Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].CNCCNC.C([Li])CCC.CC1C=CC(S(O[CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)(=O)=O)=CC=1>O1CCCC1.O>[CH3:1][C:2]1([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11]
Reactant: Cc1ccc(S(=O)(=O)OCc2cncnc2)cc1
Reactant: CC1C(=O)Nc2ccccc21
Agent: CNCCNC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(Cc2cncnc2)C(=O)Nc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Pyrimidin-5-ylmethanol (510 mg, 4.63 mmol) in tetrahydrofuran (8 mL) at room temperature was treated with sodium hydride (185 mg, 4.63 mmol) and stirred for 5 minutes. p-Toluenesulfonyl chloride (883 mg, 4.63 mmol) was added, and the resulting mixture stirred for one hour to form pyrimidin-5-ylmethyl 4-methylbenzenesulfonate. In a separate flask 3-methyloxindole (682 mg, 4.63 mmol) and N,N′-dimethylethylenediamine (1.538 mL, 10.19 mmol) in tetrahydrofuran (16 mL) were cooled to −78° C. and treated dropwise with n-butyllithium (2.5M in hexanes, 4.08 mL, 10.2 mmol). The mixture was allowed to warm to 0° C. and stirred for 15 minutes. The mixture was recooled to −78° C. To this mixture was added the tetrahydrofuran solution of pyrimidin-5-ylmethyl 4-methylbenzenesulfonate via cannula; the resulting reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. Water (50 mL) was added, and the mixture extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 25S, eluting with 0-100% ethyl acetate/hexane to afford 3-methyl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one as a white solid.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[NH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1.Cl.[OH-].[K+]>O>[CH:3]1([C:2]([OH:6])=[O:5])[C:11]2[NH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]=2[CH2:9][CH2:8][NH:7]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=CC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1NCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of glyoxylic acid monohydrate (1.51 g, 16.4 mmol) in water (10 ml) was added dropwise to a stirred solution of tryptamine.HCl (3.0 g, 15.3 mmol) in water (200 ml). KOH (0.827 g, 14.7 mmol) in water (10 ml) was added. The reaction mixture was stirred at room temperature for 1 h after which time precipitation occurred. Following filtration under reduced pressure the white precipitate was collected and washed with water to furnish 2,3,4,9-tetrahydro-1H-beta-carboline-1-carboxylic acid Yield 1.9 g (58%); m/z 217 [M++H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][N:17]=1.[OH-].[Na+]>O>[Cl:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]=[C:7]([S:9][CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][N:17]=3)[NH:6][C:5]=2[CH:10]=1
Reactant: Sc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: COc1ccnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccnc(CSc2nc3cc(Cl)c(Cl)cc3[nH]2)c1C

Procedure:
A suspension of 13 g of 5,6-dichloro-2-benzimidazolethiol in 360 ml of alcohol was treated with 13 g of 2-chloromethyl-4-methoxy 3-methylpyridine hydrochloride. A solution of 4 g of sodium hydroxide in 170 ml of water was added dropwise thereto while cooling with ice. The mixture was left to boil at reflux overnight and then concentrated to about 1/3 of its volume in a vacuum. After the addition of 600 ml of water the crystals were filtered off and thereupon washed thoroughly with water and then with ether. There was obtained 5,6-dichloro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]benzimidazole of melting point 254°-256°.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[NH:12]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>CC#N>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:12]([CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:18]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CC(=O)OCC)Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
A suspension of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (12.0 g, 34.6 mmol) and diethyl iminodiacetate (7.0 mL, 39.1 mmol) in CH3CN (350 mL) was treated with triethylamine (10.7 mL, 76.1 mmol). After stirring at room temperature under N2 for 4 h, the solvent was removed in vacuo. The resulting yellow slurry was partitioned between H2O (400 mL) and EtOAc (400 mL), and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (6.55 g, 51%) as a light tan oil: MS (ESI) m/e 374 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[CH:26]=1>>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[CH:26]=[C:22]1[CH2:21][N:17]1[CH2:18][CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: BrCc1cc2ccccc2o1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: c1ccc(Oc2ccc(C3CCN(Cc4cc5ccccc5o4)CC3)cc2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-bromomethylbenzofuran to produce the above.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)C=Cc1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cc(F)ccc1F
Yield: 73.3 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2,5-difluorocinnamic acid (2.2 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (2.8 g, 74%) as crystals.
