Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH2:13]([C:15]1[C:22]([O:23][CH3:24])=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[O:25][CH3:26])[CH3:14].[CH3:27][S:28][CH2:29][S:30]([CH3:32])=[O:31].C(Cl)Cl>CO.O1CCCC1>[CH2:13]([C:15]1[C:22]([O:23][CH3:24])=[CH:21][C:18](/[CH:19]=[C:29](\[S:28][CH3:27])/[S:30]([CH3:32])=[O:31])=[CH:17][C:16]=1[O:25][CH3:26])[CH3:14]
Reactant: CSCS(C)=O
Reactant: CCc1c(OC)cc(C=O)cc1OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1c(OC)cc(/C=C(\SC)S(C)=O)cc1OC
Yield: 68.8 %

Procedure:
130 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol (Triton B) were added to a solution of 126.5 g (651.2 mmol) of 4-ethyl-3,5-dimethoxy-benzaldehyde and 80.89 g (651.2 mmol) of methyl methylthiomethyl sulphoxide in 300 ml of tetrahydrofuran and the mixture was heated at reflux for 5 hours. After the addition of 300 ml of methylene chloride the mixture was extracted with 200 ml of 0.5M sulphuric acid. The organic phase was dried (MgSO4), filtered and evaporated. Chromatography of the resulting residue (silica gel, ethyl acetate/hexane 1:1) yielded 134.6 g (69%) of (E)-2-ethyl-5-(2-methylsulphanyl-2-methylsulphinyl-vinyl)-1,3-dimethoxybenzene as a colorless oil, which gave colorless crystals of m.p. 82-83° by crystallization from hexane.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[H-].[Na+].CI.[C:15](O)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([CH3:15])[C:7]=12
Reactant: CC(=O)O
Reactant: Clc1nccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2ccnc(Cl)c21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 259 (250 mg, 1.64 mmol) in DMF (16 mL) at 0° C. was added NaH (197 mg, 4.92 mmol, 60% in mineral oil), and the mixture was stirred for 30 min, followed by addition of MeI (112 □L, 1.80 mmol). The reaction mixture was stirred at room temperature for 2 h before acetic acid (1 mL) was added. Solvents were removed under reduced pressure, the residue was partitioned between water and EtOAc. Organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (1:1), to afford the title compound 263 (200 mg, 92% yield) as an off-white solid. MS (m/z): 167.1(M+H) (found).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:27]=[CH:26][C:25]([CH:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]6)=[CH:24][CH:23]=5)[CH:20]=4)[NH:15][CH:14]=3)[CH:10]=[N:9]2)=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:31]1[CH2:32][CH2:33][CH:28]([C:25]2[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[C:21]4[C:13]([C:11]5[CH:10]=[N:9][N:8]([CH2:7][C:4]6[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=6)[CH:12]=5)=[CH:14][NH:15][C:16]4=[N:17][CH:18]=3)=[CH:27][CH:26]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6ccncc6)c5)c4c3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)ccn1
Yield: 14.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (120 mg, 0.224 mmol) was deprotected in TFA/DCM (5/5 ml) to afford 14 mg (14.3% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.78-8.76 (d, 2H), 8.53-8.51 (t, 2H), 8.35 (s, 1H), 8.07 (s, 1H), 7.75-7.70 (m, 5H), 7.43-7.41 (d, 2H), 5.78 (s, 2H), 3.55-3.51 (d, 2H), 3.21-3.13 (td, 2H), 3.03-2.95 (m, 1H), 2.03-1.90 (m, 2H). MS: m/z=435.6 (M+1), HPLC: 99.16% in method A.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:30]3[CH2:34][CH2:33][CH2:32][NH:31]3)=[N:9][C:10]=2[C:11]2[CH:29]=[CH:28][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:35](O)(=[O:39])[C:36]#[C:37][CH3:38]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:30]3[CH2:34][CH2:33][CH2:32][N:31]3[C:35](=[O:39])[C:36]#[C:37][CH3:38])=[N:9][C:10]=2[C:11]2[CH:29]=[CH:28][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Reactant: CC#CC(=O)O
Product: CC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)nccn12
Yield: 31.1 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (intermediate 11) and 2-butynoic acid, to afford the title compound (7.1 mg, 31.1%). Data: UPLC (C) Rt: 2.63 min; m/z 534.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1.O>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9])[O:12][CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1
Reactant: Oc1ccc(C(F)(F)F)c(Cl)c1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(COc2ccc(C(F)(F)F)c(Cl)c2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a solution of 3-chloro-4-(trifluoromethyl)phenol (110 mg, 0.56 mmol) in DMSO (5.0 mL) was added potassium carbonate (155 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for 10 minutes, before addition of ethyl 4-(bromomethyl)benzoate (136 mg, 0.56 mmol). The resulting mixture was heated to 70° C. with stirring for 3 hours before cooling back to room temperature. Water (50 mL) and EtOAc (50 mL) were added and the layers partitioned. The aqueous layers were washed with EtOAc (2×50 mL) and the combined organic layers dried over magnesium sulfate, filtered and concentrated in vacuo to yield a white solid as the title compound (198 mg, 99%).
Reaction SMILES: [NH3:1].[NH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C(O)(=O)CCC(O)=[O:12]>O>[C:6]([CH2:5][CH2:4][C:3]([OH:7])=[O:12])#[N:2].[C:6]([CH2:5][CH2:4][C:3]([NH2:1])=[O:7])#[N:2].[NH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[NH3:2]
Reactant: O=C(O)CCC(=O)O
Agent: N
Agent: O=C1CCCN1
Solvent: O
Product: N#CCCC(=O)O
Product: N#CCCC(N)=O

