Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:37]([O:39]CC)=[CH2:38])CCC.CCOC(C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:37]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1)(=[O:39])[CH3:38]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in Example 11, step (f), 100 mg, 0.199 mmol), tributyl(1-ethoxyvinyl)tin (86.3 mg, 0.239 mmol) and Pd(PPh3)2Cl2 (10.5 mg, 0.0149 mmol) in 2 mL of 1,4-dioxane was stirred at 90° C. for 2 h under Ar. After cooling to RT, the reaction was treated with EtOAc (40 mL) and washed with 15% citric acid aqueous solution (2×10 mL), H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10-20% EtOAc/hexane) to give 80.1 mg (86%) of the title compound as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C25H32N4O3Si, 465.2 (M+H), found 465.1.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[O:21]1[CH2:24][C:23](=[O:25])[CH2:22]1>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[C:23]1([OH:25])[CH2:24][O:21][CH2:22]1
Reactant: O=C1COC1
Reactant: Fc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC1(c2c(F)cncc2Br)COC1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
n-BuLi (1.6 M in hexane, 4.26 mL, 6.82 mmol) was added dropwise to a solution of diisopropylamine (1.05 mL, 7.39 mmol) in THF (14 mL) at −78° C. under Nitrogen atmosphere. The resulting mixture was warmed up to −40° C. and stirred for 10 min and recooled to −78° C. A solution of 3-bromo-5-fluoropyridine (1000 mg, 5.68 mmol) in THF (5 mL) was added dropwise at this temperature. After completion of addition, the reaction mixture turned brown. After 30 min, Oxetan-3-one (491 mg, 6.82 mmol) was added dropwise and the resulting mixture was stirred for 30 min at this temperature. The reaction was quenched with saturated NH4Cl solution. The mixture was extracted with ethyl acetate, and the combined extracts were washed with saturated NaHCO3 solution, dried over Na2SO4 and filtered. After concentration, 3-(3-Bromo-5-fluoro-pyridin-4-yl)-oxetan-3-ol (1190 mg, 84%) was obtained as a dark red solid; ESI-MS m/z: 249 [M+1]+, Retention time 0.83 min; 1H-NMR (MeOD, 400 MHz) δ 4.77 (d, J=8.8 Hz, 2H), 5.25 (d, J=8.8 Hz, 1H), 5.26 (d, J=8.8 Hz, 1H), 8.45 (d, J=1.6 Hz, 1H), 8.56 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>C1COCC1.CN(C=O)C>[CH:22]([NH:26][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)N
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC(C)NC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Sec-butylamine (253 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated. It was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (89 mg, 70%). NMR 1H (ppm, CDCl3): 7.95 (s, 1H), 7.68 (d, J3=7.51 Hz, 2H), 7.59 (d, J3=7.63 Hz, 2H), 7.50-7.33 (m, 4H), 5.97 (br. s., 1H), 4.30 (hept., J3=6.86 Hz, 1H), 1.58 (quint., J3=7.26 Hz, 1H), 1.23 (d, J3=6.56 Hz, 3H), 0.97 (t, J3=7.36 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH:20][C:21]([OH:23])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][S:29][CH2:28][CH2:27]2)=[O:23])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CSCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccccc2C=CC(=O)O)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccccc2C=CC(=O)N2CCSCC2)=C(C)C1=O
Yield: 39.7 %

