Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]([CH2:8][NH2:9])[CH2:6][CH:5]([O:10][CH3:11])[O:4]1.[C:12](Cl)(=[O:14])[CH3:13]>>[C:12]([NH:9][CH2:8][CH:7]1[CH2:6][CH:5]([O:10][CH3:11])[O:4][CH:3]1[O:2][CH3:1])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: COC1CC(CN)C(OC)O1
Product: COC1CC(CNC(C)=O)C(OC)O1

Procedure:
4.0 g of 2,5-dimethoxy-3-aminomethyltetrahydrofuran and 1.75 ml of acetyl chloride were reacted as in Example 89a. 3.7 g of impure product were obtained and were immediately reacted further.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[CH:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:26])[CH3:25]>O1CCOCC1.O>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:30]2[CH2:31][CH2:32][N:27]([CH:24]([CH3:26])[CH3:25])[CH2:28][CH2:29]2)[CH:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2cc(N)c([N+](=O)[O-])cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 154) in dioxane (2 mL) was added with N-isopropylpiperazine (4 mmol). The resulting mixture was heated at reflux for 10 h. The reaction mixture was cooled to room temperature and diluted with water (20 mL) with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-N-(1H-indazol-6-yl)-2-(4-isopropyl-piperazin-1-yl)-5-nitro-benzamide as a yellow solid.
Reaction SMILES: [C:1]1([C:11]2[CH:20]=[C:14]3[NH:15][CH:16]=[CH:17][C:18](=O)[N:13]3[N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:18]1[N:13]2[N:12]=[C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH:20]=[C:14]2[N:15]=[CH:16][CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc[nH]c2cc(-c3cccc4ccccc34)nn12
Product: Clc1ccnc2cc(-c3cccc4ccccc34)nn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
2-(naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (4.0 g, 15 mmol) is heated in phosphoryl chloride (28 mL) in a sealed vial at 105° C. and stirred for 5 hours. The crude reaction mixture is cooled to room temperature and poured slowly over ice. The resulting solid is collected on a Buchner funnel to provide 7-chloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidine (4.3 g, yield 100%). LCMS: (AA) M+1 280.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11](N)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.O.CCOC(C)=O.[BrH:21]>>[Br:21][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: Br
Reactant: COc1cc(N)c2ncccc2c1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Br)c2ncccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To 5.05 g (29.0 mmol) 6-methoxy-quinolin-8-yl-amine in 25 mL of 48% HBr at 0° C. is added a solution of 2.60 g (37.7 mmol) and 20 mL H2O. After stirring at 0° C. for 15 min, the resulting mixture is added dropwise to a 75° C. solution of 5.0 g (34.8 mmol) CuBr and 60 mL of 48% HBr. After 5.5 h, the reaction mixture is neutralized with 150 mL of ice cold 5N NaOH, the resulting mixture is stirred with 300 mL EtOAc and filtered through a pad of celite. This mixture is extracted 2×100 mL EtOAc, and the combined organics are washed with 1×200 mL H2O, 1×200 mL brine, dried over Na2SO4, filtered, and the volatiles are evaporated. Flash chromatography on SiO2 gel, eluting with hexanes/EtOAc (4/1 to 1/1), gives 4.23 g (17.8 mmol, a 61% yield) of the title compound as a brown oil. MS (ES) m/z 239 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][C:13]2[C:14]([N:20]=1)=[N+:15]([O-])[CH:16]=[CH:17][CH:18]=2.Cl.[OH2:22]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:20]=[C:14]2[NH:15][C:16](=[O:22])[CH2:17][CH:18]=[C:13]2[N:12]=1
Reactant: O
Reactant: COc1ccc(-c2nc3c(ccc[n+]3[O-])[nH]2)c(OC)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C2=NC3=CCC(=O)NC3=N2)c(OC)c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Four grams of 2-(2,4-dimethoxy-phenyl)-imidazo[4,5-b]pyridin-4-oxide is suspended in 40 ml of acetic anhydride and refluxed for 2.75 hours. After cooling the mixture is poured onto 150 ml of ice, 25 ml of 6N hydrochloric acid are added, and the mixture is stirred at 120° C. for 30 minutes. It is cooled to ambient temperature, 50 ml of water are added, and the precipitate is subjected to suction filtration. The product is purified by chromatography on silica gel [eluant: methylene chloride/methanol (100:0 to 100:10)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][NH:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[N:32]=[C:31]([C:33](Cl)=[O:34])[CH:30]=[CH:29][N:28]=1)(=O)=O.[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:13][N:12]2[C:33]([C:31]2[CH:30]=[CH:29][N:28]=[C:27]([S:24][CH3:23])[N:32]=2)=[O:34])=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nccc(C(=O)Cl)n1