Procedure:
Preferably, the hydrogenation reaction is carried out in liquid phase with water being the liquid medium. The mol ratio of water to succinic reactant preferably is between 1:1 and 400:1, more preferably between 2:1 and 50:1 in the hydrogenation step reaction zone. Similar to the situation with ammonia, water may be added separately to the reaction zone if desired and also the amount of water in the reaction zone will be increased by the conversion of the succinic reactant to 2-pyrrolidone. In the case of conversion of succinic acid to 2-pyrrolidone, 3 mols of water are generated, and in the conversion of beta-cyanopropionic acid to 2-pyrrolidone, 1 mol of water will be formed, while in the conversion of beta-cyanopropionamide to 2-pyrrolidone, one mol of ammonia will be formed, but no water.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C-]#N.[K+].[CH2:13](O)[CH3:14].[NH:16]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[S:23]>CC(C)=O.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:6][CH:7]=[CH:8][C:13]=1[CH:14]1[S:23][C:17]2=[N:18][CH2:19][CH2:20][CH2:21][CH2:22][N:16]2[C:4]1([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])[OH:5]
Reactant: S=C1NCCCCN1
Reactant: O=Cc1ccccc1Cl
Reactant: CCO
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cl
Product: OC1(c2ccccc2Cl)C(c2ccccc2Cl)SC2=NCCCCN21

Procedure:
A mixture of 22.6 ml. of o-chlorobenzaldehyde, 8 g. of potassium cyanide and 100 ml. of 65% ethanol is refluxed for 2 hours and then refrigerated. Water (30 ml.) is added, refrigeration is continued, then the water layer is decanted and the oil dissolved in toluene, washed with water, dried and concentrated to an oil. The crude 2,2'-dichlorobenzoin is converted to the methanesulfonate ester as described in Example 1, giving an oil. A 14.6 g. portion of this oil is reacted with 2.6 g. of hexahydro-2H-1,3-diazepin-2-thione in 100 ml. of acetone as described in Example 13, giving 1.4 g. of the desired product, m.p. 224°-226° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[CH:18]=[CH:17][C:16](SC)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O[O:22][S:23]([O-:25])=O.[K+].[CH3:27]O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[CH:14]=[CH:15][C:16]([S:23]([CH3:27])(=[O:25])=[O:22])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C2=C(c3ccc(F)cc3)CCC2)cc1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CCC2)cc1
Reaction time: 4 h
Yield: 54 %