Procedure:
3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (20 mg, 0.058 mmol) obtained in Example 67 and thiomorpholine (0.009 ml, 0.087 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (10 mg, 0.023 mmol, yield 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]>>[C:23]([NH:22][CH2:21][CH2:20][NH:19][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1])(=[O:25])[CH3:24]
Reactant: CC(=O)NCCN
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Product: CC(=O)NCCNC(=O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
N-(2-Acetylamino-ethyl)-3-(2-chloro-4-iodo-phenylamino) -isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.32 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.44 mmol N-(2-amino-ethyl)-acetamide LC/MS [8.38 min; 4.59 (M+1)]
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=2[N:3]=1.Br[CH2:30][CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([N:10]1[C:9]2[C:8](=[O:19])[N:7]([CH2:30][CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:38])([CH3:40])[CH3:39])([CH3:35])[CH3:36])[C:6](=[O:20])[N:5]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=2[N:3]=[C:2]1[Cl:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1nc(Cl)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(COCC[Si](C)(C)C)c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To a solution of 8-chloro-7-(4-chlorobenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (250 mg, 0.568 mmol) in DMF (30 mL) was added (3-bromopropoxy)(tert-butyl)dimethylsilane (0.2 g, 0.794 mmol), followed by potassium carbonate (160 mg, 1.13 mmol). The mixture was stirred at 70° C. overnight. The reaction was cooled and partitioned between ethyl acetate and water. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 7-benzyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (340 mg, 97.4% yield) as colorless oil. LCMS retention time 4.675 min; LCMS MH+ 613.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:31].[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=5)=[C:3]([F:31])[CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)c(F)c4)CC3)n2CCS1
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: O
Solvent: COCCOC
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2F)cn1
Temperature: 25 °C
Yield: 121.1 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 25-3), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (130 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.06 mmol), and potassium carbonate (157 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (377 mg, quant.) in an orange oily form.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:34])[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21]3)=[O:19])=[CH:13][C:12]=2[Cl:33])=[CH:5][CH:4]=1)=[O:2].CC(C)=[O:37].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10](=[O:34])[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21]3)=[O:19])=[CH:13][C:12]=2[Cl:33])=[CH:7][CH:8]=1)([OH:37])=[O:2]
Reactant: CCCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C(=O)Oc3ccc(C=O)cc3)c(Cl)c2)CC1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C(=O)Oc3ccc(C(=O)O)cc3)c(Cl)c2)CC1
Reaction time: 0.67 h

Procedure:
The crude 2-chloro-4-[[(trans-4-heptylcyclohexyl)carbonyl]oxy]benzoic acid p-formylphenyl ester (19.1 g) obtained was dissolved in 800 ml of acetone. 30 ml of Jones' reagent were added dropwise to this solution within 15 minutes, the mixture warming slightly. The mixture was stirred for a further 40 minutes, then the separated inorganic material was filtered off under suction and the filtrate was concentrated. The residue was suspended in water and the suspension obtained was suction filtered. The residue was washed neutral with water on the suction filter and recrystallized from acetone, there being obtained 14.6 g of 2-chloro-4-[[(trans-4-heptylcyclohexyl)carbonyl]oxy]benzoic acid p-carboxyphenyl ester; m.p. (C-S) 135°-136° C., transition S-N 156° C., cl.p. (N-I) >300° C.
Reaction SMILES: II.S(=O)(=O)(O)O.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I:16]([O-])(=O)=O.[Na+]>O.C(O)(=O)C>[I:16][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:15])=[CH:10][CH:11]=1
Reactant: OCc1ccccc1
Reactant: [O-][I+2]([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: OCc1ccc(I)cc1
Reaction time: 1 h

