Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.CCOC(C)=O.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>[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CSc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to Method C. To a degassed suspension of (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (1.07 g, 3.97 mmol) in 10 ml of 1-propanol were added bis(triphenylphosphine)palladium dichloride (112 mg, 0.16 mmol), 4-(methylthio)phenylboronic acid (1.00 g, 5.95 mmol) and 8 ml of 2N-solution of sodium carbonate. The mixture was stirred at 85° C. for 2 hours. The reaction mixture was diluted with EtOAc, filtered through Celite and washed with water. The organic layer was dried and concentrated. The solid was purified by chromatography on silicagel (EtOAc/MeOH/ammonia:66/33/1) and crystallization from n-hexane. Yield: 1.12 g (79%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:7]2[S:8][C:9]([B:11]([OH:16])[OH:12])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1cccc2ccsc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OB(O)c1cc2cccc(Cl)c2s1
Temperature: -30 °C
Yield: 96.2 %

Procedure:
To a solution of 7-chlorobenzo[b]thiophene (1.0 g, 5.92 mmol) in THF (25 mL) at −78° C. was added nbutyllithium (7.41 mL, 11.8 mmol, 1.6 M solution). The reaction was allowed to warm to −30° C. then was cooled back to −78° C. and triisopropyl borate (2.23 g, 11.8 mmol) was added. The mixture was allowed to warm to 0° C., saturated ammonium chloride added and the organic phase separated off and concentrated in vacuo. To the residue was added aqueous sodium hydroxide (10 mL, 2N solution) followed by water (30 mL) and the mixture was washed with DCM. The aqueous phase was acidified with 2N sulfuric acid, and the resulting precipitate isolated by filtration and dried under vacuum to yield 7-chlorobenzo[b]thiophene-2-boronic acid (1.21 g, 96%) as white solid. 1H NMR (400 MHz, CDCl3) δ=7.41 (t, J=7.70 Hz, 1H), 7.50 (d, J=7.70 Hz, 1H), 7.91 (d, J=7.70 Hz, 1H), 8.03 (s, 1H), 8.63 (s, 2H); MS (ES+): m/z 211.86 [M+].
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[C:15]([OH:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[OH-].[Na+].Cl[CH:22]([F:24])[F:23]>O>[F:23][CH:22]([F:24])[O:16][C:15]1[C:7]([F:6])=[C:8]([CH:12]=[C:13]([F:18])[C:14]=1[F:17])[C:9]([OH:11])=[O:10]
Reactant: FC(F)Cl
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Reaction time: 0.5 h

Procedure:
20 ml of dimethylformamide, followed by 4.97 g (0.026 mole) of 2,4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X=X'=F], were added in portions, whilst ice-cooling, to a solution of 2.18 g (0.052 mole) of sodium hydroxide in 5 ml of water. Thereafter the solution was stirred for 30 minutes, whilst ice-cooling. The reaction mixture was then transferred to a 200 ml stainless steel autoclave, and 100 ml of dimethylformamide containing 24.0 g (0.277 mole) of chlorodifluoromethane were added to it. The mixture was then stirred at between 100° and 110° C. for 5 hours under pressure. At the end of this time, the reaction mixture was poured into water and extracted with chloroform. The chloroform extracts were washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 9:1 by volume mixture of ethyl acetate and ethanol as the eluent, to afford 2.00 g of 3-difluoromethoxy-2,4.5-trifluorobenzoic acid as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH3:25][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1