Reactant: CC(C)(C)C(=O)OC1CNN(C(=O)Cc2ccc(F)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CSc1nccc(C(=O)N2CC(OC(=O)C(C)(C)C)CN2C(=O)Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To a solution of 2,2-dimethyl-propionic acid 1-[2-(4-fluorophenyl)acetyl]-pyrazolidin-4-yl ester, 32, (427 mg, 1.79 mmol) in dichloromethane (3 mL) is added 2-methylsulfonyl-pyrimidine-4-carbonyl chloride (676 mg, 3.58 mmol) followed by dropwise addition of a 1.0 N aqueous solution of sodium hydroxide (6 mL). The mixture is vigorously stirred at room temperature for 12 hours. The reaction is diluted with dichloromethane (25 mL) and washed with water (25 mL). The aqueous layer is back-extracted with dichloromethane (25 mL). The combined organic layers are washed with a saturated aqueous solution of sodium bicarbonate (25 mL) and brine (25 mL), dried, filtered and concentrated in vacuo. The resulting crude material is purified over silica (1:1 hexane/ethyl acetate to 100% ethyl acetate) to afford 464 mg (96.6% yield) of the desired product as a brown, viscous oil.
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([S:19][C:20]#[N:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)C=CC=CC=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1>>[S:19]([C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([NH:9][C:8]([NH:32][CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[O:22])[S:11][C:12]=2[CH:18]=1)[C:20]#[N:21]
Reactant: N#CSc1ccc2nc(NC(=O)Oc3ccccc3)sc2c1
Reactant: CN1CCN(CCN)CC1
Product: CN1CCN(CCNC(=O)Nc2nc3ccc(SC#N)cc3s2)CC1

Procedure:
The 1-(6-thiocyanato-1,3-benzothiazol-2-yl)-3-[2-(4-methylpiperazin-1-yl)ethyl]urea was prepared according to the method described in Example 9c, but using 982 mg of phenyl(6-thiocyanato-1,3-benzothiazol-2-yl)carbamate and 473 mg of 2-(4-methylpiperazin-1-yl)ethylamine. The residue obtained is chromatographed on a Merck cartridge (25 g of silica 15-40 μm), elution being carried out with a 90/10 mixture of dichloromethane/methanol. 1.13 g of 1-(6-thiocyanato-1,3-benzothiazol-2-yl)-3-[2-(4-methylpiperazin-1-yl)ethyl]urea are thus recovered in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].C(OCC)(=O)C.CCCCCC>CO>[Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]([OH:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCNc2nc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: OC1CCNc2nc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
7-Bromo-2,3-dihydro-1H-[1,8]naphthyridin-4-one (1.459 g) was placed in methanol (25 mL) and sodium borohydride (437 mg, 1.84 eq) was added portionwise over five (5) minutes. The reaction was stirred at room temperature for 15 minutes and then quenched with acetic acid (3 mL). The reaction mixture was concentrated under reduced pressure and the residue was taken up in toluene (100 mL). Silica gel was added and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography using dry loading and a gradient of 0-80% ethyl acetate/hexane as the eluting solvent gave the title compound as a pale yellow solid (78% yield). M.p. 130-131° C., LCMS: m/z=230.71 (M+H+), 1H-NMR (MeOH-d4, 400 MHz) δ 1.80-1.94 (m, 2H), 3.33-3.48 (m, 2H), 4.66 (t, J=4.4 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][O:8][CH2:9][CH:10]2[CH2:12][S:11]2)=[CH:5][CH:4]=1.[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:35]CCl>>[Cl:35][CH2:12][CH:10]([S:11][C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:9][O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=1
Reactant: ClCCl
Reactant: COc1ccc(COCC2CS2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccc(COCC(CCl)SC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(((4-Methoxybenzyl)oxy)methyl)thiirane (496 mg, 2.359 mmol) was added to a solution of trityl chloride (598 mg, 2.144 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 16 hours, then evaporated under vacuum. Purification by chromatography on silica, eluting with 0-5% EtOAc/hexane, gave a crude material which was triturated with methanol to afford the title compound.
