Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:16]=2)=[CH:11][CH:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3ccc(F)cc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccc(O)cc2)ccc1C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-(4-(tert-butoxycarbonyl)oxyphenyl)-2-(4-fluorobenzamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 49 mg of 4-(4-hydroxyphenyl)-2-(4-fluorobenzamido)benzoic acid as white solid.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][S:1][C:2]2[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:10](=[O:18])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Reactant: ClCCN1CCOCC1
Product: O=c1c2ccccc2nc(SCCN2CCOCC2)n1-c1ccccc1
Yield: 49.8 %

Procedure:
The title compound was prepared in a yield of 49.8%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3- isobutyl-2-mercapto-4(3H)-quinazolinone and N-(2-chloroethyl)morpholine in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[NH2:11][C:12]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CC(N(C)C)=O.[Cu](I)I>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:11][C:12]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: NC1(C(=O)O)CC1
Agent: I[Cu]I
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(NC2(C(=O)O)CC2)cc(C)c1Br
Temperature: 120 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture of 2-bromo-5-iodo-1,3-dimethylbenzene (300 mg, 0.965 mmol), 1-aminocyclopropane carboxylic acid (195 mg, 1.93 mmol), copper iodide (I) (37 mg, 0.194 mmol), and diazabicycloundecene (0.50 mL, 3.35 mmol) in dimethylacetamide (2.6 mL) was stirred at 120° C. for three hours under nitrogen atmosphere. The reaction mixture was purified by silica gel column chromatography (Wakosil C18, acetonitrile-water (0.1% formic acid)) to afford 1-((4-bromo-3,5-dimethylphenyl)amino)cyclopropane carboxylic acid (219 mg, 80%).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C@H:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH3:10])[CH:4]=1.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C@H:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH3:10])[CH:4]=1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cc(C(F)(F)F)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethyl]-amide (122 mg, 0.20 mmol) in CH2Cl2 (3 mL) was added TFA (1 mL, 13.0 mmol). The bright yellow-orange reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (3 mL) and ethylene diamine (0.5 mL, 7.50 mmol) was added. The reaction mixture was stirred for 1 h then quenched with water and extracted with 5% MeOH/CH2Cl2 (2×). The combined organics were concentrated and triturated with MeOH/CH2Cl2 to isolate 65 mg (68%) of 2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethyl]-amide as an off-white solid. MS: (M+Na)+=506; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.79 (br. s., 1H), 9.12 (s, 1H), 8.86 (d, J=7.9 Hz, 1H), 8.71-8.81 (m, 2H), 8.43 (s, 1H), 7.91 (s, 1H), 7.60-7.73 (m, 2H), 7.03 (td, J=9.2, 2.1 Hz, 1H), 5.55 (quin, J=7.3 Hz, 1H), 4.15 (s, 3H), 1.64 (d, J=6.8 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])[CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27].O>ClCCl.CCCCCCC>[CH2:8]([O:28][C:29]([CH3:37])([CH3:38])[C:30]([OH:32])=[O:31])[CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(C)(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)-2-methylpropanoate (600 mg, 1.39 mmol) in dichloromethane (20 mL) under nitrogen and the reaction mixture was stirred at room temperature for two hours. Water was added and the aqueous phase was extracted twice with dichloromethane. The combined organic extract was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using a mixture of heptane, ethyl acetate and formic acid (80:20:1) as eluent. The appropriate fractions were concentrated and the residue (135 mg) was purified further by flash chromatography on silica gel using a gradient of 5-10% of a mixture of ethyl acetate and formic acid (95:5) in heptane as eluent. Concentration of the appropriate fractions afforded 80 mg slightly impure product. This material was dissolved in heptane (5 mL), washed twice with water (5 mL), dried (Na2SO4), filtered and concentrated to afford 40 mg (8% yield) of the title compound as an oil. 1H-NMR (300 MHz, CDCl3): δ 0.99 (t, 3H), 1.47 (s, 6H), 1.64 (m, 2H), 2.07 (m, 4H), 2.81-2.88 (m, 8H), 3.46 (t, 2H), 5.29-5.44 (m, 10H); MS (electro spray): 373.3 [M-H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][CH2:17][C:18]([OH:20])=O)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:21]=1.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.N1C=CC=CC=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][CH2:17][C:18]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=3)=[O:20])([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:21]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)CCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(CCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[6-Chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]propanoic acid (50 mg, 0.15 mmol) and 4-fluoroaniline (21 mg, 0.18 mmol) were dissolved in DMF (1 mL), and then, pyridine (31 μL, 0.39 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (35 mg, 0.18 mmol) were sequentially added thereto. After the reaction solution was stirred overnight at room temperature, water was added thereto. Then, the resulting solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by thin-layer silica gel column chromatography (ethyl acetate/hexane=1/1), whereby the objective compound (33.1 mg, 51%) was obtained as a white solid.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:18]=1>>[CH3:16][C:17]1[CH:21]=[C:20]([NH:22][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:18]=1
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cc(C)nn1-c1ccccn1)C(=O)OCC
Temperature: 120 °C
Yield: 95.4 %

Procedure:
A mixture of diethyl ethoxymethylenemalonate (32.5 g, 0.15 mol) and 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine (23.8 g, 0.137 mol) was heated under reflux at 120° C. for 1 hour. After the mixture was allowed to cool to room temperature, the reaction solvent was evaporated under reduced pressure. The crude crystals thus obtained were filtered and washed with diethylether to give the title compound (45 g, 96% yield).
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[Br:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C(N(CC)CC)C>[Br:18][CH2:19][CH2:20][C:21]([N:9]1[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][CH2:10]1)=[O:22]
Reactant: c1ccc(C2CNCO2)cc1
Reactant: O=C(Cl)CCBr
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCBr)N1COC(c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Four and five tenths (4.5) grams of 5-phenyl oxazolidine contained in 44.7 g. of benzene solution was mixed with 3.1 g. of triethylamine and stirred in a room temperature water bath, while 5.2 g. of 3-bromopropionyl chloride was added dropwise. After standing for about 30 minutes, the solution was washed with water, separated, dried over magnesium sulfate and the solvent stripped under vacuum. There was obtained a yield of 6 g. of an oil, the title compound, ND30 =1.5591.
Reaction SMILES: C(=O)([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH2:23][CH2:24][C:25]([O:28][CH3:29])([CH3:27])[CH3:26])[CH:9]=1)OC(C)(C)C.Cl>C(OCC)(=O)C>[F:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][C:10]=1[CH2:23][CH2:24][C:25]([O:28][CH3:29])([CH3:27])[CH3:26]
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2CCC(C)(C)OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2ccc(O)cc2CCC(C)(C)OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 134.1 %

Procedure:
To a solution of tert-butyl 2′-fluoro-5′-methoxy-2-(3-methoxy-3-methylbutyl)biphenyl-4-yl carbonate (199 mg) in ethyl acetate (5 mL) was added a solution (4 M, 2 mL) of hydrogen chloride in ethyl acetate, and the mixture was stirred at room temperature for 20 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (203 mg) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][NH:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1
Reactant: CNc1nc(SC)ncc1CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CNc1nc(SC)ncc1C=O
Yield: 91.7 %

Procedure:
A mixture of Example C1 (22.0 g, 119 mmol) and MnO2 (44 g, 506 mmol) in CHCl3 (300 mL) was stirred at RT for 3 h. The reaction was filtered and the filtrate was concentrated to give 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde as a pale solid (20 g, 92% yield). 1H NMR (400 MHz, DMSO-d6): 9.71 (s, 1 H), 8.60 (br s, 1 H), 8.49 (s, 1 H), 2.96 (d, J=4.8 Hz, 3 H), 2.48 (s, 3 H) MS (ESI) m/z: 184.0 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24]>CS(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:12](=[O:23])[CH2:11][C@H:10]1[OH:24]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Solvent: CS(C)=O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
The scheme (A) indicates that a regioselectively silylated compound, i.e., bis-triethylsilyl-PGF2α, triethylsilyl ester, can be obtained by reacting PGF2α, with TESiD under 15˜35° C. for 18˜36 hours. Next, the oxidation of the 9-hydroxy group into ketone group is carried out by reacting with a Cr (VI)-based reagent under 15˜35° C. for 10˜15 minutes or activated dimethyl sulfoxide reagent under −78° C. for 2˜3 hours. Last, PGE2 is obtained via a desilylation reaction performed in an acidic aqueous solution reagent having pH=4˜6 under 15˜35° C. for 12˜24 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:38]([OH:40])=[O:39])[CH2:22][CH2:23][C:24]([N:26]1[CH:34]2[CH:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][CH:27]1[C:35]([OH:37])=[O:36])=[O:25])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:47][O:48][C:49]1[CH:63]=[CH:62][CH:61]=[CH:60][C:50]=1[CH2:51][O:52]N1C(=O)CCC1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:38]([OH:40])=[O:39])[CH2:22][CH2:23][C:24]([N:26]1[C@@H:34]2[C@@H:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][C@H:27]1[C:35]([OH:37])=[O:36])=[O:25])=[O:19])[NH:17][C:51](=[O:52])[C:50]1[CH:60]=[CH:61][CH:62]=[CH:63][C:49]=1[O:48][CH3:47])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@H](CCC(=O)N1C(C(=O)O)CC2CCCCC21)C(=O)O
Reactant: COc1ccccc1CON1C(=O)CCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@H](CCC(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2S,3aS,7aS)-1-(N6 -benzyloxycarbonyl-L-lysyl-gamma-D-glutamyloctahydro-1H-indole-2carboxylic acid was dissolved in 6 ml of water, and sodium carbonate and 10 ml of THF were added. With vigorous stirring, N-(2-methoxybenzyloxy)succinimide was added. The mixture was stirred overnight at room temperature. The reaction mixture was acidified with 10% citric acid, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was chromatographed on a column of CHP20P using acetonitrile/water (30%→70% gradient) as an eluent. Fractions containing the desired product were concentrated to dryness under reduced pressure to give 1.0 g of (2S,3aS,7aS)-1-[N6 -benzyloxycarbonyl-N2 -(2-methoxybenzoyl)-L-lysyl-gamma-D-glutamyl]octahydro-1H-indole-2-carboxylic acid.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH:38][C:39]2[CH:44]=[CH:43][C:42]([C@@H:45]3[CH2:47][C@H:46]3[C:48]([OH:50])=O)=[CH:41][CH:40]=2)=[CH:33][CH:32]=1.[OH-].[NH4+].O>CN(C=O)C.ClCCl>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:32]=[CH:33][C:34]([CH2:37][NH:38][C:39]2[CH:40]=[CH:41][C:42]([C@@H:45]3[CH2:47][C@H:46]3[C:48]([NH2:2])=[O:50])=[CH:43][CH:44]=2)=[CH:35][CH:36]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2ccc(-c3ccccn3)cc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: NC(=O)[C@@H]1C[C@H]1c1ccc(NCc2ccc(-c3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.4 %

Procedure:
HATU (0.11 g, 0.29 mmol) and racemic-(trans)-2-[4-({[4-(2-pyridinyl)phenyl]methyl}amino)phenyl]cyclopropanecarboxylic acid (I-2c) (0.077 g, 0.22 mmol) in DMF (5 mL) were stirred at RT for 10 min, then ammonium hydroxide (2 mL) was added. The solution was stirred at RT for 16 h, then water (50 mL) and dichloromethane (50 mL) were added and the organic layer was separated, washed with water (50 mL), dried over Na2SO4, filtered and concentrated to give the title compound as a white powder (0.029 g, 38%). 1H NMR (400 MHz, DMSO) δ8.64 (d, J=3.8 Hz, 1H), 8.02 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.0 Hz, 1H), 7.86 (t, J=7.9 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.33 (t, J=5.3 Hz, 1H), 6.81-6.79 (m, 3H), 6.50 (d, J=8.4 Hz, 2H), 6.19 (t, J=6.1 HZ, 1H), 4.30 (d, J=6.0 Hz, 2H), 2.05-2.00 (m, 1H), 1.64-1.60 (m, 1H), 1.20-1.15 (m, 1H), 1.03-0.98 (m, 1H). ES-MS m/z 344.2 (MH+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]([CH3:15])[CH3:14].[CH3:16][CH:17]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH3:18]>C1COCC1.CCOC(C)=O.O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:16])[CH:8]=[C:7]2[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)c1c[nH]c2ccc(Br)cc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a suspension of NaH (509 mg, 20.16 mmol) in THF (50 ml) was added 5-bromo-3-isopropyl-1H-indole (4.55 g, 19.20 mmol). The reaction mixture was stirred at r.t. for 30 min, and TIPSCl was then added at r.t. The reaction was stirred further for 1 hr, diluted with EtOAc, and water was added to quench the reaction. The organic layer was collected and the water layer was further extracted with EtOAC once. The combined organic layer was dried over MgSO4, filtrated and concentrated. The residue was purified by column chromatography on silica gel, eluting with hexane to afford 5-bromo-3-isopropyl-1-triisopropylsilyl-1H-indole (5.1 g, 67.6%): 1H NMR (200 MHz, CDCl3): δ 7.53 (d, J=1.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.99 (m, 1H), 6.76(s, 1H), 2.92 (m, 1H), 1.44 (m, 3H), 1.14 (d, J=6.6 Hz, 6H), 0.93 (d, J=7.4 Hz, 18H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=Hexane (1:9); Rf=0.65.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1.[CH:14](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[CH:14][N:10]=[C:8]([OH:9])[C:6]=2[N:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Product: Oc1ncnc2ccc(Cl)nc12
Yield: 82 %