Reaction SMILES: N1CCCCC1.C([O:10][C:11]1[C:16]([CH3:17])=[C:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][C:21]=3[CH:22]=2)[O:14][C:13](=[O:29])[C:12]=1[CH3:30])(=O)C.[S:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].[OH-].[Na+]>C1COCC1>[CH3:30][C:12]1[C:13](=[O:29])[O:14][C:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][C:24]([CH:27]=[C:35]4[C:34](=[O:36])[NH:33][C:32](=[O:37])[S:31]4)=[CH:23][C:21]=3[CH:22]=2)=[C:16]([CH3:17])[C:11]=1[OH:10]
Reactant: O=C1CSC(=O)N1
Reactant: CC(=O)Oc1c(C)c(-c2cc3cc(C=O)ccc3o2)oc(=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: Cc1c(-c2cc3cc(C=C4SC(=O)NC4=O)ccc3o2)oc(=O)c(C)c1O
Reaction time: 1 h

Procedure:
Piperidine (100 mg) was added to a solution of 4-acetyloxy-3,5-dimethyl-6-(5-formylbenzofuran-2-yl)-2H-pyran-2-one (374 mg) and 1,3-thiazolidine-2,4-dione (135 mg) in THF (50 ml), and the mixture was subjected to heated reflux for 4 hours. After cooling, a 15% sodium hydroxide aqueous solution (10 ml) was added to the reaction solution, and then after stirring for one hour it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH=5/1) to obtain 3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].O.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1(C)C=CC=CC=1>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:17]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccccc1N
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 120.2 g (1 mole) of 4-tolualdehyde and 108.1 g (1 mole) of o-phenylenediamine in toluene is heated at reflux with azeotropic removal of water. After 20 hours at reflux, the reaction is cooled to room temperature, then 443.4 g (1 mole) of lead tetraacetate is added, and the reaction is stirred at room temperature for 20 hours The solids are removed by filtration, and the filtrate is swirled with basic alumina. The mixture is filtered, and the filtrate is evaporated to dryness The product is purified by recrystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]([C:4]1([CH3:17])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)=[O:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH3:17][C:4]1([C:2]([NH2:1])=[O:3])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC1(C(N)=O)CCNCC1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
A 500-mL three-neck round bottom flask was equipped with an overhead mechanical paddle stirrer, thermocouple with N2-inlet, and reflux condenser that was vented to the atmosphere. The reactor was charged with the product of Example 9 (45.68 g, 188.5 mmol), p-toluenesulfonic acid monohydrate (46.67 g, 2453 mmol, 1.3 equiv) and isopropanol (179.2 g). The mixture was warmed to 80±10° C. After 45 minutes, the reaction solution was allowed to slowly cool; at about 78° C. the p-toluenesulfonate salt of the title compound began to precipitate from the reaction mixture. When the mixture had reached 70° C., heptane (40.2 g) was added to the mixture, which was then stirred for about 30 minutes. The mixture was then allowed to cool to ambient temperature over about 3 hours. The suspension was filtered and the reactor and cake were rinsed with a mixture of isopropanol (90.2 g) and heptane (78.7 g). The cake was dried under vacuum (˜100 mmHg w/N2 bleed) at a temperature of about 55-60° C. to give the p-toluenesulfonate salt of the title compound 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (s, 3H) 1.39-1.55 (m, 2H) 2.08 (d, J=14.55 Hz, 2H) 2.28 (s, 3H) 276-2.89 (m, 2H) 3.07-3.19 (m, 2H) 7.04 (s, 1H) 7.09-7.14 (m, 2H) 7.33 (s, 1H) 7.45-7.51 (m, 2H) 8.30 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][C:13](=[O:15])[CH3:14])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:7]([O:12][C:13](=[O:15])[CH3:14])[CH:6]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)c(OC(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
The compound of step 1 of example 252 (20 g, 89.2 mmol) was dissolved in DMF (100 ml) and cooled in an ice bath. Potassium carbonate (18.4 g, 134 mmol) and, immediately thereafter, benzyl bromide (15.2 g, 89.2 mmol) were added. The mixture was stirred for 30 min at room temperature, filtered into a mixture of 2 N hydrochloric acid and diethyl ether. The solid was washed repeatedly with diethyl ether. The combined ethereal phases were washed with water, dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield 21 g of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C1CN2C(=NCCC2)C1.C([O:41][C:42](=[O:45])[CH2:43]Br)C1C=CC=CC=1.COC(C)(C)C>[Cl-].C[N+](C)(C)C.C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[O:7][CH2:43][C:42]([OH:45])=[O:41])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(CBr)OCc1ccccc1
