CH:51]=2)(=[O:46])=[O:45])=[CH:33][C:32]=1[S:31][CH2:30][CH2:29][OH:28].[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][C:22]1[N:26]([CH3:27])[N:25]=[N:24][N:23]=1
Reactant: O=C1C(SCCO)=CC(=NS(=O)(=O)c2cccs2)c2ccccc21
Agent: Cn1nnnc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: O=S(=O)(Nc1cc(SCCO)c(O)c2ccccc12)c1cccs1

Procedure:
N-(4-hydroxy-3-(2-hydroxyethylthio)naphthalen-1-yl)thiophene-2-sulfonamide (14k) was prepared according to the procedure for 14d except using N-(3-(2-hydroxyethylthio)-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (13k), which, after purification via flash chromatography (Hex/EtOAc), afforded the title compound 20.3 mg (53.1%) as a grey solid, m.p.: ° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH:9]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O>C(O)C.O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH:9]([CH:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: CN1CCC(C2Cc3ccc([N+](=O)[O-])cc3C2=O)CC1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCC(C2Cc3ccc(N)cc3C2=O)CC1
Reaction time: 2.5 h
Yield: 105.9 %

Procedure:
A solution of 1.86 g (0.0068 mol) of 6-nitro-2-(1-methyl-4-piperidyl)indan-1-one in 50 mL of absolute ethanol and 50 mL of tetrahydrofuran was hydrogenated at 10 psi over Raney nickel catalyst. After 2.5 hours, the catalyst was removed by filtration and the solvent was evaporated to give 1.76 g of crystalline 6-amino-2-(1-methyl-4-piperidyl)indan-1-one. To a solution of 1.04 g (0.00426 mol) of the 6-amino compound in 20 mL of methylene chloride and 3.4 g of pyridine was added 0.61 g (0.005 mol) of methanesulfonyl chloride. The mixture was stirred at room temperature for two hours, after which time it was poured onto water and made basic by the addition of a saturated sodium bicarbonate solution. The mixture was concentrated to dryness in vacuo, and the solid residue was extracted with two 50 mL portions of methylene chloride. Evaporation of the methylene chloride gave 1.56 g of 6-methanesulfonamido-2 -(1-methyl-4-piperidyl)indane-1-one as a colorless foam.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.Cl.[F:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:52]=1[C@H:58]([NH2:60])[CH3:59]>>[F:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:52]=1[C@H:58]([NH:60][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([I:25])=[CH:27][C:28]=1[NH:35][S:36]([C:39]1[C:40]2[N:41]=[CH:42][CH:43]=[N:44][C:45]=2[CH:46]=[CH:47][CH:48]=1)(=[O:38])=[O:37])[CH3:59]
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: C[C@@H](N)c1ccc(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(F)cc1F

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-iodo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 4, Step D) and (R)-1-(2,4-difluorophenyl)ethylamine hydrochloride (EXAMPLE 2, Method 1, Step C) and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C23H17F2IN4O3S, 594.0; m/z found, 593 [M−H]−. HPLC (reverse phase): RT=10.16 min. 1H NMR (500 MHz, CDCl3): 11.22 (s, 1H), 8.84 (d, J=1.8 Hz, 1H), 8.79 (d, J=1.8 Hz, 1H), 8.55 (dd, J=7.4, 1.4 Hz, 1H), 8.30 (dd, J=7.4, 1.4 Hz, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.32-7.27 (m, 2H), 6.99 (d, J=8.2, 1H), 6.89-6.85 (m, 1H), 6.85-6.80 (m, 1H), 6.33 (br d, J=7.7 Hz, 1H), 5.35-5.27 (m, 1H), 1.53 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([S:9][CH2:10][C:11]#[N:12])[S:5][C:6]=1[C:7]#[N:8].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[C:7]([C:6]1[S:5][C:4]([S:9][CH2:10][C:11]#[N:12])=[N:3][C:2]=1[N:1]=[CH:15][N:16]([CH3:18])[CH3:17])#[N:8]
Reactant: COC(OC)N(C)C
Reactant: N#CCSc1nc(N)c(C#N)s1
Product: CN(C)C=Nc1nc(SCC#N)sc1C#N

