Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[O:19][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:21][CH:22]=3)[S:17][C:10]=12.C1(C)C=CC=CC=1.C(O)C.[C:42]1([CH2:48][C:49]([N:51]=[C:52]=[S:53])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:31][C:52]([NH:51][C:49](=[O:50])[CH2:48][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[S:53])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[O:19][C:20]([CH2:23][N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[CH:21][CH:22]=3)[S:17][C:10]=12
Reactant: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)o2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=S)NC(=O)Cc6ccccc6)cc5F)c4s3)o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a 5 mL round bottom flask was added 3-fluoro-4-(2-(5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine (32 mg, 0.0713 mmol) and 1:1 toluene/ethanol (1 mL). 2-Phenylethanoyl isothiocyanate (25.3 mg, 0.143 mmol; prepared according to the procedure described by J. Org. Chem. 1964, 29, 1115-1119) was added as a solution in toluene (0.5 mL). After stirring for 30 minutes at room temperature, the crude was concentrated in vacuo. The crude was dissolved in MeOH and purified by preparative TLC, eluting with 9:1 CH2Cl2/MeOH. The product was collected at Rf 0.4 just above the unreacted starting material at Rf 0.3 to provide the product (5 mg, 10%) as a white solid. LRMS (APCI+) m/e 626 (M+1) detected; 1H NMR (CDCl3, 400 MHz) δ 9.98 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.22 (s, 1H), 7.75 (d, J=13.7 Hz, 1H), 7.62 (s, 1H), 7.45 (m, 2H), 7.24 (m, 2H), 7.07 (t, J=8.6 Hz, 2H), 6.71 (s, 1H), 6.35 (s, 1H), 3.66 (s, 2H), 2.58 (m, 8H), 2.29 (s, 3H), 1.79 (m, 4H).
Reaction SMILES: CO[Si](OC)(OC)[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([Si](OC)(OC)OC)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.CO[Si](C1C=CC(C2C=CC([Si](OC)(OC)OC)=CC=2)=CC=1)(OC)OC>C(O)(=O)C>[C:7]1([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: CO[Si](OC)(OC)c1ccc(C=Cc2ccc([Si](OC)(OC)OC)cc2)cc1
Agent: CO[Si](OC)(OC)c1ccc(-c2ccc([Si](OC)(OC)OC)cc2)cc1
Solvent: CC(=O)O
Product: C(=Cc1ccccc1)c1ccccc1
Yield: 70 %

Procedure:
The procedure of Example 1 was repeated employing 4,4′-bis(trimethoxysilyl)stilbene) in place of bis(trimethoxysilyl)biphenyl (2 g, 4.75 mmol) and using a 1% acetic acid solution (9 ml) to give a ratio of 2.94 equivalents of stilbene to 1 equivalent of acetic acid. The reaction mixture was stirred for a period of 10 days and a yellow coloured powder was recovered at 70% yield. (1.12 g, 3.32 mmol)
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].C(=O)(O)[O-:10].[Na+].OOS([O-])=O.[K+].Cl>[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O.CC(C)=O.O>[CH2:4]([CH:3]1[O:10][CH:2]1[C:1]([OH:8])=[O:7])[CH2:5][CH3:6]
Reactant: CCC/C=C/C(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: O=S([O-])OO
Solvent: O
Solvent: CC(C)=O
Product: CCCC1OC1C(=O)O
Temperature: 0 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
A flask equipped with an overhead stirrer, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with trans-2-hexenoic acid (69.8 g, 611 mmol), water (420 mL) and acetone (420 mL). Sodium bicarbonate (NaHCO3, 224 g, 2.66 mol) was then added portion-wise keeping the reaction temperature at 25±5° C. Once all of the sodium bicarbonate had been added, a solution of OXONE® (454 g, 738 mmol) in 4×10−4 M ethylenediaminetetraacetic acid disodium salt dehydrate (Na2EDTA; 1.32 L) was charged to the addition funnel and added over 90 minutes keeping the reaction temperature at 25±5° C. and the pH between 9.5 and 7.5. The reaction mixture was then allowed to stir for 16 h, after which time no (E)-hex-2-enoic acid was observed by HPLC analysis. The mixture was cooled to 0±5° C., acidified to pH 2 with 6 N HCl (515 mL, 2.8 mol) and extracted with ethyl acetate (EtOAc; 3×250 mL). The combined organic phases were dried over sodium sulfate (Na2SO4), filtered then concentrated under reduced pressure to provide the title compound (60.4 g, 76%) as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[CH3:12][C:10]1[N:9]=[C:8]([C:13]([F:16])([F:14])[F:15])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:11]=1