Agent: C1CN=C2CCCN2C1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: COC(C)(C)C
Product: CC(=O)OC[C@H]1OC(OCC(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture that consists of 34.83 g (100 mmol) of 2,3,4,6-tetra-O-acetylglucopyranose, 0.55 g (5 mmol) of tetramethylammonium chloride and 12.42 g (100 mmol) of DBN in 350 ml of benzene is cooled to 0° C. At 0° C., 34.36 g (150 mmol) of 2-bromoacetic acid benzyl ester, dissolved in 50 ml of benzene, is added in drops over 30 minutes while being stirred vigorously. It is stirred for two hours at 20° C. 250 ml of methyl-tert-butyl ether is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol. 5 g of palladium (10%) on activated carbon is added thereto, and it is hydrogenated until hydrogen absorption is completed. Catalyst is filtered out, it is rewashed with a little ethanol, and the combined solutions are evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n-hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2(N(C)C)CC=CC=C2C2C=CC=CC=2)CCCCC1.Br[Zn][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]>O1CCCC1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH2:55]([O:54][C:52](=[O:53])[CH2:51][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1)[CH3:56]
Reactant: Brc1ccc(OCCOC2CCCCO2)c2ccoc12
Reactant: CCOC(=O)C[Zn]Br
Agent: [Pd]
Agent: CN(C)C1(P(C2CCCCC2)C2CCCCC2)CC=CC=C1c1ccccc1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OCCOC2CCCCO2)c2ccoc12
Temperature: 25 °C
Yield: 54 %

Procedure:
Combine 7-Bromo-4-[2-(tetrahydropyran-2-yloxy)ethoxy]benzofuran (2.598 g, 7.61 mmol), bis(dibenzylideneacetone) palladium (0.461 g, 0.802 mmol), and 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl (0.308 g, 0.783 mmol) in tetrahydrofuran (15 ml) under nitrogen. Add bromo(2-ethoxy-2-oxoethyl)zinc (2 equiv.), and heat the mixture at 80° C. for 16 hours. (Knochel, P.; Honed, P.; Eds. Organozinc Reagents: A Practical Approach; Oxford University Press, Inc: London, 1999). Cool the mixture to room temperature, filter through a silica plug eluting with ethyl ether, and concentrate. Purify by flash chromatography and elute with hexane:ethyl acetate to give 1.422 g (54%) of the title compound as an oil. Mass spectrum: electrospray (m/z) 265 (M++1-85).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1.[CH3:15][NH2:16]>>[CH3:15][NH:16][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: CNc1ccc2c([N+](=O)[O-])cccc2n1

Procedure:
1.0 g (4.8 mmol) of 2-chloro-5-nitroquinoline and 20 ml of 2 M methanolic methylamine solution are heated in a pressure vessel for 8 hours to 120° C. The batch is concentrated by evaporation after the addition of toluene. The residue is purified by column chromatography on silica gel with hexane-ethyl acetate: 580 mg of product.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[NH2:29][C:30]1[C:31]([C:45](O)=[O:46])=[N:32][C:33]([C:37]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=2[F:44])=[C:34]([F:36])[CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:45]([C:31]3[C:30]([NH2:29])=[CH:35][C:34]([F:36])=[C:33]([C:37]4[C:38]([F:44])=[CH:39][CH:40]=[CH:41][C:42]=4[F:43])[N:32]=3)=[O:46])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)c(F)cc1N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (6.0 mg, 0.015 mmol), 3-amino-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (4.9 mg, 0.018 mmol), HATU (15 mg, 0.038 mmol), DMF (0.036 mL) and DIPEA (6.0 mg, 0.046 mmol) were mixed together and stirred at room temperature for 16 h. The mixture was filtered, concentrated under reduced pressure, and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the sub-title compound as a colorless gum (4 mg, 41%). LCMS calc. for C32H36F3N6O5 (M+H)+: m/z=641.3. Found: 641.0.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:17])[CH:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:15]>CN(C=O)C.[Cl-].[Na+].O>[CH3:5][O:6][C:7](=[O:17])[CH:8]([N:1]=[N+:2]=[N-:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:15]
Reactant: COC(=O)C(Br)c1ccccc1I
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(N=[N+]=[N-])c1ccccc1I