Procedure:
The title compound was prepared from the reaction of 4-Amino-2-cyanomethylsulfanyl-thiazole-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]([NH:16][CH:17]2[CH2:22][CH2:21][N:20](C(OCC)=O)[CH2:19][CH2:18]2)=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][CH:12]=2.[OH-].[K+].CC(O)C>O>[OH2:1].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]([NH:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][CH:12]=2.[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]([NH:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][CH:12]=2
Reactant: CCOC(=O)N1CCC(Nc2nc3cncnc3n2Cc2ccco2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: c1coc(Cn2c(NC3CCNCC3)nc3cncnc32)c1
Reaction time: 48 h

Procedure:
A mixture of 60.5 parts of ethyl 4-[[9-(2-furanylmethyl)-9H-purin-8-yl]amino]-1-piperidinecarboxylate, 90 parts of potassium hydroxide, 800 parts of 2-propanol and 20 parts of water was stirred for 48 hours at reflux temperature. The reaction mixture was evaporated. The reaction mixture was poured into water while stirring. The product was filtered off and dried, yielding a first fraction of 36.2 parts of 9-(2-furanylmethyl)-N-(4-piperidinyl)-9H-purin-8-amine hemihydrate. The aqueous phase was extracted with dichloromethane. The organic layer was dried, filtered and evaporated. The oily residue was stirred in acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried, yielding a second fraction of 5.6 parts of 9-(2-furanylmethyl)-N-(4-piperidinyl)-9H-purin-8-amine. Total yield 41.8 parts (86%) of 9-(2-furanylmethyl)-N-(4-piperidinyl)-9H-purin-8-amine hemihydrate; mp. 164.1° C. (compound 33).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]=[CH:10]2)#[N:2].[BH4-].[Na+]>C(O)C>[C:1]([CH2:3][O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)#[N:2]
Reactant: COc1ccc2c(c1OCC#N)CCC=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1OCC#N)CCCC2
Temperature: 25 °C
Yield: 79 %

Procedure:
The product from Example 1 (10.5 g) was refluxed for 2.5 hours in ethanol (200 ml) containing sodium borohydride (6 g). The reaction was cooled to room temperature and evaporated to dryness. Aqueous hydrochloric acid (50 ml) was carefully added followed by extraction with dichloromethane. The organic layer was separated, dried and evaporated affording 8.4 g. of the desired product (79% yield); m.p. 50°-1° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](=O)[CH2:20]Br)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[CH:23]1[N:27]=[C:26]([NH2:28])[S:25][CH:24]=1>CCO>[CH2:17]([S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[C:3]([C:19]3[N:28]=[C:26]4[N:27]([CH:20]=3)[CH:23]=[CH:24][S:25]4)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])[CH3:18]
Reactant: Nc1nccs1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)CBr)n2)CC1
Solvent: CCO
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cn4ccsc4n3)n2)CC1
Temperature: 25 °C
Yield: 156.7 %

Procedure:
1-[3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazin-2-yl]-2-bromo-ethanone (35 mg, 0.08922 mmol) was suspended in EtOH (2 mL) and 2 aminothiazole (8.935 mg, 0.08922 mmol) was added. The mixture was heated at reflux for 4 hours and then allowed to cool to ambient temperature. The solution was filtered through a 0.45 μnm PTFE filter and the solvent removed under a stream of nitrogen. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (55 mg, 10% Yield). 1H NMR (400.0 MHz, DMSO) d 1.14 (t, J=7.3 Hz, 3H), 3.01 (q, J=7.4 Hz, 2H), 3.21-3.23 (m, 4H), 3.34-3.36 (m, 4H), 7.28 (d, J=4.4 Hz, 1H), 7.67 (s, 1H), 7.89 (d, J=4.4 Hz, 1H) and 8.23 (s, 1H) ppm; MS (ES+) 394.0
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[C:10]1([NH:9][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Ic1ccccc1
Reactant: Nc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: c1ccc(Nc2ccccc2)cc1
Yield: 40.8 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), aniline (109 μL, 1.20 mmol), iodobenzene (112 μL, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL) at 90° C. Column chromatography using a solvent mixture (hexane/ethyl acetate=5/1, Rƒ=0.4) afforded N-(phenyl)aniline (69 mg, 41% isolated yield) as light yellow solid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity.