Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[C:13](OC)(=[O:19])[C:14]#[C:15][CH2:16][CH2:17][CH3:18]>C1COCC1>[O:19]=[C:13]([CH2:14][CH2:15][CH2:16][C:17]#[CH:18])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCC#CC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCCCC(=O)CP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of dimethyl methylphosphonate (2.16 mL, 20 mmol) in anhydrous THF (30 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 13.75 mL, 22 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl hexynoate (1.26 g, 10 mmol) was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (MeOH:CH2Cl2=2:98) to give the product (370 mg) with colorless oil in 17% yield. 1HNMR (CDCl3, ppm) δ 1.80 (t, J=7.0 Hz, 2H), 1.95 (s, 1H), 2.24 (dt, J=2.9 and 7.0 Hz, 2H), 2.73 (t, J=7.0 Hz, 2H), 3.06 (d, J=22.7 Hz, 2H), 3.77 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[C:6](=O)[NH:5]2.P(Cl)(Cl)([Cl:24])=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[C:6]([Cl:24])=[N:5]2
Reactant: O=c1[nH]c2cc(Br)ccc2n2c(-c3ccccc3)nnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1nc2cc(Br)ccc2n2c(-c3ccccc3)nnc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
5z (197 mg, 0.58 mmol) was dissolved in DMF (3 mL) with heating, and then phosphorus oxychloride (0.27 mL, 2.9 mmol) was added, and the reaction was heated to 80° C. for 1.5 hours. After cooling to room temperature, the mixture was quenched with NaHCO3, and the resulting slurry was stirred at room temperature for 30 minutes and filtered. The solid material was washed with water and dried to obtain the desired product, 5aa.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][NH:5][CH2:6][C:7]#[C:8][C:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[S:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[CH:10]=1>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[S:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[CH:10]=[C:9]([C:8]#[C:7][CH2:6][N:5]([CH3:4])[CH2:2][CH2:1][OH:3])[C:15]=2[CH:16]=1
Reactant: C1CO1
Reactant: CNCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Solvent: CCO
Product: CN(CC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21)CCO

Procedure:
A solution of 2 ml. of ethylene oxide in 10 ml. of ethanol is treated with a solution of 0.6 g. of N-methyl-3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynylamine in 5 ml. of ethanol and stirred at room temperature for about 14 hours. The solvent is evaporated and the residue partitioned between water and ether. The ethereal phase is washed with a dilute aqueous ammonia solution, dried over sodium sulfate and evaporated, whereby there is obtained 2-{[3-(8-chloro-dibenzo[b,f]thiepin-10yl)-2-propynyl]-methylamino}-ethanol which melts at 86°-88° C. after recrystallization from ether/n-pentane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6][C:5]2=[O:15].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][C:7]([C:12]([O:14][CH2:21][CH3:22])=[O:13])=[CH:6][C:5]2=[O:15]
Reactant: O=C(O)c1cc(=O)c2cc(O)ccc2s1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(=O)c2cc(O)ccc2s1

Procedure:
A solution of 10.6 parts of 6-hydroxy-1-thiachromone-2-carboxylic acid and 9 parts of concentrated sulphuric acid in 750 parts of ethanol was heated under reflux for 20 hours. Most of the ethanol was evaporated off and the residual solution was diluted with 500 parts of water, which caused precipitation of a solid. The solid was filtered off, washed with dilute sodium bicarbonate solution and with water and was finally crystallised from ethanol to give 9.4 parts of ethyl 6-hydroxy-1-thiachromone-2-carboxylate, melting point 217°-8°C.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:5]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[CH2:31][O:32][Si](C(C)C)(C(C)C)C(C)C)[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:5]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[CH2:31][OH:32])[CH:2]=[CH2:3]
Reactant: C=CCn1c(-c2ccc(OC)cc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCn1c(-c2ccc(OC)cc2CO)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Methyl 1-allyl-3-cyclohexyl-2-(4-methoxy-2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate (1 eq.) was dissolved in THF (0.28M solution) and a 1M solution of tetrabutylammonium fluoride in THF (1 eq.) was added. The mixture was left stirring at RT for 2 h, then all volatiles were evaporated in vacuo and the residual material was dissolved in Et2O. The solution was washed with 1N HCl, saturated aq. NaHCO3 solution and with brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was purified by flash chromatography (PE:EtOAc, 8:2). After evaporation of the solvents the product was obtained as colorless foam (88%). MS (ES+): 434.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]#[N:12].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(SCC#N)cc1

Procedure:
The compound 4-methylthiophenoxyacetonitrile was prepared by heating 4-methylthiophenol, chloroacetonitrile and anhydrous K2CO3 in DMSO, employing substantially the same procedure described in previous examples.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br>CN(C)C=O>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: BrCc1cccc(Br)c1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Product: OC1CCN(Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
0.202 g (0.002 mol) of 4-hydroxypiperidine and 0.55 g (0.0022 mol) of 3-bromobenzyl bromide were dissolved in 5 ml of dimethylformamide and stirred at room temperature for 2 hrs. The solvent was distilled off and the residue was taken up in dichloromethane and washed with saturated bicarbonate solution and sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. 0.52 g (96%) 1-(3-bromo-benzyl)-piperidin-4-ol was obtained as a brown oil. MS: me/e (% basic peak)=271, 269 (C12H16BrNO+, 26, 26.6), 270, 268 (25.5, 22), 171, 169 (47, 48.3), 114 (76.6), 100 (100).
Reaction SMILES: I.[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[NH:8][C:9](SC)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CCOCC>CC(O)(C)C>[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[NH:8][C:9]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1COCCN1
Reactant: CSC(=Nc1ccccc1)Nc1nccn1C
Agent: I
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: Cn1ccnc1NC(=Nc1ccccc1)N1CCOCC1

Procedure:
A solution of 1.5 g (0.004 mole) of methyl N-(1-methylimidazol-2-yl)-N'-phenylcarbamimidothioate hydroiodide and 0.73 g (0.0084 mole) of morpholine in 30 ml of t-BuOH is refluxed overnight. Upon cooling, ether is added and morpholine hydroiodide is removed by filtration. The filtrate is taken to dryness and the residue is taken up in CH2Cl2 and converted to the free base with 3 N NaOH. The organic layer is separated, dried over K2CO3, filtered and the solvent is removed in vacuo to give a residue of N-(1-methylimidazol-2-yl)-N'-phenyl-4-morpholine carboximidamide, which is taken up in acetone and converted to the hydrochloride salt with ethereal HCl.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18]Br)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:11][CH2:18][CH:17]([O:20][CH2:21][CH3:22])[O:16][CH2:14][CH3:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(CBr)OCC
Reactant: Nc1ccc(OC2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CNc1ccc(OC2CCCC2)cc1)OCC
Temperature: 80 °C

Procedure:
A suspension of 4-cyclopentyloxyaniline (8.86 g), bromoacetaldehyde diethyl acetal (13 g), potassium carbonate (13.8 g) and dimethylformamide (100 ml) was heated at 80° C. for 6 hours. Cooling was followed by filtration and concentration of the filtrate. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 2:1). The product with the molecular weight of 293.41 (C17H27NO3) was obtained in this way; MS (ESI): 294 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH2:15](O)[CH3:16]>S(=O)(=O)(O)O>[CH2:15]([O:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[CH:8]=1)=[O:14])[CH3:16]
Reactant: CCO
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2cc(O)ccc2c1
Reaction time: 16 h

Procedure:
A solution of 6-hydroxy-2-naphthoic acid (75.9 g, 0.40 mol) in ethanol (1.0 L) and sulfuric acid (5.0 mL) was heated to reflux under an atmosphere of nitrogen. After 16 hours, the volume was removed to approximately half via simple distillation and the resulting solution was diluted with water. The resulting cloudy mixture was extracted with EtOAc (4×) and the combined organics were successively washed with NaHCO3 (0.25 M, twice), water, brine and dried (MgSO4). The mixture was filtered and evaporated to give 6-hydroxy-naphthalene-2-carboxylic acid ethyl ester, 85.4 g (98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[C:19]=2[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:34][CH2:35][CH2:36]OS(C)(=O)=O)[CH:26]=2)[C:12]2[O:16][CH:15]=[CH:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>CN1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[C:19]=2[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:34][CH2:35][CH2:36][N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH:26]=2)[C:12]2[O:16][CH:15]=[CH:14][C:13]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCCCn1cc(C2=C(c3cc(OCc4ccccc4)cc4ccoc34)C(=O)NC2=O)c2ccccc21
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(c2cc(OCc3ccccc3)cc3ccoc23)=C1c1cn(CCCN2CCCC2)c2ccccc12
Temperature: 55 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Dissolve methanesulfonic acid 3-{3-[4-(5-benzyloxybenzofur-7-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]indol-1-yl}propyl ester (220 mg, 0.39 mmol) and pyrrolidine (411 mg, 5.78 mmol) in 1-methylpyrrolidine (6 ml) and heat to 55° C. for 5 hours. Allow the reaction to cool to room temperature and stir overnight. Dilute the reaction in ethyl acetate, wash with water and brine, and dry with magnesium sulfate. Purification by flash chromatography gives the title compound (200 mg, 95%). MS(ES+): 546.13.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.CO.B(F)(F)F.[CH3:27]COCC>C(Cl)(Cl)Cl>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([O:19][CH3:27])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: CCOCC
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CO[C@H]1O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of the crude dihydroartemisinin in chloroform (40 mL) and methanol (1 mL, 24.8 mmol) was added boron trifluoride etherate (0.16 mL, 1.24 mmol) at 0° C. The reaction was stirred at 0° C. for 15 minutes, slowly warmed up to room temperature and stirred at room temperature for 3 hours. The reaction was monitored by TLC until all starting material was consumed. The reaction mixture was quenched with water (50 mL) and diluted with chloroform (25 mL). The two phases were separated, and the aqueous layer was extracted with chloroform (30×2 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford crude product which was further purified by column chromatography on Florisil (1%-10% EtOAc/hexanes) to give two artemether isomers as white solids: β-isomer (0.29 g, 0.98 mmol, 79%) mp 73°-74.5° C.; α-isomer (0.05 g, 0.17 mmol, 14%), with each having a 1H NMR spectrum identical to that reported in the literature.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][O:18][NH2:19]>N1C=CC=CC=1>[CH3:17][O:18][N:19]=[C:9]1[C:8]2[C:13](=[CH:14][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[O:12][CH2:11][CH2:10]1
Reactant: CON
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2=O
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCOc2cc(C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
The product of Example 1A (1.50 g, 7.3 mmol) and methoxyamine hydrochloride (0.69 g, 8 mmol) were dissolved in 7 mL of pyridine. The reaction mixture was stirred at ambient temperature for 16 hours, and the pyridine removed under reduced pressure. The residue was taken in diethyl ether and sequentially washed with water and 1N aqueous hydrochloric acid. The isolated organic layer was then dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give 1.53 g of the title compound, which was used without further purification. MS (DCI) m/e 234 (M+H)+
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:40][C:41](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:42].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([O:38][C:41](=[O:42])[CH3:40])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](O)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)spirostan-11,12-diol was selectively acetylated with acetic arthydride, pyridine and dimethylaminopyridine in methylene chloride to give the title compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]([C:18]3([C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:30]([CH3:33])([CH3:32])[CH3:31])=[N+]=[N-].CO.[CH3:36][C:37](O)=[O:38]>[Pd]>[C:37]([NH:1][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]([C:18]3([C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:38])[CH3:36]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21