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of NaN3 (10.6 g, 163 mmol) in DMF (100 mL) is added bromo-(2-iodophenyl)-acetic acid methyl ester (19.3 g, 54.4 mmol) and the mixture is stirred at RT for 18 h. Brine is added and the mixture is extracted with ether (10×100 mL). The combined organic layers are washed with brine and dried over sodium sulfate. The solvent is removed under reduced pressure to afford the title compound which is used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1([N:19]2[C:27]3[C:22](=[C:23](O)[CH:24]=[C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:26]=3)[CH:21]=[CH:20]2)[CH2:18][CH2:17]1.N1C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[CH:16]1([N:19]2[C:27]3[C:22](=[C:23]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:24]=[C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:26]=3)[CH:21]=[CH:20]2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)c1cc(O)c2ccn(C3CC3)c2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c2ccn(C3CC3)c2c1
Reaction time: 0.5 h

Procedure:
In a 500-mL egg plant-type flask, a chloroform (50 mL) solution of trifluoromethanesulfonic acid anhydride (6.30 mL, 37.5 mmol) was dropwise added to a chloroform (100 mL) solution of ethyl 1-cyclopropyl-4-hydroxy-1H-indole-6-carboxylate (6.12 g, 25 mmol) and pyridine (6.06 mL, 75 mmol) with cooling with ice, and stirred at that temperature for 30 minutes, then poured into aqueous hydrochloric acid solution, extracted with chloroform, washed with aqueous saturated sodium hydrogencarbonate solution, and dried with sodium sulfate. The reaction solution was filtered, concentrated, and purified through silica gel column chromatography (Biotage [SiO2, 40+M]) with a hexane/ethyl acetate developer system to obtain the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[NH3:19]>C1COCC1>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([NH2:19])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1csnc1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2.92 g (0.010 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride in 10 ml of THF was added to a solution of excess ammonia gas in THF stirred in a dry ice acetone bath. The mixture was slowly warmed to 23° with stirring. The solid NH4Cl was removed by filtration, and the filtrate was concentrated to about 20 ml. Then 100 ml of ether was added, and the solution was extracted with two portions of 10% Na2CO3 solution and once with saturated NaCl solution. The ether layer was dried (CaSO4) and concentrated to 2.25 g (83%) of white solid, m.p. 141°-141.5°; infrared (mineral oil mull) 2.92, 3.11, 6.09, 6.11μ.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:10]1[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[N:14][CH:15]=1)=O.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:42])[CH3:41])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[OH-].[K+].[ClH:45]>CCO>[ClH:45].[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:35]=[CH:36][C:37]([C:40](=[O:42])/[CH:41]=[CH:8]/[C:10]3[CH:15]=[N:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=3)=[CH:38][CH:39]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1ccc(/C=C/C(=O)O)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid trifluoroacetate (272 mg, 0.93 mmol), 4-(4-acetyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (obtained as described in Preparation 9, 283 mg, 0.93 mmol) and 1.7 M KOH (0.820 ml) in EtOH (10 ml) was stirred at 0° C. for 8 h and then at room temperature for 6 days. The mixture was acidified with 10% HCl until reaching a pH value of 3 and the resulting precipitate was filtered to give 184 mg of 4-(4-{(E)-3-[6-((E)-2-carboxy-vinyl)-pyridin-3-yl]-acryloyl}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester hydrochloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.O.S(OCC)(O[CH2:20][CH3:21])(=O)=O.[OH-].[Na+]>COCCOC>[CH2:20]([CH:2]([OH:1])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:21]
Reactant: O=[N+]([O-])c1cc(NCCO)ccc1O
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CCC(O)CNc1ccc(O)c([N+](=O)[O-])c1
Temperature: 5 °C

Procedure:
39.6 g (200 mmol) 4-(2-hydroxyethylamino)-2-nitrophenol is added to a mixture of 150 ml water and 15 ml 1,2-dimethoxyethane. 33.9 g (220 mmol) diethyl sulfate is added dropwise at an internal temperature of 60° C. so that the pH of the solution is maintained between 6 and 8 by simultaneous dropwise addition of 10% sodium hydroxide (ca. 62 ml). After complete reaction, the solution is filtered through a pleated filter and cooled with stirring to 5° C. The product is allowed to crystallize.