Reactant: CCOC(=O)c1cc(C)nc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
1.3 g (5.551 mmol) of 6-methyl-2-trifluoromethyl-pyrimidine-4-carboxylic acid ethyl ester were dissolved in 30 ml dioxane and treated with 11.1 ml (11.1 mmol) 1 N NaOH and stirred for 2 hours at RT. The reaction mixture was then treated with 11.1 ml (11.1 mmol) 1 N HCl and concentrated in vacuo. The resulting solid residue was then suspended in DCM-methanol, filtered-off, washed with additional DCM-methanol and the combined organic phases were then concentrated in vacuo, to yield 1.1 g (96%) of 6-methyl-2-trifluoromethyl-pyrimidine-4-carboxylic acid. MS: 205.1 (M−H)−.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:10]=[C:11]([NH:16][CH:17]([C:19]2[CH:20]=[C:21]([C:34]([O:36][CH3:37])=[O:35])[CH:22]=[C:23]3[C:28]=2[O:27][C:26](S(CC)=O)=[CH:25][C:24]3=[O:33])[CH3:18])[CH:12]=[C:13]([F:15])[CH:14]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[F:8][C:9]1[CH:10]=[C:11]([NH:16][CH:17]([C:19]2[CH:20]=[C:21]([C:34]([O:36][CH3:37])=[O:35])[CH:22]=[C:23]3[C:28]=2[O:27][C:26]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[CH:25][C:24]3=[O:33])[CH3:18])[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: CCS(=O)c1cc(=O)c2cc(C(=O)OC)cc(C(C)Nc3cc(F)cc(F)c3)c2o1
Reactant: C[C@H]1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C(C)Nc2cc(F)cc(F)c2)c2oc(N3CCOC[C@@H]3C)cc(=O)c2c1
Temperature: 75 °C
Reaction time: 7 h
Yield: 34.4 %

Procedure:
(S)-3-methylmorpholine (87 mg, 0.86 mmol) was added to a stirred solution of methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-(ethylsulfinyl)-4-oxo-4H-chromene-6-carboxylate (250 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.150 mL, 0.86 mmol) in acetonitrile (3 mL) at RT. The resulting brown mixture was stirred at 75° C. for 7 hours. The reaction mixture was concentrated, diluted with DCM, washed with a 1M hydrochloric acid 1M, brine dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-((S)-3-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (90 mg, 34%) as a yellow foam. Spectrum: [M−H]− 457.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[C:12]([CH3:29])([CH2:13][CH2:14][CH:15]([NH2:28])[CH2:16]3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:30]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.C(Cl)Cl.CCOC(C)=O>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:17]23[CH2:16][CH:15]([NH:28][C:38](=[O:39])[CH2:37][CH2:36][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:14][CH2:13][C:12]2([CH3:29])[CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]3)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(C23CCN(CCCc4ccccc4)CC2(C)CCC(N)C3)c1
Reactant: O=C(O)CCN1CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C23CCN(CCCc4ccccc4)CC2(C)CCC(NC(=O)CCN2CCCCC2)C3)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
To compound 24 (105 mg, 0.267 mmol) dissolved in anhydrous THF (15 mL) was added 1-piperidinepropionic acid (63 mg, 0.40 mmol), triethylamine (0.17 mL, 1.33 mmol), and BOP reagent (140 mg, 0.32 mmol), and the reaction mixture was allowed to stir at room temperature for 1.5 h. Reaction progress was monitored by TLC (50% CMA 80 in CH2Cl2). The reaction mixture was diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO3 (25 mL) followed by water (25 mL). The aqueous layers were back extracted with EtOAc (2×20 mL). The combined organic layers were washed with 1 N NaOH (25 mL), dried (MgSO4), and concentrated under reduced pressure to afford crude amide. The crude product was purified by flash chromatography (30% CMA 80 in CH2Cl2) to afford 121 mg (85%) of 25a as a shiny white solid: LCMS (ESI): m/z 532.8 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 8.77 [d, J=6 Hz, 1H], 7.15-7.30 [m, 8H], 6.72-6.75 [m, 1H], 4.24 [m, 1H], 3.82 [s, 3H], 2.76 [br, 1H], 2.65-2.68 [m, 2H], 2.42-2.56 [m, 3H], 2.32-2.37 [m, 6H], 2.07-2.30 [m, 7H], 1.62-1.83 [m, 5H], 1.59-1.61 [m, 4H], 1.48-1.59 [m, 4H], 1.25-1.27 [br, 1H], 1.21 [s, 3H]; 13C NMR (CDCl3, 300 MHz) δ 172.2, 159.2, 148.8, 142.8, 128.8, 128.7, 128.6, 126.0, 122.2, 116.2, 110.9, 62.4, 58.4, 55.6, 54.9, 54.0, 51.4, 45.5, 44.1, 38.1, 37.0, 36.8, 35.5, 34.0, 32.5, 29.2, 28.4, 26.9, 26.7, 24.6.
