Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2/[C:15](=[N:17]/[NH2:18])/[NH:14][C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]([O-])([O-])OCC>>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][N:18]=[CH:25][N:14]3[C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC([O-])[O-]
Reactant: CCCCCn1c(=O)[nH]/c(=N\N)c2c1ncn2Cc1ccccc1
Product: CCCCCn1c(=O)n2cnnc2c2c1ncn2Cc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
(6Z)-7-Benzyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 6-hydrazone (0.50 g, 1.5 mmol) was mixed with ethyl orthoformate (5 mL, 30 mmol). After being stirred at 60° C. for 1 h, the reaction mixture was concentrated in vacuum. The residue was treated with ether to yield the desired product as a white solid (0.25 g, 48.5%). LCMS calculated for C18H21N6O (M+H): 337.2. found: 337.1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([F:17])=[CH:4][N:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([F:17])=[CH:4][N:3]=[C:2]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Fc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cnc(-c2cccs2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 28.1 %

Procedure:
A mixture of 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoropyrimidin-4-amine (250 mg, 0.84 mmol, 1.0 eq), thiophen-2-ylboronic acid (150 mg, 1.18 mmol, 1.4 eq), Pd(dppf)Cl2 (69 mg, 0.084 mmol, 0.1 eq), Na2CO3 (356 mg, 3.36 mmol, 4 eq), 1,4-dioxane (10 ml) and water (1.5 ml) was stirred at 100° C. under a nitrogen atmosphere for 15 h. The reaction mixture was allowed to cool to room temperature and concentrated to give a residue. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 100:1 as eluent) to afford title compound N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-2-(thiophen-2-yl)pyrimidin-4-amine (Compound 41) (71.2 mg, 28.1%) as a solid. LC-MS (m/z)=302.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.77 (d, J=4 Hz, 2H), 1.01 (d, J=7.2 Hz, 2H), 1.97 (t, J=4.4 Hz, 1H), 6.58 (s, 1H), 7.21 (t, J=4.2 Hz, 1H), 7.76 (m, 2H), 8.32 (d, J=3.2 Hz, 1H), 10.12 (s, 1H), 12.24 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[CH:13]=[CH:14][C:15]4[O:19][C:18]([C:20](OC)=[O:21])=[CH:17][C:16]=4[CH:24]=3)=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[CH:13]=[CH:14][C:15]4[O:19][C:18]([CH2:20][OH:21])=[CH:17][C:16]=4[CH:24]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2cc(-c3ccc4ccc(Cl)cc4n3)ccc2o1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc2cc(-c3ccc4ccc(Cl)cc4n3)ccc2o1
Reaction time: 2 h

Procedure:
To a mixture of 7-chloro-2-(2-methoxycarbonylbenzofuran-5-yl)quinoline (0.92 g) in tetrahydrofuran (10 ml), lithium aluminum hydride (76.7 mg) was added dropwise under ice cooling. After being stirred for 2 hours, the resulting mixture was poured into a mixture of ice and diluted aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and toluene. The fractions containing object compound were combined, concentrated under reduced pressure, and recrystallized from toluene to give 7-chloro-2-(2-hydroxymethylbenzofuran-5-yl)quinoline (0.58
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[CH:19]([NH2:23])([CH2:21][CH3:22])[CH3:20]>C(O)C>[CH:19]([NH:23][C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([Cl:11])[C:7]=1[N+:8]([O-:10])=[O:9])([CH2:21][CH3:22])[CH3:20]
Reactant: CCC(C)N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCO
Product: CCC(C)Nc1c(C(F)(F)F)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]

Procedure:
To a stirred mixture of 20 g. (0.0655 mole) of 2,4-dichloro-3,5-dinitrobenzotrifluoride and 150 ml. of absolute ethanol was added 9.58 g. (0.131 mole) of sec-butylamine, dropwise, over a period of about 15 minutes. The resultant solution was refluxed for two hours and the ethanol then removed by distillation under reduced pressure. The solid yellow residue was triturated with 300 ml. water to dissolve the sec-butylamine hydrochloride. The water insoluble product was isolated by filtration, washed with water, and then dissolved in 600 ml. of refluxing 95% ethanol. Upon cooling, the product crystallized. Filtration gave 20.4 g. of a yellow crystalline solid, melting at 90.5° - 91.5°C.
Reaction SMILES: [CH2:1]1[S:18][CH:5]([CH2:6][C@@H:7]([N:15]=[N+]=[N-])[C@H:8]([C:12]([OH:14])=[O:13])[C@@H:9]([CH3:11])[OH:10])[S:4][CH2:3][CH2:2]1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CO.[Pd]>[CH2:3]1[S:4][CH:5]([CH2:6][C@@H:7]([NH2:15])[C@H:8]([C:12]([OH:14])=[O:13])[C@@H:9]([CH3:11])[OH:10])[S:18][CH2:1][CH2:2]1
Reactant: C[C@@H](O)[C@@H](C(=O)O)[C@@H](CC1SCCCS1)N=[N+]=[N-]
Agent: [Pd]
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CO
Product: C[C@@H](O)[C@@H](C(=O)O)[C@H](N)CC1SCCCS1
Reaction time: 5 h