Reaction SMILES: [C:1]([NH2:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:12](N(C(C)C)C(C)C)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[CH3:12][NH:11][C:1]([C@@H:2]([O:3][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:10]
Reactant: NC(=O)C(O)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CNC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
To the solution of mandelic acid amide in dichloromethane is added N-ethyldiisopropylamine (1.1 equivalents) at RT. Subsequently p-toluene sulfonic acid chloride (1.0 equivalent) is added keeping the temperature below 25° C. The reaction mixture is stirred at RT until a satisfactory conversion is reached and then washed with saturated sodium bicarbonate solution and water. After a solvent switch to ethyl acetate the solution is concentrated, cooled to −2° C. and the precipitate filtered. The crystals are washed with cooled ethyl acetate and dried in vacuo at 40° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:4][N:5]([C:7]2[N:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]([NH:11][CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]([OH:17])[C:14](O)=[O:15])=[O:10])[CH:6]=1.Cl.[CH3:36][O:37][NH2:38]>>[Cl:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:4][N:5]([C:7]2[N:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]([NH:11][CH:12]([CH:13]([OH:17])[C:14]([NH:38][O:37][CH3:36])=[O:15])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:10])[CH:6]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc(Cl)c(-c2ccccc2)n1
Reactant: CON
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(Cl)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(4-Chloro-3-phenyl-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 506.2
Reaction SMILES: [CH2:1](O)[CH3:2].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([OH:11])=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([O:11][CH2:1][CH3:2])=[O:10]
Reactant: O=C(O)c1ccco1
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccco1
Yield: 88.3 %

Procedure:
Toluene (100 ml), ethanol (12.33 g, 267.67 mmol) and 2-furancarboxylic acid (25 g, 223.05 mmol) were added into a 200-ml flask in this order at room temperature and then p-toluenesulfonic acid monohydrate (6.65 g, 34.96 mmol) was charged thereto. The solution was gently heated and subjected to reflux dehydration for 3 to 5 hours. After reflux dehydration, the solution was cooled to around room temperature, added with triethylamine (5.64 g, 55.76 mmol) at room temperature, stirred and then added with silica gel. After stirring for a while, the silica gel was filtered off. After the solvent of the filtrate was removed in vacuum distillation, ethyl 2-furancarboxylate (27.60 g, 88%) was isolated in distillation.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:11][CH3:12])=[C:7]([CH2:9][NH2:10])[CH:8]=1.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:21].[OH2:35]>O1CCCC1>[ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:11]([CH3:12])(=[O:21])=[O:35])=[C:7]([CH2:9][NH2:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O
Reactant: CSc1ccc(Br)cc1CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Br)cc1CN
Reaction time: 14 h

Procedure:
(Step 4) To a solution of 1-[5-bromo-2-(methylsulfanyl)phenyl]methanamine hydrochloride obtained in Step 3 (6.25 g) and triethylamine (4.72 g) in tetrahydrofuran (150 ml) was added di-t-butyl dicarbonate (7.62 g) at room temperature. The mixture was stirred at the same temperature for 14 hr, treated with water, and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (200 ml), and m-chloroperbenzoic acid (14.4 g, containing water: Wako Pure Chemical Industries, Ltd.) was added at room temperature. The mixture was stirred at the same temperature for 4 hr, and treated with aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=2:1). The obtained residue was dissolved in methanol (100 ml), 4N hydrogen chloride-ethyl acetate solution (15 ml) was added, and the mixture was stirred at 60° C. for 1 hr, and concentrated under reduced pressure to give crystals. The obtained crystals were washed with ethyl acetate to give 1-[5-bromo-2-(methylsulfonyl)phenyl]methanamine hydrochloride (5.85 g) as a solid.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4](Cl)=[O:5].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)=[O:5])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: NCc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1ccccc1C(=O)NCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