Procedure:
A mixture of 2 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]-pyridazin-6-yl)phenyl]butanamide, 0.32 g sodium hydride (50% in oil), 0.41 ml of methyl iodide and 200 ml of dimethylformamide was reacted in the manner described in Example 2. The desired product was obtained as white crystals, 1.45 g, mp 140°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1>C1C=CC=CC=1>[C:26]([O:13][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][CH2:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1
Reactant: OCc1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(OCc1ccc(OCc2ccc(Cl)cc2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1.2g of 4-(4'-chlorobenzyloxy)benzyl alcohol, 1.0g of triethylamine and 25 ml of anhydrous benzene was added 0.9g of hydrochloride of nicotinoyl chloride at 10° C. The whole mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water. The organic layer was dried over sodium sulfate and then concentrated in vacuo to give a crystalline residue. The residue was recrystallized from ethanol to give 1.2g of 4-(4'-chlorobenzyloxy)benzyl nicotinate, mp 101°-2° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](Cl)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:17][C:18]1[CH:23]=[C:22]([O:8][C:6]2[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([NH2:1])[CH:7]=2)[CH:21]=[N:20][CH:19]=1
Reactant: Nc1cc(O)c(F)cc1F
Reactant: Clc1cncc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Oc2cncc(Cl)c2)c(F)cc1F
Temperature: 190 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 5-amino-2,4-difluorophenol (0.3 g, 2.07 mmol) in DMSO (2 mL) was added potassium t-butoxide (0.23 g, 2.07 mmol) at RT. After stirring for 1 h, 3,5-dichloropyridine (0.37 g, 2.5 mmol) and potassium carbonate (0.14 g, 1 mmol) were added and the mixture was heated to 190° C. for 1 h in microwave reactor. Water (30 mL) was added, and the product was extracted with EtOAc (2×35 mL) and the combined organic layers were washed with brine solution, dried (Na2SO4), concentrated in vacuo and purified by chromatography (EtOAc/hexane) to afford 5-(5-chloropyridin-3-yloxy)-2,4-difluorobenzenamine (0.35 g, 66% yield) as a solid. 1H NMR (400 MHz, Acetone-d6) δ 8.33-8.30 (m, 2H), 7.44 (t, J=2.4 Hz, 1H), 7.13 (t, J=10.8 Hz, 1H), 6.78 (t, J=8.4 Hz, 1H), 4.85 (brs, 2H); MS (ESI) m/z: 257.0 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[O:8][C:9]2[C:15]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]3=[O:28])=[C:14]([F:29])[CH:13]=[C:12]([Cl:30])[C:10]=2[N:11]=1)(=[O:5])[CH3:4].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>O1CCCC1>[C:3]([N:6]([C:7]1[O:8][C:9]2[C:15]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[N:18]([CH3:27])[C:17]3=[O:28])=[C:14]([F:29])[CH:13]=[C:12]([Cl:30])[C:10]=2[N:11]=1)[S:32]([CH3:31])(=[O:34])=[O:33])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1)S(C)(=O)=O
Reaction time: 1 h

Procedure:
A stirred suspension of 2.0 grams (51 mmole) of 60% sodium hydride (in mineral oil) in 25 mL of tetrahydrofuran is cooled in an ice bath. To this is added a solution of 10.2 grams (25.5 mmole) of 3-(2-acetylamino-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione in 25 mL of tetrahydrofuran. Upon completion of the addition 2.9 grams (25.3 mmole) of methanesulfonyl chloride is added. The reaction mixture is heated to reflux, where it stirs for one hour and then concentrated under reduced pressure, yielding 3-[2-(N-acetyl-N-methylsulfonylamino)-4-chloro-6-fluorobenzoxazol-7-yl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]1([CH3:19])[CH2:18][O:17]1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.[OH-].[Na+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]([OH:17])([CH3:19])[CH2:18][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: c1nc[nH]n1
Reactant: CC1(c2ccc(Oc3ccc(Cl)cc3)cc2Cl)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 110 °C

Procedure:
A mixture of 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-methyloxirane (109 g), 1,2,4-triazole (27 g) and sodium hydroxide (16 g) in NMP (1 L) was heated to 110° C. for 1 h. The reaction mixture was then partitioned between MTBE and aq. NaHCO3 solution and the aq. phase was extracted twice with MTBE. The combined organic phases were washed with water (2×), dried and evaporated. The crude product was crystallized from diisopropyl ether.
Reaction SMILES: C([O:4][C:5](=[O:36])[CH2:6][C@@H:7]([N:20]1[CH:24]=[CH:23][C:22]([C:25](=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[CH:21]1)[C:8]([NH:10][C@H:11]([C:16](=[O:19])[NH:17][CH3:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:9])C=C.N1CCOCC1>C(#N)C.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>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:25]([C:22]2[CH:23]=[CH:24][N:20]([C@@H:7]([C:8]([NH:10][C@H:11]([C:16](=[O:19])[NH:17][CH3:18])[C:12]([CH3:15])([CH3:13])[CH3:14])=[O:9])[CH2:6][C:5]([OH:36])=[O:4])[CH:21]=2)=[O:35])=[CH:28][CH:29]=1)#[N:34]
Reactant: C=CCOC(=O)C[C@H](C(=O)N[C@H](C(=O)NC)C(C)(C)C)n1ccc(C(=O)Cc2ccc(C#N)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CC#N
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)n1ccc(C(=O)Cc2ccc(C#N)cc2)c1)C(C)(C)C
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
Routine allyl ester cleavage conditions were previously described by Friedrich-Bochnitschek, S.; Waldmann, H.; Kunz, H. J. Org. Chem. 1989, 54, 751-756. To a solution of 3(R)-[3-[(4-cyanophenyl)acetyl]-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid allyl ester (247 mg, 0.501 mmol) in acetonitrile (2 mL) was added in succession Pd(PPh3)4 (29 mg, 0.026 mmol) and morpholine (226 μL, 2.60 mmol). The resultant mixture was carefully purged with argon. After 30 min, the resultant green mixture was stirred with 10% aqueous KHSO4 (20 mL) and extracted with CHCl3 (35 mL). The organic layer was washed with 10% aqueous KHSO4 (20 mL), dried over Na2SO4, and concentrated. Flash column chromatography with 1% HOAc/3% MeOH/CHCl3 and drying via azeotrope with n-heptane gave 243 mg (94%) of 3(R)-[3-[(4-cyanophenyl)acetyl]-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid as a yellow solid. 1H NMR (CD3OD): δ 8.09 (d, 1H, J=8.7 Hz), 8.05 (dd, 1H, J=2.8, 6.9 Hz), 7.78 (dd, 1H, J=1.9, 1.9 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.46 (d, 2H, J=8.4 Hz), 6.90 (dd, 1H, J=2.2, 2.2 Hz), 6.59 (dd, J=1.9, 3.1 Hz), 5.33 (t, 1H, J=7.5 Hz), 4.22-4.15 (m, 3H), 3.24 (t, 1H, J=8.7 Hz), 2.98 (dd, 1H, J=5.3, 17.4 Hz), 2.66 (d, 3H, J=4.7 Hz), 0.99 (s, 9H). IR (KBr): 3332, 2696, 2230, 1719, 1654, 1532, 1412, 1177 cm-1. HRFABMS: Calculated for C24H29N4O5 (M+H+): 453.2125. Found: 453.2125. Anal. Calculated for C24H28N4O5.0.5 HOAc.0.3 CHCl3 : C, 58.62; H, 5.89; N, 10.81. Found: C, 58.41; H, 5.72; N, 10.50.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][CH2:8][C:7]1=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][CH2:8][C:7]2=[O:18])[CH2:29][CH2:30]1
Reactant: O=C1CNc2ccccc2C(=O)N1CCCCBr
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: C1COCCO1
Product: O=C1CNc2ccccc2C(=O)N1CCCCN1CCN(c2ccccn2)CC1
Yield: 97 %