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.FC1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].C(O)(=O)C>O1CCCC1>[F:21][C:20]1[C:19]([F:22])=[CH:18][CH:17]=[C:16]([N+:23]([O-:25])=[O:24])[C:5]=1[CH2:4][C:3]([OH:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reaction time: 2 h
Yield: 57.4 %

Procedure:
64 g of 60% sodium hydride was added to 200 ml of tetrahydrofuran, and, while the mixed solution was stirred and cooled on ice, a solution obtained by dissolving 258 g of diethyl malonate in 400 ml of tetrahydrofuran was dropped to the mixed solution through 1 hour and 40 minutes so that the reaction temperature was kept below 20° C. Then, while the reaction solution was stirred and cooled on ice, 200 ml of tetrahydrofuran solution dissolving 142 g of 2,3,4-trifluoronitrobenzene was dropped to the reaction solution through 2 hours so that the reaction temperature was kept below 10° C. After reacting at room temperature for 2 hours, 100 ml of acetic acid was added to the reaction solution and tetrahydrofuran was removed by distillation. To the residue, 1 l of chloroform, 1.5 l of water and 100 ml of concentrated hydrochloric acid were added, and the solution was separated. The organic layer was separated from the solution, and the solvent was removed by distillation. To the residue, 250 ml of 4N hydrochloric acid and 200 ml of acetic acid were added, and the solution was heated under reflux for 11 hours. After removing 150 ml of content solution by distillation, 50 ml of acetic acid and 50 ml of water were added to the solution, and the solution was heated under reflux for 31 hours. After the solution was air-cooled, the precipitated crystal was filtered off, washed with diisopropyl ether and was dissolved in 400 ml of methanol. After treating with active carbon, the solvent was removed by distillation. The precipitated crystal was dispersed in diisopropyl ether and was filtered off to obtain 100 g of the subject compound (1) in a 56% yield.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1([S:10](Cl)(=[O:12])=[O:11])[NH:8][C:7]([Cl:9])=[CH:6][S:5]1>>[CH3:1][NH:2][S:10]([C:4]1([Cl:3])[NH:8][C:7]([Cl:9])=[CH:6][S:5]1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Reactant: CN
Product: CNS(=O)(=O)C1(Cl)NC(Cl)=CS1
Reaction time: 0.5 h

Procedure:
21 g of a 30% strength aqueous methylamine solution were added dropwise at approx. -75° C. in the course of 45 minute$ to 25.25 g (0.1 mol) Df 2,4-dichloro-thiazole-sulphonyl chloride from Example 1 in 250 ml of the cold bath was then removed and the temperature was subsequently allowed to rise to room temperature, the mixture was subsequently stirred for 30 minutes, the resulting suspension was evaporated under a waterpump vacuum, and the residue was stirred with 300 ml of water. The solid was filtered off with suction and chromatographed on silica gel (eluent toluene/EtOH 15:1) in order to remove small amounts of starting material and product which is substituted in the 2-position. 22 g of product were obtained (89% of the theoretical yield) m.p.: 72-3° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][NH:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][N:5]([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1cccs1)OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(CN(Cc1cccs1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
2,2-Dimethoxy-N-(thiophen-2-ylmethyl)ethanamine (5 g, 24 mmol) was dissolved in anhydrous dichloromethane and pyridine (5.82 mL, 72 mmol) was added to the reaction. The mixture was cooled down to 0° C. and was treated with para-toluenesulfonyl chloride (5.6 g, 29 mmol) added portionwise. The reaction was allowed to stir at 0° C. for 4 h and was then washed 3 times with 1 N HCl, water and a saturated solution of sodium bicarbonate. The organic layer was dried with sodium sulfate. Purification by flash chromatography using a gradient of 5-30% ethyl acetate in hexanes yielded a white crystalline solid (7.4 g) MS (M+H)+ 356.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([CH:42]=[C:43]([F:46])[C:44]=1F)[C:38]([O:40][CH3:41])=[O:39].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:44]2[C:43]([F:46])=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][C:35]=2[F:34])[CH2:10]1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(F)c(F)c(F)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(F)c(N2CCC(c3ccccc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(F)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