Procedure:
A solution of N-(1-(2-azidoethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (13 mg, 0.029 mmol) in MeOH—AcOH (0.2 mL, 99:1) in the presence of Pd—C (2 mg) was stirred at room temperature under 1 atm of H2 for 2 h, filtered through Celite, and concentrated under reduced pressure. The crude product was treated with AcCl (0.05 mL) and Et3N (0.05 mL) in anhydrous THF (0.2 mL) at 0° C. for 30 min and then 1 h at room temperature. The mixture was purified by preparative HPLC providing N-(1-(2-acetamidoethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 462.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[C:9]#[C:10][C:11]([CH3:18])([O:13][Si](C)(C)C)[CH3:12])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:19])[C:9]#[C:10][C:11]([OH:13])([CH3:12])[CH3:18])=[CH:6][CH:7]=1
Reactant: CC(C)(C#CC(=O)c1ccc(Cl)cc1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (3.7 g, 12.50 mmol) in DCM (20 mL) was added PTSA (2.87 g, 15.01 mmol) at RT. The reaction mixture was stirred for 1 h and diluted with water (10 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 1-(4-chlorophenyl)-4-hydroxy-4-methylpent-2-yn-1-one (2.40 g) as a pale red oil.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[C:19]([F:20])=[CH:18][C:17]([NH:21]C(=O)C)=[CH:16][C:15]=3[F:25])[N:6](S(C3C=CC(C)=CC=3)(=O)=O)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[C:15]([F:25])=[CH:16][C:17]([NH2:21])=[CH:18][C:19]=3[F:20])[NH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)Nc1cc(F)c(Oc2ccnc3c2c(C2CC2)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(F)c(Oc2ccnc3[nH]cc(C4CC4)c23)c(F)c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
624 mg (1.25 mmol) of N-[4-({3-cyclopropyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]-pyridin-4-yl}oxy)-3,5-difluorophenyl]acetamide are dissolved in 17 ml of ethanol. 10 ml of semiconcentrated aqueous sodium hydroxide solution are added, and the reaction mixture is stirred at 90° C. for 15 h. The reaction mixture is partitioned between ethyl acetate and water. The organic phase is washed twice with water, dried over sodium sulfate and concentrated under reduced pressure. This gives a crystalline residue.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[N:10]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>CN(C)C=O>[NH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[N:10]=2)[N:7]=1
Reactant: CC(C)C(=O)Nc1cn2nc(I)ccc2n1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Yield: 45.9 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylpropanamide (0.60 g, 1.82 mmol), N,N-dimethylformamide (6.0 mL), potassium carbonate (502 mg, 3.63 mmol) and 3-aminophenol (278 mg, 2.54 mmol) as starting materials and in the same manner as in Example 91, the title compound (0.26 g, 47%) was obtained as a dark brown powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][NH:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][O:3]1.[CH2:12]=O>C(O)C.[Pd]>[CH3:12][N:6]1[CH2:7][C:2]([CH3:11])([CH3:1])[O:3][CH2:4][CH:5]1[C:8]([OH:10])=[O:9]
Reactant: CC1(C)CNC(C(=O)O)CO1
Reactant: C=O
Agent: [Pd]
Solvent: CCO
Product: CN1CC(C)(C)OCC1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a suspension of 6,6-dimethyl-morpholine-3-carboxylic acid (Intermediate 19, 540 mg) in 17 ml of ethanol (under nitrogen) was added 100 mg of 10% Pd on charcoal and 830 ul (˜3 eq.) of 37% aqueous formaldehyde. The mixture was purged with hydrogen (balloon) and stirred at ambient temperature for 5 hrs. To the resulting gray mixture were added 4 ml of water and 4 ml of methanol to help dissolution. The catalyst was removed by filtration and the filtrate was concentrated to dryness. The residue was triturated with EtOAc. The generated white solid was filtered off and dried under high vacuum to give 574 mg of 4,6,6-trimethyl-morpholine-3-carboxylic acid (97% yield).
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>C(O)C>[NH2:8][C@@H:12]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[N:16]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2cccc(C(F)(F)F)n2)COC1(C)C
Agent: Cl
Solvent: CCO
Product: N[C@H](CO)CCc1cccc(C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
(S)-2,2-Dimethyl-4-[2-(6-trifluoromethyl-pyridin-2-yl)-ethyl]-oxazolidine-3-carboxylic acid tert-butyl ester (0.522 g, 1.39 mmol) was dissolved in ethanol (2.5 ml), hydrochloric acid in ethanol (5N, 2.5 ml) was added and the mixture was stirred at 60° C. for 2 hours. The solvent was evaporated and the residue was dissolved in dichloromethane. A solution of ammonia in methanol (2N, 2 ml) was added and the mixture was evaporated over Isolute® Flash-NH2 silicagel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=90:10) yielded a colourless liquid, (0.237 g, 73%); MS (ISP): 235.1 ((M+H)+.).
Reaction SMILES: [C:1]([C:3]([C:14](=[O:30])[N:15]([CH2:26]CCC)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[CH:4][NH:5][C:6](=[NH:13])[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])#[N:2].[C:31]([CH2:33]C(O)=O)#N>C(O)(=O)C>[CH3:26][N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=1)[C:14]([C:3]1[C:1]([NH2:2])=[N:13][C:6]([N:7]2[CH2:11][CH:10]([CH:31]=[CH2:33])[NH:9][C:8]2=[O:12])=[N:5][CH:4]=1)=[O:30]
Reactant: CCCCN(C(=O)C(C#N)=CNC(=N)N1CCNC1=O)c1cccc(C(F)(F)F)c1
Reactant: N#CCC(=O)O
Solvent: CC(=O)O
Product: C=CC1CN(c2ncc(C(=O)N(C)c3cccc(C(F)(F)F)c3)c(N)n2)C(=O)N1
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
A mixture of 2.84 g (7 mmol) of a compound II (R1 =CH=CH2 ; R2, R3, R5, R6 =H; R4 =CH3), 486 mg (5.5 mmol) of cyanoacetic acid and 5 ml of glacial acetic acid was stirred at 75° for 1.5 hours and subsequently worked up as in Example 5. Crystallization from ether resulted in 1.75 g (=61.6% yield) of 4-amino-2-(4-vinyl-2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-methyl-N-(3-trifluoromethylphenyl)amide, melting point 203°-204°.