Procedure:
To a solution of 70 mg of the compound of Example 14 dissolved in 10 ml of dioxane was added 0.105 ml (3 equivalents) of 1-(2-pyridyl)piperazine and the mixture heated under reflux for 8 hours. The reaction treatment and purification were conducted as in Example 17, to obtain 86.2 mg of the desired compound (yield 97%). The maleate was obtained by converting the product to maleate in a conventional manner, followed by recrystallization from methylene chloride-ether.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].[F:34][C:35]1[CH:36]=[N:37][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[N:39][CH:40]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[N:37]=[CH:36][C:35]([F:34])=[CH:40][N:39]=3)[CH2:42][CH2:43]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Reactant: NC1(c2ncc(F)cn2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.089 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06 g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.023 g (44%). 1H NMR (400 MHz, CD3OD): δ 8.59 (d, J=0.4 Hz, 2H), 7.98-7.94 (m, 2H), 7.87 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.18 (s, 1H), 4.09 (s, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.79-1.76 (m, 2H), 1.52-1.48 (m, 2H). 19F NMR (376.57 MHz, CD3OD) δ−77.62 (TFA), −112.36, −122.73, −145.58 LCMS: (ES+) m/z=587.2 (M+H)+
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](O)(=[O:5])=[O:4].[NH2:9][C:10]1[CH:35]=[CH:34][C:13]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29](C)[C:28](=[O:31])[N:27](C)[C:26](=[O:33])[CH:25]=3)[CH2:20][CH2:19]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]([F:8])([F:7])[S:3]([NH:9][C:10]1[CH:35]=[CH:34][C:13]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:24]3[NH:29][C:28](=[O:31])[NH:27][C:26](=[O:33])[CH:25]=3)[CH2:22][CH2:23]2)=[CH:12][CH:11]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Cn1c(N2CCN(CCCOc3ccc(N)cc3)CC2)cc(=O)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=c1cc(N2CCN(CCCOc3ccc(NS(=O)(=O)C(F)(F)F)cc3)CC2)[nH]c(=O)[nH]1
Yield: 62.5 %