Procedure:
A solution of 1.5 g (5. mmol) of 1-[2-(4-fluorophenyl) cyclopenten-1-yl]-4-(methylthio)benzene (Step 3) in 46 mL of methanol/thf (1:1) was slowly treated with 5.2 g (8.4 mmol) of Oxone® [2 KHSO5.K2SO4 ] in 23 mL of water. After stirring for 4 h, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried (MgSO4), and reconcentrated. Recrystallization from ethyl acetate/hexane provided 960 mg (54%) of 1-[2-(4-fluorophenyl) cyclopenten-1-yl]-4- (methylsulfonyl)benzene (41 in Synthetic Scheme X when R5 =SO2CH3, R10 =F, and R1, R2, R3, R4, R6, R7, R8, R9, R11, and R12 =H) as a colorless solid: mp 138°-139° C.; NMR (CDCl 3) d 2.09 (m, J=7 Hz, 2H) , 2.91 (t, J=7 Hz, 4H) , 3.04 (s, 3H) , 6.88-6.96 (m, 2H) , 7.06-7.14 (m, 2H) , 7.32 (d, J=8 Hz, 2 H), 7.76 (d, J=8 Hz, 2H). MS (EI) m/e (rel intensity) 316 (100) , 237 (41) , 161 (13); HRMS. Calc'd for C18H17FO2S: 316.0933. Found: 316.0943. Anal. Calc'd for C18H17FO2S: C, 68.33; H, 5.42; F, 6.00; S, 10.13 . Found: C, 68.08; H, 5.45; F, 6.42; S, 9.98.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH2:15][CH:16](Br)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].CS(C)=O.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH:15]=[C:16]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2Br
Reactant: Nc1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CC=C2Nc1ccccc1
Reaction time: 84 h
Yield: 59.3 %

Procedure:
40.0 g. (0.127 mole) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester are dissolved in 80 ml. of dimethylsulfoxide and 26 ml. (0.285 mole) of aniline are added. The solution is allowed to stand at room temperature for 3-4 days. The mixture is then diluted with 100 ml. of water, shaken out with 3×50 ml. of benzene. The combined organic layers are dried with calcinated sodium sulfate and evaporated in vacuo. The residue is recrystallized from ethanol and thus 24.5 g. (59.3%) of 9-(phenyl-amino)-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic ethyl ester is obtained, melting point: 119°-120° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][OH:10].[N+:11]([C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:17]1[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: C[C@H]1CCCN1CCCO
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: C[C@H]1CCCN1CCCOc1ccc([N+](=O)[O-])cc1

Procedure:
The target compound was obtained by the method according to Example 18, using 3-[(2S)-2-methylpyrrolidin-1-yl]propanol and 4-nitrophenol as starting materials.
Reaction SMILES: [C:1]1(C2(C(O)=O)CCCC2)C=CC=CC=1.[CH3:15][CH:16]([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH3:15][C:16]([CH3:1])([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19]
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: CC(C)(C)C(C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3,3-dimethyl-2-phenylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4R*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 2: 1H NMR (400 MHz,) δ ppm 8.47 (t, J=6.7, 1H), 7.77 (s, 0.5H), 7.71 (d, J=7.3, 2H), 7.60 (d, J=7.7, 0.5H), 7.54 (s, 1H), 7.43 (dd, J=8.1, 16.6, 1H), 7.35-7.24 (m, 4H), 4.39-4.29 (m, 1H), 3.62 (d, J=13.6, 0.5H), 3.53 (d, J=13.5, 0.5H), 3.47 (d, J=13.6, 0.5H), 3.44 (s, 1H), 3.38 (d, J=13.5, 0.5H), 2.92 (dd, J=2.9, 9.0, 0.5H), 2.62-2.54 (m, 1H), 2.54-2.46 (m, 1H), 2.46-2.36 (m, 0.5H), 2.32 (dd, J=9.1, 12.0, 1H), 2.27 (d, J=5.2, 1H), 2.21 (d, J=5.6, 1H), 2.17-2.07 (m, 0.5H), 1.86 (ddd, J=6.4, 13.3, 21.3, 1H), 1.71 (tdd, J=6.4, 13.0, 19.3, 1H), 1.36 (ddt, J=8.2, 14.4, 20.6, 1.5H), 1.14 (d, J=1.3, 9H); MS (ESI+) m/z 459 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([C:25](Cl)=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Sn](Cl)(Cl)(Cl)Cl.Cl.C(=O)(O)O.[NH2:38][NH:39][C:40]([NH2:42])=[NH:41]>C(Cl)Cl.C(O)(C)C>[CH:19]1([C:25]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=2)=[N:38][NH:39][C:40](=[NH:41])[NH2:42])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Reactant: O=C(Cl)C1CCCCC1
Reactant: N=C(N)NN
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(O)O
Solvent: CC(C)O
Solvent: ClCCl
Product: N=C(N)NN=C(c1cn(S(=O)(=O)c2ccccc2)c2ccccc12)C1CCCCC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 17.8 %