To a mixture of phthaloyl dichloride (3 g, 15 mmol, 1 eq) in toluene (HPLC grade, 20 mL), cooled to 0° C., was added slowly a solution of 4-fluorobenzylamine (4.62 g, 37 mmol, 2.2 eq) in toluene (5 mL). After stirring at ambient temperature for 24 h, the reaction mixture was concentrated in vacuo to remove toluene. The resultant residue was dissolved in DCM, washed with brine and dried over Na2SO4. The organic layer was evaporated under reduced pressure. Recrystallization from DCM:hexane afforded the desired compound (4.6 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ 9.3 (s, 2H), 9.1 (s, 2H), 8.64 (s, 1H), 7.39-7.34 (m, 4H), 7.17-7.12 (m, 4H), 4.48-4.46 (d, 4H). MS (ESI): 381.2 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(COc2ccnc(NC(=O)OC(C)(C)C)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1csc(COc2ccnc(N)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
tert-Butyl N-{4-[(4-isopropyl-1,3-thiazol-2-yl)methoxy]-2-pyridyl}carbamate (706 mg, 2.202 mmol) dissolved in dichloromethane (20 ml) was added dropwise with trifluoroacetic acid (20 ml) under ice cooling, then warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with chloroform, then neutralized with saturated aqueous sodium hydrogencarbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=50:1→30:1→20:1) to obtain 331 mg (66%) of the title compound.
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]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][CH:36]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[OH-].[K+]>CCO>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[O:43])/[CH:42]=[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:37][CH:36]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1ccc(/C=C/C(=O)O)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Temperature: 4 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid trifluoroacetate (described in Example 45 STEP A, 206 mg, 0.71 mmol), 4-(4-acetyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (described in Preparation 12, 368 mg, 1.16 mmol) and 1.7 M KOH (2 ml) in EtOH (12 ml) was stirred at 4° C. overnight. The resulting precipitate was filtered and washed with AcOEt to give 250 mg of 4-(4-{(E)-3-[6-((E)-2-carboxy-vinyl)-pyridin-3-yl]-acryloyl}-benzyl)-piperazine-1-carboxylic acid tert-butyl ester as its potassium salt.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH2:16][C:17]([NH2:19])=[O:18].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29](=O)[C:30]([O-])=[O:31])=[CH:21]1.C(O[K])(C)(C)C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[CH:4][C:3]=1[C:16]1[C:17](=[O:18])[NH:19][C:30](=[O:31])[C:29]=1[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:20][CH:21]=1
Reactant: O=C([O-])C(=O)c1c[nH]c2ccccc12
Reactant: Cc1cc(N2CCN(C)CC2)cc(CC(N)=O)c1Cl
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCN(C)CC2)cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c1Cl
Temperature: 35 °C
Reaction time: 8 h

Procedure:
2-[2-Chloro-3-methyl-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide (211 mg, 0.75 mmol) and 3-indoleglyoxylate (270 mg, 1.35 mmol) are dissolved in THF (5 mL). A solution of 1.0 M tert-BuOK in THF (2.98 mL, 4 eq) is added and the mixture is stirred at 35° C. overnight. The reaction is diluted with AcOEt (20 mL) and washed with H2O (20 mL) and brine (10 mL). The organic phase is dried over Na2SO4 and the solvent is evaporated. The residue is purified by FCC (AcOEt/AcOH/H2O 7:1:1) to afford the title compound in the form of its acetate salt. 1H NMR (DMSO, 400 MHz) δ 2.16 (s, 3H), 2.31 (s, 3H), 2.32-2.38 (m, 4H), 2.97-3.10(m, 4H), 6.61 (d, J=8.0 Hz, 1H), 6.71-6.77 (m, 2H), 7.04 (d, J=2.8 Hz, 1H), 7.08(dd,J=7.4, 7.2 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.98 (d, J=1.5Hz, 1H), 11.05 (br s, 1H), 11.90(br s, 1H); ES-MS: 435 [M+H]+.
