Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[Br:2][C:3]1[C:4]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([Cl:9])[S:6][C:7]=1[Cl:8]>>[Br:2][C:3]1[C:4]([S:10]([NH2:1])(=[O:12])=[O:11])=[C:5]([Cl:9])[S:6][C:7]=1[Cl:8]
Reactant: N
Reactant: O=S(=O)(Cl)c1c(Cl)sc(Cl)c1Br
Product: NS(=O)(=O)c1c(Cl)sc(Cl)c1Br
Reaction time: 15 h

Procedure:
90 ml of an aqueous solution of NH3 (32%) is added at room temperature to a solution of 8.88 g of 4-bromo-2,5-dichloro-thiophene-3-sulfonylchloride in 120 ml of EtAc. The mixture obtained is stirred for ca. 15 hours. Two phases obtained are separated, the organic layer is washed with 1 N HCl and H2O, and dried. Solvent of the organic phase obtained is evaporated. 4-Bromo-2,5-dichloro-thiophene-3-sulfonamide is obtained in the form of a white powder. m.p. 113-117°; 13C—NMR (CDCl3): δ=108.287; 125.342; 130.404; 135.716.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:20]([O:22]C)=[O:21].O[Li].O>C1COCC1.CO.O>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1sc2ncn(CCN3CCCC3=O)c(=O)c2c1C
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)sc2ncn(CCN3CCCC3=O)c(=O)c12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
Methyl 5-methyl-4-oxo-3-(2-(2-oxopyrrolidin-1-yl)ethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (0.5 g, 1.5 mmol) was dissolved in a mixture of THF-MeOH—H2O (10 mL-3 mL-3 mL) followed by the addition of LiOH—H2O (0.250 g). The mixture was stirred at RT over night. The solvent evaporated and the residue was dissolved in 4 mL of water and then acidified with 2N HCl to pH˜3. The solid was filtered off, dried to gave 0.290 g of 5-methyl-4-oxo-3-(2-(2-oxopyrrolidin-1-yl)ethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, in 60% yield.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29]1[CH:30]=[CH:31][C:32]([F:38])=[C:33](B(O)O)[CH:34]=1)[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:31]4[CH:30]=[C:29]([O:28][CH2:26][CH3:27])[CH:34]=[CH:33][C:32]=4[F:38])[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(F)c(-c2cccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C(C)C)c2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 5-ethoxy-2-fluorophenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(5′-ethoxy-2′-fluoro-biphenyl-3-yl)-3-isopropyl-imidazolidin-2-one as a light yellow oil. MS: 483.2 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:23](=[O:24])[O:25][CH2:26][CH3:27])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: NC1CCN(c2ccc(Br)cc2)CC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1CCN(c2ccc(Br)cc2)CC1
Reaction time: 2 h