Procedure:
A solution of indole (11.7 g, 0.1 mol) in THF is added to a stirred mixture of NaH (60% dispersion in mineral oil, 4.2, g 0.105 mol), DMSO and THF. The reaction mixture is stirred for 1 h at room temperature, cooled to 0° C., treated with phenylsulfonyl chloride (13.3 mL, 0.15 mol), stirred at ambient temperatures for 3 h, quenched with water and extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized in ethanol and filtered. The filtercake is air-dried to give 1-phenylsulfonylindole. A portion of this 1-phenylsulfonylindole (257 mg, 1.0 mmol) and cyclohexylcarbonyl chloride (0.175 mL, 1.3 mmol) in methylene chloride is treated with tin tetrachloride (97 μL, 1.9 mmol) at room temperature, shaken for 6 h, quenched with saturated NaHCO3 and extracted with ethylacetate. The extracts are combined and concentrated in vacuo to give a residue. The residue is suspended in isopropanol, treated sequentially with concentrated HCl (50 μL) and aminoguanidine bicarbonate (100 mg, 0.5 mmol), heated at 80° C. for 4 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to afford the title product 37.7 mg (17% yield), identified by HPLC1 and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C:10](=[O:12])[CH:9]=[CH:8][O:7]1)=[O:5])[CH3:2].[H][H]>CCOC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1CC(=O)C=CO1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(=O)CCO1
Yield: 33.1 %

Procedure:
A mixture of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (8.0 g, 46.0 mmol) and PdlC (10%, 0.20 g,) in EtOAc (70 mL) was shaken in a Parr bottle with hydrogen at 50 psi overnight and filtered through a pad of Celite. The filtrate was concentrated and the residue was distilled to give 2.62 g (33%) of yellowish oil: 1H NMR (CDCl3) δ 1.29 (t, 3H), 2.40 (d, 1H), 2.58-2.75 (m 3H), 3.79 (tt, 1H), 4.23 (q, 2H), 4.28 (m 1H), 4.40 (m, 1H).
Reaction SMILES: C1(CS(N2C3C(=CC(NC(C4OC(N5CCCC(C)C5)=NC=4C(F)(F)F)=O)=CC=3)C=C2)(=O)=O)C=CC=CC=1.[NH:39]1[C:47]2[C:42](=[CH:43][C:44]([NH:48][C:49]([C:51]3[O:55][C:54]([N:56]4[CH2:61][CH2:60][CH2:59][CH:58]([CH3:62])[CH2:57]4)=[N:53][C:52]=3[C:63]([F:66])([F:65])[F:64])=[O:50])=[CH:45][CH:46]=2)[CH:41]=[N:40]1.[CH:67]([S:70](Cl)(=[O:72])=[O:71])([CH3:69])[CH3:68]>>[CH3:68][CH:67]([S:70]([N:39]1[C:47]2[C:42](=[CH:43][C:44]([NH:48][C:49]([C:51]3[O:55][C:54]([N:56]4[CH2:61][CH2:60][CH2:59][CH:58]([CH3:62])[CH2:57]4)=[N:53][C:52]=3[C:63]([F:66])([F:65])[F:64])=[O:50])=[CH:45][CH:46]=2)[CH:41]=[N:40]1)(=[O:72])=[O:71])[CH3:69]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4[nH]ncc4c3)o2)C1
Agent: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(ccn4S(=O)(=O)Cc4ccccc4)c3)o2)C1
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(cnn4S(=O)(=O)C(C)C)c3)o2)C1

Procedure:
Compound 53 was prepared by the general procedure for compound 46, by using compound 49 and isopropylsulfonyl chloride as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (br s, 1H), 8.63 (br s, 1H), 8.36 (br s, 1H), 7.97 (br d, 1H, J=9.1 Hz), 7.83 (dm, 1H, J=8.8 Hz), 4.12 (m, 2H), 3.87 (h, 1H, J=7.0 Hz), 3.07 (br t, 1H, J=13.0 Hz), 2.77 (t, 1H, J=11.8 Hz), 1.78 (m, 2H), 1.68 (m, 1H), 1.55 (m, 1H), 1.18 (d, 6H, J=7.0 Hz), 1.16 (m, 1H), 0.95 (d, 3H, J=6.6 Hz). MS (M+1): 500.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8].[C:14]1([Si:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>N1C=CC=CC=1>[C:27]1([Si:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]2=[O:8])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn(CCCCO)c(=O)[nH]1
Solvent: CO
Solvent: c1ccncc1
Product: O=c1ccn(CCCCO[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reaction time: 2 h