Procedure:
A solution of glacial acetic acid (1350 ml.) and iodine (250 g.) was heated to 100° and then concentrated sulfuric acid (140 ml. of 95-97%) added, followed by benzyl alcohol (216 g.). Sodium iodate (92 g.) in water (500 ml.) was then introduced dropwise with stirring over a period of 1 hour. The temperature was maintained at 100°-110° for an additional 30 min. before the reaction mixture was poured onto 1 Kg. of crushed ice. The mixture was extracted with chloroform, the combined chloroform solution washed with water, dried, and concentrated. The remaining oil was distilled at reduced pressure to give p-iodobenzyl alcohol. A mass spectrum (70 ev) parent ion was measured at m/e 233.9545; calculated for C7H7IO, 233.9544. The ir and nmr spectrum were in agreement with the proposed structure. The use of a mass spectrum for identification of compounds is shown, for example, in R. Venkataraghaven, R. D. Board, R. Klimowsky, J. W. Amy, and F. W. McLafferty, Adv. Mass Spec., 4, 65 (1967) and R. Venkataraghaven, R. J. Klimowksy, F. W. McLafferty, Acc. Chem. Res., 3, 158 (1970).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([OH:11])=O)[CH:2]=[CH2:3].[CH2:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH3:13].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.S([O-])(O)(=O)=O.[K+]>ClCCl>[CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([CH2:12][CH3:13])[CH:15]=1)=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCn1cccc1C(=O)O
Reactant: CCc1cccc(N)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCn1cccc1C(=O)Nc1cccc(CC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A mixture of 1-allyl-1H-pyrrole-2-caboxylic acid (270 mg, 1.79 mmol), m-ethylaniline (0.43 g, 2.48 mmol), BOP-Cl (500 mg, 1.96 mmol) and triethylamine (210 mg, 2.08 mmol) in dichloromethane (3 ml) was stirred for 2 hours at room temperature. To the reaction mixture was added an aqueous 5% potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=5:1→3:1) to give the subject compound (229 mg, 50%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].[CH:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:21]([CH3:31])[CH:20]=1)=O.[OH-].[Na+]>CO.Cl>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH:9]=[CH:17][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:21]([CH3:31])[CH:20]=2)=[C:5]2[CH2:11][CH2:12][C:13]([CH3:15])([CH3:16])[CH2:14][C:4]=12)[CH3:2]
Reactant: Cc1cc(C=O)cc(C)c1CCC(=O)O
Reactant: CCc1sc(C(C)=O)c2c1CC(C)(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1sc(C(=O)C=Cc2cc(C)c(CCC(=O)O)c(C)c2)c2c1CC(C)(C)CC2
Yield: 86.4 %

Procedure:
A solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (400 mg, 1.69 mmol), 3-(4-formyl-2,6-dimethyl-phenyl)-propionic acid (419 mg, 2.03 mmol) and NaOH (1.7 g, 42.5 mmol) in methanol (17 mL) is stirred at 75° C. for 75 min before it is diluted with 1 N aq. HCl and extracted twice with EA. The organic extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with DCM containing 6% of methanol to give 3-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propenyl]-2,6-dimethyl-phenyl}-propionic acid (620 mg) as a pale yellow solid; LC-MS: tR=1.17 min; [M+1]=425.34; 1H NMR (CDCl3): δ 7.68 (d, J=15.8 Hz, 1H), 7.28 (s, 2H), 7.27 (d, J=15.8 Hz, 1H), 3.18 (t, J=7.0 Hz, 2H), 3.06-2.98 (m, 2H), 2.78 (q, J=7.6 Hz, 2H), 2.54-2.48 (m, 2H), 2.39 (s, 6H), 2.34 (s, 2H), 1.58 (t, J=7.0 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[NH:20][C:21](=[O:25])[N:22]=[CH:23][CH:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Br[CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][N:22]([CH2:31][CH3:32])[C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:27])([F:29])[F:28]
Reactant: CCBr
Reactant: N#Cc1cc(COc2ccnc(=O)[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Product: CCn1ccc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(C#N)c2)nc1=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(2-oxo-2,3-dihydro-4-pyrimidinyl)oxy]methyl}benzonitrile and bromoethane. LC-MS (ESI): m/z 450 [M+H]+; 4.11 min (ret time).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[N:22]=[C:21]([N:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][N:18]=1>O>[CH3:24][N:23]([CH3:25])[C:21]1[CH:20]=[CH:19][N:18]=[C:17]([NH:15][CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)[N:22]=1
Reactant: NC1CCN(CCc2ccccc2)CC1
Reactant: CN(C)c1ccnc(Cl)n1
Solvent: O
Product: CN(C)c1ccnc(NC2CCN(CCc3ccccc3)CC2)n1
Temperature: 120 °C
Reaction time: 20 h
Yield: 28.4 %