Procedure:
1-(4-Bromophenyl)piperidin-4-amine (255 mg) and triethylamine (280 μL) are dissolved in dichloromethane (3 mL), treated with ethyl chloroformate (105 μL) and stirred for 2 hours. The mixture is partitioned between dichloromethane and water. The organic phase is washed with water and the combined aqueous phases are extracted with dichloromethane. The organic phases are combined, washed with brine and dried (MgSO4). The solvents are evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:50) to give the title compound. LC (method 2): tR=1.04 min; Mass spectrum (ESI+): m/z=327 [M+H]+.
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.C(N1CCNCC1)CC1C=CC=CC=1.Br[C:26]1[C:31]([F:32])=[CH:30][C:29]([O:33][CH3:34])=[C:28]([F:35])[CH:27]=1.[CH:36]1([CH2:42][CH2:43][CH2:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([CH2:42][CH2:43][CH2:44][CH:45]2[CH2:46][CH2:47][N:48]([C:26]3[CH:27]=[C:28]([F:35])[C:29]([O:33][CH3:34])=[CH:30][C:31]=3[F:32])[CH2:49][CH2:50]2)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: C1CCC(CCCC2CCNCC2)CC1
Reactant: COc1cc(F)c(Br)cc1F
Agent: COc1ccc(Br)cc1C
Agent: c1ccc(CCN2CCNCC2)cc1
Product: COc1cc(F)c(N2CCC(CCCC3CCCCC3)CC2)cc1F
Yield: 98.2 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-phenethylpiperazine were replaced with 4-bromo-2,5-difluoroanisole (338 mg) and 4-(3-cyclohexylpropyl)-piperidine (953 mg), respectively. The resulting crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=3:1) to provide 4-(3-cyclohexylpropyl)-1-(2,5-difluoro-4-methoxyphenyl)piperidine (523 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH2:10][CH2:9]2)[C:3]=1[CH:22]=[O:23].C([CH:26]1[CH2:31][N:30]([CH:32]2[CH2:35][O:34][CH2:33]2)[CH2:29][CH2:28][N:27]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)=[N:40][CH:41]=1)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:58][N:45]1[C:44](=[O:59])[C:43]([NH:42][C:39]2[CH:38]=[CH:37][C:36]([N:27]3[CH2:28][CH2:29][N:30]([CH:32]4[CH2:33][O:34][CH2:35]4)[CH2:31][CH2:26]3)=[CH:41][N:40]=2)=[CH:48][C:47]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[S:18][C:17]5[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=5[C:11]=4[CH2:10][CH2:9]3)[C:3]=2[CH:22]=[O:23])=[CH:46]1
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: CCC1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCc4c(sc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 110 °C
Yield: 16.1 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 169a (150 mg, 0.43 mmol), 3-(5-(2-ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridine-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101 l (200 mg, 0.43 mmol), Pd2(dba)3 (37 mg, 0.040 mmol), tricyclohexylphospine (120 mg, 0.43 mmol), Cs2CO3 (281 mg, 0.86 mmol), dioxane (10 mL), and water (0.1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 4 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 169b as a yellow solid (45 mg, 16%). LCMS-ESI: [M+H]+ 652
Reaction SMILES: [CH2:1]([S:6][C:7]1[N:12]=[C:11]([C:13]2[S:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](=[O:19])[N:18]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:6]([C:7]1[N:12]=[C:11]([C:13]2[S:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](=[O:19])[N:18]=2)[CH:10]=[CH:9][CH:8]=1)=[O:32])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)CCS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
2-[6-(Isoamylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.15 g, 0.44 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.10 g, 0.46 mmol) in chloroform (10 ml) was added dropwise thereto. The reaction mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from hexane-ethyl acetate to give the titled compound (0.15 g, 96%) as pale yellow amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:14])[CH2:5][C:6](Br)([N+]([O-])=O)[C:7]=1[O:8][CH3:9].[N:15]#N>C(O)C.[Pd]>[F:14][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[CH:2][C:3]=1[NH2:15]
Reactant: N#N
Reactant: COC1=C(Br)C=C(F)CC1(Br)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A 2.0 L pressure reactor was charged with 10% Pd/C (50% wet paste, 10 g). A solution of 1,5-dibromo-3-fluoro-6-methoxy-5-nitrobenzene (50 g, 0.152 mol) in ethanol (absolute grade, 1.5 L) was added to the catalyst under N2. The stirred reaction mixture was subjected to three cycles of vacuum followed by N2 purge. The reaction mixture was evacuated prior to the introduction of H2 at a pressure of 4 bars. The reaction mixture was evacuated and H2 was introduced until a pressure of 7 bars was reached. The reaction mixture was stirred at 25° C. for 48 hours, with periodic injections of H2 to maintain the internal pressure at 7 bars (note that after 24 hours, the catalyst was replaced). After the reaction had reached completion, the catalyst was removed by filtration through 2 glass microfibre pads under an atmosphere of N2 and the filtrate was concentrated to dryness under reduced pressure at 45° C. The resulting dark orange solid was dissolved in water (500 mL) and the pH of the resulting solution adjusted to >12 using aqueous NaOH (1N, 400 mL). The resulting brown suspension was extracted with tert-butylmethylether (2×1 L). The combined organic extracts were washed with water (500 mL), dried over sodium sulfate, filtered and concentrated in vacuo at 40° C. to afford 2-Fluoro-5-methoxyaniline (18.0 g, 84%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[N:13]=1.C(N(CC)CC)C.[Cl:38][C:39]1[S:43][C:42]([S:44](Cl)(=[O:46])=[O:45])=[CH:41][CH:40]=1.O>ClCCl>[Cl:38][C:39]1[S:43][C:42]([S:44]([O:30][C:27]2[CH:26]=[CH:25][C:24]([N:10]3[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:15])[N:13]=[C:9]3[C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[CH:29][CH:28]=2)(=[O:46])=[O:45])=[CH:41][CH:40]=1
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)c2ccc(Cl)s2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide, prepared as described in Ex. 2, Step 1 (100 mg, 0.22 mmol) and triethylamine (0.16 ml, 1.12 mmol) in dichloromethane (2.5 ml) were cooled to −78° C. 5-Chlorothiophen-2-sulfonyl chloride (244 mg, 1.12 mmol) in dichloromethane (2.5 ml) was carefully added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h, and at room temperature overnight. Water was added to the reaction, the phases were separated and the organic phase washed with water and dried. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (84 mg, 60%) as a solid.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][O:10][C:11](=[O:17])[CH2:12][C:13]([CH2:15]Cl)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:26]1([CH2:32][CH2:33][OH:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][O:10][C:11](=[O:17])[CH2:12][C:13](=[O:14])[CH2:15][O:34][CH2:33][CH2:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCC1CCCCC1
Reactant: O=C(CCl)CC(=O)OCCC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCCC1CCCCC1)CC(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2.5 ml of a solution of 610 mg (1.84 mmol) of (3,3-diphenylpropane-1-yl)4-chloroacetoacetate in THF was added dropwise to a suspension of 158 mg (3.95 mmol) of sodium hydride (60% oily) in 5 ml of THF at 0° C., and they were stirred at room temperature for 20 minutes. An alkoxide solution previously prepared by adding 397 mg (3.09 mmol) of 2-cyclohexylethanol to 5 ml of a solution of 134 mg (3.36 mmol) of sodium hydride (60% oily) in THF was added to the obtained mixture at 0° C., and they were stirred at room temperature for 3 nights. THF was evaporated under reduced pressure. Water was added to the residue. The obtained mixture was washed with ethyl acetate. The aqueous layer was acidified with 2 N hydrochloric acid. After the extraction with ethyl acetate followed by drying over sodium sulfate, ethyl acetate was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: NC1N2N=C(C)C=C2N=CC=1C=O.[NH2:14][C:15]1[N:20]2[N:21]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:23]=[C:19]2[N:18]=[CH:17][C:16]=1[C:30](OCC)=[O:31]>>[NH2:14][C:15]1[N:20]2[N:21]=[C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:23]=[C:19]2[N:18]=[CH:17][C:16]=1[CH:30]=[O:31]
Reactant: CCOC(=O)c1cnc2nc(N3CCOCC3)nn2c1N
Agent: Cc1cc2ncc(C=O)c(N)n2n1
Product: Nc1c(C=O)cnc2nc(N3CCOCC3)nn12