Procedure:
5 ml of a dichloromethane solution containing 0.65 ml of anhydrous trifluoromethanesulfonic acid was added at -78° C. to 25 ml of a dichloromethane solution containing 1.3 g of 6-[4-(3-[4-aminophenoxy]propyl)piperazin-1-yl]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione obtained in Example 6, and the temperature of the solution was then gradually elevated to room temperature, while it was stirred. 20 ml of dichloromethane and a 2% aqueous potassium carbonate solution were added to the reaction solution, followed by stirring until insolubles were dissolved therein. After the separation of the resultant organic layer, the aqueous layer was neutralized and then extracted with chloroform (50 ml×2), and the extract layers were joined and mixed with the organic layer previously obtained. The mixture was dried over sodium sulfate and then concentrated to obtain 1.1 g (yield: 62.5%) of 6-[4-(3-[4-trifluoromethanesulfonylaminophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione in a crystalline state.
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([C:10](=[O:12])[CH3:11])[S:8][CH:9]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC>C([O-])(O)=O.[Na+]>[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([C:10]2([CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[S:8][CH:9]=1
Reactant: OCCO
Reactant: CC(=O)c1nc(CCl)cs1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2nc(CCl)cs2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a condenser under inert atmosphere (N2), a solution of 1-(4-chloromethyl-thiazol-2-yl)-ethanone (992 mg, 5.65 mmol) in ethylene glycol (6.30 mL, 112.96 mmol) was treated with trimethylorthoformate (1.24 mL, 11.30 mmol) followed by LiBF4 (106 mg, 1.13 mmol). The reaction mixture was heated at 95° C. for 2 h. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (50 mL). The org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (4:1 hept-EA)=0.30. LC-MS-conditions 02: tR=0.84 min, [M+H]+=220.36.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([NH:11][NH:12][CH:13]=O)=O.C(N(CC)CC)C.Cl[Si](C)(C)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:13]=[N:12][N:11]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=CNNC=O
Reactant: Nc1ccc(Br)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Brc1ccc(-n2cnnc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 4-bromoaniline (1.71 g, 9.94 mmol), N′-formylformohydrazide (2.64 g, 30.0 mmol), and triethylamine (9.74 mL, 69.9 mmol, 7.00 equiv) in pyridine (40 mL). Chlorotrimethylsilane (19.2 mL, 151 mmol) was added drop-wise and the resulting solution was stirred for 18 h at 100° C., then cooled to room temperature. The resulting mixture was concentrated under reduced pressure and the residue was diluted with brine (50 mL) and extracted with ethyl acetate (6×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was washed with ether (30 mL) and the solids were collected by filtration to yield the title compound as a pink solid (1.6 g, 72%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:19][C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1ccncc1
Product: S=C(NN=Cc1ccncc1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.55 mmol) and 4-pyridine-carboxaldehyde (54 μL, 0.56 mmol) similar to Example 1 and isolated as a white solid (30 mg, 20%). 1H NMR (CDCl3): 10.74 (s, 1H), 8.66 (dd, J=1.5, 4.5 Hz, 2H), 7.93 (s, 1H), 7.51 (s, 1H), 7.48 (dd, J=1.5, 4.5 Hz, 2H), 6.24-6.13 (m, 2H), 4.29-4.24 (m, 1H), 3.05 (s, 1H), 2.97 (s, 1H), 1.94-1.87(m, 1H), 1.68 (d, J=9.0 Hz, 1H), 1.50(d, J=9.0 Hz, 1H), 1.45-1.39 (m, 1H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].[CH2:9](C(CC)C=O)[CH3:10]>O>[CH2:5]([CH:4]([CH2:9][CH3:10])[CH:3]=[CH:2][C:1]([OH:8])=[O:7])[CH3:6]
Reactant: CCC(C=O)CC
Reactant: CCCC=CC(=O)O
Solvent: O
Product: CCC(C=CC(=O)O)CC
Temperature: 90 °C
Yield: 84.1 %

Procedure:
The procedure followed was analogous to part (b) of Example 1, with the exception that, before the cracking reaction, the mixture, together with the added water, was boiled under reflux for 50 minutes at 90° C. and under a correspondingly reduced pressure. 260 g of 4-ethylhexenoic acid (boiling point 139°-141° C./25) were obtained, corresponding to a yield of 84.1%, relative to 2-ethylbutanal which had reacted.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][NH:5][CH3:6].C([O-])([O-])=O.[K+].[K+].[C:21]([O:30]N1C(=O)CCC1=O)([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=O>CC(C)=O.O>[C:10]([O:9][C:8]([NH:7][C@H:3]([CH2:4][N:5]([CH3:6])[C:21]([O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])[CH2:2][OH:1])=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CNC[C@H](CO)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Yield: 20 %

Procedure:
To a solution of crude tert-butyl (R)-3-hydroxy-1-(methylamino)propan-2-ylcarbamate in acetone (30 mL) and water (10 mL), there was added K2CO3 (12.8 g, 92.4 mmol), followed by Teoc-OSu (8.0 g, 30.8 mmol). The resulting mixture was stirred at rt until no starting material remained (˜1 h). Acetone was removed under vacuum and the aqueous residue was extracted with CH2Cl2 (4×15 mL). The combined organic layers were concentrated and the crude residue was purified by flash column chromatography to give (2R)-2-(t-butoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol (2.12 g, 20% steps). 1H NMR (400 MHz, CDCl3): 5.08 (br, 1H), 4.14 (m, 2H), 3.66-3.42 (m, 4H), 3.02 (m, 1H), 2.90 (s, 3H), 1.40 (S, 9H), 0.98 (m, 2H), 0.02 (s, 9H); MS m/z 349 (M+H+).