Procedure:
A mixture of 1-(2-phenylethyl)-4-piperidinamine (8.17 g) and 2-chloro-N,N-dimethyl-4-pyrimidinamine (6.3 g) was stirred for 20 hours at 120° C. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic layer was washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH(NH3) 96/4). The pure fractions were collected and the solvent evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 3.69 g (28.4%) of N4,N4-dimethyl-N2-[1-(2-phenylethyl)-4-piperidinyl]-2,4-pyrimidinediamine (comp. 11).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][CH2:12]1)[C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])=[O:4]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To 3-[(4-Methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (43 mg, 0.098 mmol) in dichloroethane (1.0 ml) was added benzaldehyde (15 ul, 0.146 mmol), followed by sodium triacetoxyborohydride (41 mg, 0.195 mmol). The reaction mixture was stirred at room temperature for 4 h, quenched with a saturated NaHCO3 solution, and then extracted with Ethyl acetate (3×5 ml). The combined extracts were then washed with brine and dried on Na2SO4, filtered and concentrated. The residue was purified by preparative chromatography (50% EtOAc/Hex) to give 32 mg (61%) of 3-[(1-Benzyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([F:14])([F:13])[C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=1>CC(C)=O.CCOC(C)=O>[Cl:21][C:22]1[N:27]=[C:26]([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:7][C:8]([F:13])([F:14])[C:9]([O:11][CH3:12])=[O:10])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=1
Reactant: COC(=O)C(F)(F)CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound methyl 3-(cyclopentylamino)-2,2-difluoropropanoate (400 mg, 2 mmol) was solubilized in acetone (20 mL, dry). The solution was cooled in an ice water bath under a nitrogen atmosphere and K2CO3 (552 mg, 4 mmol) added. To this, a solution of 2,4-dichloro-5-nitropyrimidine (407 mg, 2.1 mmol) in acetone (5 mL, dry) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 4 hr. After that, it was diluted with EtOAc and washed by brine and water. The organic extracts were dried over MgSO4, filtered and concentrated to yield the desired product which was used directly for next step without further purification. [M+H] calc'd for C13H15ClF2N4O4, 365. found 365.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[C:7]([C:26](=[O:28])[CH3:27])=[CH:6]1.[OH-].[Na+]>C1COCC1.O>[C:26]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:17]([CH3:18])[CH3:19])[CH:20]([CH3:21])[CH3:22])[CH:9]=2)[N:5]([CH2:4][C:3]([OH:29])=[O:2])[CH:6]=1)(=[O:28])[CH3:27]
Reactant: COC(=O)Cn1cc(C(C)=O)c2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cn(CC(=O)O)c2ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc12
Reaction time: 16 h

Procedure:
To a solution of (3-acetyl-5-triisopropylsilanyloxymethyl-indol-1-yl)-acetic acid methyl ester (109 mg, 0.138 mmol) in THF (5 mL) and water (0.5 mL) was added 1N NaOH (0.69 mL, 0.69 mmol), and stirring was continued at RT for 16 h. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAC (2×), the combined organics were dried (phase separator) and concentrated in vacuo to afford the title compound as a yellow wax. MS (LC/MS): 404 [M+H]+; tR (HPLC conditions k): 4.35 min.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[OH-].[Na+].CN(C)[CH2:10][CH2:11][C:12]([C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[CH:17][CH:18]=1)=O>CO>[NH2:5][C:3]([N:2]1[CH2:10][CH2:11][C:12]([C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:17][CH:18]=2)=[N:1]1)=[S:4]
Reactant: NNC(N)=S
Reactant: CN(C)CCC(=O)c1ccc(-c2cccc(Cl)c2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=S)N1CCC(c2ccc(-c3cccc(Cl)c3)o2)=N1

Procedure:
Thiosemicarbazide (1.0 equiv.) was dissolved in MeOH upon heating under nitrogen. Aqueous sodium hydroxide (6 M, 9.0 equiv.) was added to the reaction. A methanol solution of 3-(dimethylamino)-1-[5-(3-chlorophenyl)(2-furyl)]propan-1-one (1.0 equiv) was then added dropwise to the reaction mixture. The solvent was removed and the residue was dissolved in DCM and washed with water, brine, dried over MgSO4, and concentrated. The final compound was purified by preparative-HPLC to give amino{3-[5-(3-chlorophenyl)(2-furyl)](2-pyrazolinyl)}methane-1-thione; LC/MS m/z 306.2 (MH+); Rt=3.06 minutes.