A mixture of 150 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate, 96.2 mg of methyl 3,4,5-trifluorobenzoate, 93.3 mg of potassium carbonate, and 1.0 mL of DMSO was stirred at 110° C. for 1 hour. After cooling to room temperature, to the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 127 mg of methyl 4-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]-3,5-difluorobenzoate as a colorless foamy substance. ESI+: 615
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[O:5][C:4](=O)[CH:3]=1.Cl.[NH2:18][OH:19].NC1C=CC=CN=1.NO>>[OH:19][N:18]1[C:6]([CH2:8][CH:9]([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: NO
Reactant: Cc1cc(CC(C)CC(C)(C)C)oc(=O)c1
Agent: Cl
Agent: Nc1ccccn1
Product: Cc1cc(CC(C)CC(C)(C)C)n(O)c(=O)c1
Yield: 66.5 %

Procedure:
10 g of 4-methyl-6-(2,4,4-trimethylpentyl)-2-pyrone, 5 g of hydroxylamine hydrochloride and 20 g of 2-aminopyridine were heated for 26 hours to 70°C, whereupon after 17 hours a further 2 g of hydroxylamine were added. Working up was effected as usual and there were obtained 7.1 g (67 %) of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone melting at 108° C (Calc.: 5.9 % N, found 5.9 % N).
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH:4]([CH3:5])CO1.[NH:8](CCO)[CH2:9][CH2:10][OH:11]>>[OH:11][CH2:10][CH2:9][N:8]1[CH2:5][CH2:4][O:6][C:1]1=[O:7]
Reactant: CC1COC(=O)O1
Reactant: OCCNCCO
Product: O=C1OCCN1CCO
Temperature: 120 °C

Procedure:
5.1 mol of propylene carbonate were provided as an initial charge at 23° C. under a nitrogen atmosphere. 5 mol of diethanolamine were added over 30 to 120 minutes with stirring, and the temperature of the reaction mixture rose. On completion of the addition the mixture was heated to 120° C. in the course of 10 to 120 minutes and left to stir at 120° C. for 2 hours. Then a 10 to 20 mbar vacuum was applied, the temperature was raised from 120° C. to 160° C. and propylene glycol was distilled off. The N-(2-hydroxyethyl)oxazolidin-2-one obtained almost quantitatively as undistilled bottom product comprised 96 to 98% by weight of product of value and had a Hazen color number in the range from 0 to 15.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]2)(=[O:19])=[O:18])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC.O>C1COCC1>[OH:26][CH:22]1[CH2:23][CH2:24][CH2:25][N:20]([S:17]([C:4]2[S:3][CH:2]=[C:6]([C:7]3[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=3[CH3:16])[CH:5]=2)(=[O:19])=[O:18])[CH2:21]1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCCC(O)C3)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N3CCCC(O)C3)c2)s1
Temperature: -70 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
N-(5-{2-bromo-5-[(3-hydroxypiperidin-1-yl)sulfonyl]-3-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide obtained in Step I as described above (54 mg; 0.112 mmol; 1 eq), is dissolved in dry THF (5 ml) at −70° C. under an inert atmosphere. n-Butyllithium (0.15 ml; 1.6 M; 0.24 mmol; 2.20 eq) is added slowly and reaction stirred at −70° C. for 1 hour before being hydrolyzed with water (0.3 ml). Reaction is warmed up to room temperature before being concentrated to dryness. Residue is taken up with water (2 ml) and EtOAc (10 ml). The organic phases are decanted, dried over MgSO4, filtrated and evaporated. Title compound is purified by reverse preparative HPLC, affording expected Compound (48) as a white solid (20 mg; 43%).