Procedure:
Compound (12-2) was synthesized in a similar manner to the procedure for example (1-1) and (1-2), but using ethyl 7-amino-2-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (12-1) as a starting material.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:24])([CH3:23])[CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[C:27](B(O)O)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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]>[Cl:25][C:26]1[C:27]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N:8]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][C:19]([CH3:23])([CH3:24])[CH2:18]3)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[N:7]=2)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N(CC1CCOC(C)(C)C1)c1cccc(Br)n1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(CC1CCOC(C)(C)C1)c1cccc(-c2cc(F)ncc2Cl)n1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 6-bromopyridin-2-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (710 mg, 1.778 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid, PdCl2(dppf).CH2Cl2 adduct (145 mg, 0.178 mmol) in DME (7 mL) and 2M aqueous Na2CO3 solution (2.3 mL, 1.778 mmol) was heated in a sealed tube at about 98° C. for 2 hr. The mixture was cooled to ambient temperature and diluted with EtOAc (˜100 mL) and saturated aqueous NaHCOs solution. The separated organic layer was washed with saturated aqueous NaHCO3 (2×), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, 25 min, EtOAc/heptane=0/100 to 25/75over 25 min] providing (R/S)-tert-butyl 5′-chloro-2′-fluoro-2,4′-bipyridin-6-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate as a highly viscous, colorless oil. Yield: 605 mg. LCMS (m/z): 394.1 {loss of tert Bu-group}/450.2[M+H]+; Retention time=1.24 min.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[N:18]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[CH:17]=2)=[O:15])=[N:10][CH:9]=1)C.C1(CN2C3C(=CC=C(F)C=3)C(C(NC3SC=C(SCC(O)=O)N=3)=O)=C2)CC1>>[CH:27]1([CH2:26][N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:16]([C:14]([NH:13][C:11]3[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:9][N:10]=3)=[O:15])=[CH:17]2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)CCSc1cnc(NC(=O)c2cn(CC3CC3)c3cc(F)ccc23)s1
Agent: O=C(O)CSc1csc(NC(=O)c2cn(CC3CC3)c3cc(F)ccc23)n1
Product: O=C(O)CCSc1cnc(NC(=O)c2cn(CC3CC3)c3cc(F)ccc23)s1