Reaction SMILES: [C:1](/[C:4](/[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)([OH:3])=O.[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[NH2:34]>>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19](/[C:4](/[C:1](=[O:3])[NH:34][C:30]2[S:29][CH:33]=[CH:32][N:31]=2)=[CH:5]\[CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:8][CH2:7]2)=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C(/C(=O)O)c2ccc(S(C)(=O)=O)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(/C=C(/C(=O)Nc2nccs2)c2ccc(S(C)(=O)=O)cc2)CC1

Procedure:
(E)-tert-Butyl 4-[2-carboxy-2-(4-methanesulfonylphenyl)vinyl]piperidine-1-carboxylate (Preparation 35, 3.17 g, 7.7 mmol) was condensed with thiazol-2-ylamine (2.32 g, 23.2 mmol), employing the procedure described in EXAMPLE 65, to give (E)-tert-butyl 4-[2-(4-methanesulfonylphenyl)-2-(thiazol-2-ylcarbamoyl)vinyl]piperidine-1-carboxylate: m/z (ES+)=492.2 [M+H]+. TFA (20 mL) was added to a stirred solution of the abovementioned carbamate (1.40 g, 2.8 mmol) in CH2Cl2 (20 mL). After 2 h, the solution was concentrated in vacuo. The residue was dissolved in H2O, then the solution was washed with EtOAc. The aqueous layer was concentrated to furnish the trifluoroacetate salt of (E)-2-(4-methanesulfonylphenyl)-3-piperidin-4-yl-N-thiazol-2-ylacrylamide: m/z (ES+)=392.1 [M+H]+. A stirred solution of imidazole (102 mg, 1.5 mmol) in anhydrous DMF (1 mL) was treated with Me3SiCl (114 μL, 0.9 mmol). After 20 min, the above trifluoroacetate salt (150 mg, 0.3 mmol) was added. The mixture was stirred for 16 h, before being partitioned between CH2Cl2 and 1M HCl. The organic layer was dried (MgSO4), filtered, concentrated, and flash chromatographed (EtOAc-MeOH, 97:3 to 19:1). Recrystallisation (EtOAc) of the residue gave the title compound: RTA=3.05 min; m/z (ES+)=420.2 [M+H]+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:38])[C@@H:6]([NH:16][C:17]([C:19]1[CH:23]=[C:22]([O:24][CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:21]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:20]=1)=[O:18])[CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Cl>C1COCC1>[C:12]([O:11][C:9](=[O:10])[CH2:8][CH2:7][C@H:6]([NH:16][C:17]([C:19]1[CH:23]=[C:22]([O:24][CH2:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[N:21]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:20]=1)=[O:18])[C:5]([OH:38])=[O:4])([CH3:13])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1)C(=O)O
Yield: 94.2 %

Procedure:
1 M aqueous NaOH was added to a solution of 11.8 g (S)-2-{[5-(3,3-dimethyl-2-oxo-butoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-pentanedioic acid 5-tert-butyl ester 1-methyl ester in 31 ml THF at RT. After 2 h 5 M HCl was added to bring the reaction mixture to pH 5. Extraction with DCM yielded the product as colorless solid (10.8 g).