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[CH:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-])=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])C.CCOC(C)=O.CCCCCC>C(O)C.[Pd]>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH:5]1[CH2:12][C:13]2[C:14](=[CH:15][CH:16]=[C:17]([OH:19])[CH:18]=2)[NH:20][C:4]1=[O:3])[CH3:11]
Reactant: CCOC(=O)CC(=Cc1cc(O)ccc1[N+](=O)[O-])C(=O)OCC
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1Cc2cc(O)ccc2NC1=O
Reaction time: 20 h
Yield: 43.5 %

Procedure:
A solution of 2-(5-hydroxy-2-nitro-benzylidene)-succinic acid diethyl ester (3.8 g, 12 mmol) in ethanol (35 mL) was hydrogenated over 10% Pd—C (0.8 g) at 25° C. and 1 atm. After 20 h, the catalyst was filtered through diatomaceous earth and washed with ethanol (3×35 mL). The filtrate was concentrated giving a mixture of solid and foam (2.8 g). Flash chromatography (190 g silica; 20%, then 40% EtOAc-hexane) gives the title compound (1.3 g, 45% yield) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH:32]=[CH2:33].CCN(CC)CC>CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:8][C:5]1[N:6]=[CH:7][C:2](/[CH:33]=[CH:32]/[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cn1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(/C=C/C(=O)OC(C)(C)C)cn1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2-methylpyridine (5 g, 29.06 mmol) in NMP (60 mL), were added Pd(OAc)2 (0.325 g, 1.45 mmol) and P(o-tol)3 (0.883 g, 2.9 mmol). Subsequently, a solution of tert-butyl acrylate (13.02 g, 101.7 mmol) in Et3N (16.1 mL, 116.2 mmol) was added under N2 to the above mixture and stirred at 90° C. After 16 h, water was added to the reaction mixture and extracted with Et2O (3×). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford a residue. Purification of the residue by column chromatography (SiO2, 100-200 mesh, Et2O/Pet ether 1:9) afforded the title compound. MS: 220 [M+H]+;
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[S:13][C:12]([C:14]([NH:16][C@@H:17]([CH2:22][N+:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][C:19]([O-:21])=[O:20])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[CH2:8]([C:9]1[S:13][C:12]([C:14]([NH:16][C@@H:17]([CH2:22][N+:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][C:19]([O-:21])=[O:20])=[O:15])=[CH:11][CH:10]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)c1ccc(C#Cc2ccccc2)s1
Solvent: CO
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)c1ccc(CCc2ccccc2)s1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
(R)-3-(5-(phenylethynyl)thiophene-2-carboxamido)-4-(trimethylammonio)-butanoate (15 mg, 0.04 mmol) was dissolved into MeOH (3 mL). The solution was purged with nitrogen and 10% palladium on carbon (5 mg) was added. The vessel was purged with hydrogen and stirred for 1 h. The mixture was filtered through celite and solvents removed in vacuo to give the title compound (13 mg, 88%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.51 (d, 1H, J=3.9 Hz), 7.27-7.23 (m, 2H), 7.19-7.14 (m, 3H), 6.81 (d, 1H, J=3.8 Hz), 4.85-4.77 (m, 1H), 3.72-3.58 (m, 2H), 3.22 (s, 9H), 3.16 (t, 2H, J=7.8 Hz), 2.98 (t, 2H, J=7.4 Hz), 2.59-2.48 (m, 2H); MS ESI 375.2 [M+H]+, calcd for [C20H26N2O3S+H]+ 375.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20].C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:21][C:18]=4[C:19]#[N:20])[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: N#Cc1cc(F)ccc1N1CCNCC1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: N#Cc1cc(F)ccc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Yield: 59.6 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.199 g), 5-fluoro-2-(piperazin-1-yl)benzonitrile (0.203 g), triethylamine (0.110 g), and ethylene glycol (2 mL) give 0.218 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/hexane; mp 179-180° C.; MS m/z 369; IR (mineral oil) 1494, 1329, 808, 1452, 1072 cm-1. 1H NMR (CDCl3) δ2.78, 3.20, 3.78, 6.99, 7.13, 7.19, 7.26, 7.51, 7.52.8.14.