Procedure:
3-{2-[(1-Cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester was hydrolysed according to the procedure given in the procedure for the synthesis of {2-[(1-cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol-4-ylsulfanyl}-acetic acid
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])[C:3]=1[CH3:32]>[OH-].[Pd+2].[OH-]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[CH2:16][CH:17]2[CH2:18][CH2:19]2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([OH:24])=[O:23])[C:3]=1[CH3:32]
Reactant: Cc1c(Cl)nc(NC[C@H]2CCCCN2CC2CC2)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Product: Cc1c(Cl)nc(NC[C@H]2CCCCN2CC2CC2)c(=O)n1CC(=O)O

Procedure:
The title compound was prepared by a similar method to preparation 44 from benzyl 2-[3-chloro-5-({[(2R)-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate [see preparation 71] and palladium hydroxide. To afford the product as a yellow foam, (100%). LRMS: m/z=369 (MH+).
Reaction SMILES: C([NH:4][C@@H:5]1[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([CH2:21][OH:22])[O:15][C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.Cl.[CH3:24][C:25]([CH:27]1[C:33](=[O:34])[CH2:32][C:31]([CH3:36])([CH3:35])[CH2:30][C:28]1=[O:29])=O.C(N(CC)C(C)C)(C)C>[OH-].[Na+]>[CH3:35][C:31]1([CH3:36])[CH2:32][C:33](=[O:34])[C:27](=[C:25]([NH:4][C@@H:5]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([CH2:21][OH:22])[O:15][C@@H:6]2[O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:24])[C:28](=[O:29])[CH2:30]1
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Reactant: CC(=O)N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: CC(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Yield: 57.7 %

Procedure:
A solution of Benzyl 2-Acetamido-2-deoxy-α-D-glucopyranoside (4.70 g, 15.11 mmol) in 1 M NaOH solution was refluxed at 120° C. for 15 h. The reaction mixture was cooled to room temperature, neutralised with 1 M HCl solution and concentrated. The residue was dissolved in dry ETOH (50 ml) and filtered. 2-Acetyldimedone (4.11 g, 22.6 mmol) and N,N-diisopropylethylamine (2 ml) were added to the filtrate, and the mixture was refluxed for 2 h. The reaction mixture was evaporated to dryness, and the residue was taken up in EtOAc (50 ml), washed with 1M KHSO4 solution, brine, and evaporated to give Benzyl 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-α-D-glucopyranoside (7) (3.78 g, 58%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.O.[NH2:16][NH2:17].O1CCOCC1>O>[NH:16]([C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1)[NH2:17]
Reactant: NN
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)n(-c2ccc(NN)nn2)n1