Procedure:
A suspension of 6-chloro-3-nitropicolinamide (12 g, 70 mmol) in triethyl orthoformate (490 ml) was refluxed for 3 hours. A yellow suspension was formed which was cooled to room temperate. The precipitate was collected by filtration, and dried under vacuum to obtain 6-chloropyrido[3,2-d]pyrimidin-4-ol (10.44 g, 82% yield).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=[C:5]2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12.I[CH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([CH2:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=[C:5]2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12
Reactant: ICC1CCOCC1
Reactant: CN1C(=O)c2c(n[nH]c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2c(nn(CC3CCOCC3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 140 °C

Procedure:
A mixture of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (50 mg, 0.155 mmol), 4-(iodomethyl)-tetrahydro-2H-pyran (70 mg, 0.310 mmol), and Cs2CO3 (101 mg, 0.310 mmol) in DMF (1 mL) is heated in microwave at 140° C. for 30 min. After cooling, the mixture is filtered through a 0.45 μm microfilter, and the filtrate is purified by a semi-preparative HPLC to give pure product as white powder. MS (ESI) m/z 421.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH:4]=[CH2:5])[CH3:3]>CC(O)C>[CH3:1][C:2]([OH:6])([CH2:5][CH2:4][C:2]([CH3:3])([OH:6])[CH3:1])[CH3:3]
Reactant: C=CC(C)(C)O
Solvent: CC(C)O
Product: CC(C)(O)CCC(C)(C)O

Procedure:
2-Methyl-3-buten-2-ol, 2-propanol and tert.-butyl peroxy pivalate (75% solution in aliphates) are reacted in a molar ratio of 1:15:0.3 at 90° C. and a pressure of 500 kPa as described in example 1. After a contact period of 20 minutes of the reaction mixture in a tube reactor 95% of the olefin used has been converted. 2,5-dimethylhexane-2,5-diol is formed with a selectivity of 76%.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38]C3CCCCO3)=[CH:34][CH:33]=2)[C:28](=[O:45])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][N:29]([C:32]2[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=2)[C:28](=[O:45])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Pyridinium p-toluenesulfonate (65 mg) was added to an ethanol solution (16 mL) of 4-benzyloxy-1-{4-[(2-tetrahydropyranyl)oxy]phenyl}-1H-pyridin-2-one (982 mg, 2.60 mmols) and refluxed for an hour. The reaction liquid was cooled to room temperature and the precipitate was recovered by filtration and washed with water and ethyl acetate to provide the title compound (746 mg, 98%).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:2]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([N:2]3[CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]4[CH2:5][CH2:6][CH:1]3[CH2:8][CH2:7]4)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: CCOC(=O)C1NC2CCC1CC2
Product: CCOC(=O)C1C2CCC(CC2)N1S(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1

Procedure:
Ethyl 2-azabicyclo[2.2.2]octane-3-carboxylate is subjected to a reaction similar to the reaction (c) of Example 1 using [4-(4-methoxyphenyl)phenyl]sulfonyl chloride in place of 4-methoxybenzenesulfonyl chloride, to give ethyl 2-{[4′-methoxy(1,1′-biphenyl)-4-yl]sulfonyl}-2-azabicyclo[2.2.2]octane-3-carboxylate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])(C)(C)C.C(O[C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[N:36]=2)[CH:30]=1)=O)(C)(C)C>>[CH3:41][C:37]1[N:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:42])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[CH:39][N:38]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: Cc1nccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (138 mg, 0.5 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (46 mg).