Procedure:
1-(4′-Hydroxybutyl)uracil (0.048 g, 0.26 mmol) was dissolved in dry pyridine (1.5 mL) and cooled in an ice-salt bath. A solution of triphenylsilyl chloride (0.099 g, 0.34 mmol) in dry pyridine (1.5 mL) was added drop-wise. The reaction mixture was kept at 0° C. under nitrogen for 2 h 30. CH3OH (15 μL) was added and after 10 min the solution was concentrated on the rotary evaporator. The resultant crude transparent oil was purified by silica gel chromatography using a gradient elution of 0→3% CH3OH in CHCl3. The title compound was obtained as a white solid (0.085 g, 74%) from the fractions with Rf=0.50 (10% CH3OH/CHCl3).
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[CH2:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH2:27]C)=[CH:22][CH:21]=1)[CH:17]([CH3:19])[CH3:18].[CH3:30][O:31][CH:32](OC)[O:33]C.S(=O)(=O)(O)O>>[CH3:30][O:31][C:32]([CH:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:16][CH:17]([CH3:18])[CH3:19])=[CH:25][CH:24]=1)[CH3:27])=[O:33]
Reactant: CCC(=O)c1ccc(CC(C)C)cc1
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C)c1ccc(CC(C)C)cc1
Reaction time: 6 h
Yield: 79 %

Procedure:
To a suspension of iodobenzene diacetate (322 grams(g), 1.0 mol) in a solution of p-isobutylpropiophenone (190 g, 1.0 mol) in trimethylorthoformate (109 ml, 1.0 mol) was added, dropwise, concentrated sulfuric acid (about 96% H2SO4, 10.7 ml, 0.2 mol) at 3° C. with stirring over 40 minutes. The resulting reaction mixture was stirred 6 hours at 0° C. to 15° C. The ensuing reaction was quenched by adding 200 ml deionized water. HPLC (high performance liquid chromatography) analysis of the resulting reaction product, comparing to an external standard, demonstrated 79% yield of ibuprofen methylester. The mixture obtained can be separated into an aqueous phase and an organic phase, followed by isolation of purified ibuprofen methyl ester from the organic phase by column chromatography or distillation. Alternatively, the crude ester can be hydrolyzed by treating with 50% aqueous sodium hydroxide, followed by extraction of the resulting aqueous phase with heptane. Acidification of the aqueous phase and recrystallization of the solid precipitate yields high-purity ibuprofen.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:12]=[C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=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][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([C:37]2[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=2)[CH:12]=[C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
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: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C

Procedure:
A mixture of 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (4.3 g, 9.4 mmol), 4-trifluoromethylphenylboronic acid (2.6 g, 13.7 mmol), K2CO3 solution (2M, 9.4 mL) and DME (50 mL) was purged with N2 three times before adding Pd(PPh3)4 (400 mg, 0.3 mmol). The mixture was heated at 95° C. for 5 h (followed by HPLC). The reaction was diluted with EtOAc (200 mL) and then was washed successively with NaHCO3 solution and brine. The organic layer was dried (Mg2SO4), filtered and concentrated in vacuo to give the title compound as an oil. The residue was used crude in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=2)=[C:13]([CH3:25])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH2:28].CC(C)=O.C(Cl)Cl>CCO>[CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[C:22]([NH:28][CH3:27])[N:21]=[CH:20][N:19]=2)=[C:13]([CH3:25])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(=O)OCc2ccccc2)ccc1Oc1cc(Cl)ncn1
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Solvent: CC(C)=O
Product: CNc1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2C)ncn1

Procedure:
The title compound is prepared from [4-(6-chloro-pyrimidin-4-yloxy)-3-methyl-phenyl]-carbamic acid benzyl ester by aminomethylation (30% CH3NH2 in EtOH, 60 min, rt): M+H=363.9; Rf (acetone/CH2Cl2=3:7): 0.26.