Procedure:
A mixture of 34.2 g. of 3-chloro-6-(3,5-dimethyl-1-pyrazolyl)-pyridazine, 100 ml of 72% hydrazine hydrate and 200 ml of dioxane is stirred at 90°-95° C. for 14 hours, then the mixture is poured into 1 liter of water, extracted three times with 150 ml of chloroform each, and the combined organic phases are dried over magnesium sulphate. After evaporation of the solvent, the residue is recrystallized from isopropanol. Yield: 27 g /80%/; m.p.: 142°-143° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[N:7]1([CH2:12][CH2:13][O:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:20])=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=[CH:8]1>C(Cl)(Cl)Cl>[C:4]([O:25][CH2:24][CH2:23][CH2:22][O:21][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[CH:27][CH:26]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: O=C(OCCCO)c1ccc(OCCn2ccnc2)cc1
Reactant: C=C1CC(=O)O1
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(=O)OCCCOC(=O)c1ccc(OCCn2ccnc2)cc1
Yield: 78 %

Procedure:
After adding at room temperature 4.1 ml of diketene dropwise to 10 g of 3-hydroxypropyl 4-[2-(1-imidazolyl)ethoxy]benzoate dissolved in 300 ml of chloroform, the resultant mixture was stirred for further 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 10.1 g of 3-[4-[2-(1-imidazolyl)ethoxy]benzoyloxy]propyl acetoacetate as colorless crystals (m.p. 49.5°-51.5° C.; yield: 78%)
Reaction SMILES: [CH3:1][C:2]1([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[C:3]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=3)[CH:8]=2)[C:3]1=[O:21]
Reactant: CCOC(=O)CC1(C)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC1(C)CCc2cc(-c3ccc([N+](=O)[O-])cn3)ccc2C1=O
Yield: 101 %

Procedure:
Pd(PPh3)4 (0.248 g, 0.215 mmol) was added to a solution of 3E (1.6 g, 4.3 mmol) in 20 mL of 1,4 dioxane-H2O (3:1) mixture under argon atmosphere, followed by cesium carbonate (4.2 g, 12.89 mmol) and 2-bromo-5-nitropyridine (0.872 g, 4.3 mmol). The mixture was degassed for 5 min. The reaction mixture was refluxed for 3 h, and solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The separated organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The product was purified by triturating in ethanol to afford the title compound (1.6 g, 69%) as a solid. 1H NMR (400 MHz, CDCl3): δ 9.52 (d, J=2.6 Hz, 1H), 8.57 (dd, J1=2.6 Hz, J2=8.7 Hz, 1H), 8.20 (d, J=8.2 Hz, 1H), 8.02 (s, 1H), 7.97 (dd, J1=3.2 Hz, J2=8.0 Hz, 2H), 4.10 (q, J=7.2 Hz, 2H), 3.19 (m, 1H), 3.06 (dt, J1=17.2 Hz, J2=4.4 Hz, 1H), 2.98 (d, J=15.6 Hz, 1H), 2.56-2.43 (m, 2H), 2.00 (dt, J1=13.5 Hz, J2=4.6 Hz, 1H), 1.31 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). ESI-MS m/z: 369 (M+H)+.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5].[CH3:23]O>S(Cl)(Cl)=O>[ClH:1].[NH2:2][CH:3]([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)[C:4]([O:6][CH3:23])=[O:5]
Reactant: CO
Reactant: CCCCCCCCc1ccc(CCC(N)C(=O)O)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCc1ccc(CCC(N)C(=O)OC)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-Amino-4-(4-octylphenyl)butanoic acid hydrochloride (20 g) in methanol (500 ml), thionyl chloride (7.2 ml) was added under ice-cooling and the mixture was left standing overnight. The reaction mixture was concentrated under reduced pressure to give the subject compound (16 g).