Procedure:
A mixture of 3-azido-4-C-carboxy-2,3,4,6-tetradeoxy-D-arabino-hexose trimethylene dithioacetal (920 mg, 3.01 mmol) and 5% palladium-on-charcoal (375 mg) in methanol (25 ml) is hydrogenated at a pressure of 1 atmosphere for 5 hours at room temperature. The catalyst is then removed by filtration through Celite and the filtrate evaporated and dried in vacuo to give TLC-chromatographically-homogeneous, ninhydrin-positive amino acid trimethylene dithioacetal; yield 816 mg (97%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:13]=[CH:14][C:15]([C:17](O)=O)=[CH:16][C:4]=2[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].N>>[N:20]1[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:17]=1[C:15]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]([CH3:1])=[N:3][C:4]=2[CH:16]=1
Reactant: Nc1ccccc1N
Reactant: Cc1nc2cc(C(=O)O)ccc2n1-c1ccccc1
Agent: N
Product: Cc1nc2cc(-c3nc4ccccc4[nH]3)ccc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 130.6 %

Procedure:
A 2-neck flask (20 mL) equipped with reflux condenser was charged with 2-methyl-1-phenylbenzimidazole-5-carboxylic acid (see Synthesis Example 1-3) (0.15 g, 0.59 mmol) and polyphosphoric acid (approx. 2 g), and this was heated to 120° C. To this was added 1,2-diaminobenzene (0.09 g, 0.83 mmol), and this was heated to 160° C. and stirred under those conditions for 20 hours. After being allowed to cool to room temperature, ice was added and concentrated aqueous ammonia (28%) was added to the liquid to give approx. pH 9. The precipitated crystals were filtered off, these were washed with distilled water (approx. 3 mL, 2 times), and then dried to yield the title compound (0.25 g, quant.) as greenish pale yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1.[Li+].CC([N-]C(C)C)C.CC(O)=O>C1COCC1.O>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2cccnc2)nc(N2CCOCC2)n1
Reaction time: 0.08 h
Yield: 43 %

Procedure:
1-[4-Chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (U.S. Pat. Appl. Publ. No. US 2007/244110) (0.183 g, 0.5 mmol) was added to a mixture of 3-aminopyridine (0.20 g, 2 mmol) and LDA (1.0 mL, 2 M in THF, 2 mmol) in 10 mL THF at room temperature. After 5 min, the mixture was neutralized with HOAc, diluted with water, extracted with EtOAc, and dried (Na2SO4). Chromatography on alumina eluting with CH2Cl2/EtOAc (4:1) gave a solid, which was recrystallized from i-Pr2O to give 92 mg (43% yield) of (4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridinyl)-1,3,5-triazin-2-amine: mp (i-Pr2O) 228-230° C.; 1H NMR (CDCl3) δ 8.86 (br, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.38 (d, J=6.2 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.89 (dd, J=6.2, 2.9 Hz, 1H), 7.58 (br t, JHF=53.8 Hz, 1H), 7.42 (m, 2H), 7.34 (dd, J=8.3, 4.7 Hz, 1H), 7.28 (m, exchangeable with D2O, 1H), 3.93 (m, 4H), 3.82 (m, 4H); Anal. Calcd. for C20H18F2N8O: C, 56.6; H, 4.3; N, 26.4. Found: C, 56.5; H, 4.4; N, 26.1%.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:9]1[C:10]2[NH:14][C:13]([C:15]([C:49]3[CH:54]=[CH:53][C:52]([C:55]([O:57]C)=[O:56])=[CH:51][CH:50]=3)=[C:16]3[N:48]=[C:19]([C:20]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[C:21]4[NH:41][C:24](=[C:25]([C:31]5[CH:36]=[CH:35][C:34]([C:37]([O:39]C)=[O:38])=[CH:33][CH:32]=5)[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.Cl>CO.C1COCC1>[C:37]([C:34]1[CH:33]=[CH:32][C:31]([C:25]2[C:24]3[NH:41][C:21]([C:20]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[C:19]4[N:48]=[C:16]([C:15]([C:49]5[CH:50]=[CH:51][C:52]([C:55]([OH:57])=[O:56])=[CH:53][CH:54]=5)=[C:13]5[NH:14][C:10](=[C:9]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:29]6[CH:28]=[CH:27][C:26]=2[N:30]=6)[CH:11]=[CH:12]5)[CH:17]=[CH:18]4)=[CH:22][CH:23]=3)=[CH:36][CH:35]=1)([OH:39])=[O:38]
Reactant: CCCCCCc1c2nc(c(-c3ccc(C(=O)OC)cc3)c3ccc([nH]3)c(CCCCCC)c3nc(c(-c4ccc(C(=O)OC)cc4)c4ccc1[nH]4)C=C3)C=C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCc1c2nc(c(-c3ccc(C(=O)O)cc3)c3ccc([nH]3)c(CCCCCC)c3nc(c(-c4ccc(C(=O)O)cc4)c4ccc1[nH]4)C=C3)C=C2
Reaction time: 48 h

Procedure:
In a typical experiment, a solution of KOH (200 mg, 3.6 mmol) in methanol (1 ml) was added to a stirred solution of 5,15-dihexyl-10,20-bis-(4-methoxycarbonylphenyl)-porphyrin (31 mg, 0.04 mmol) in THF (8 ml) and the reaction mixture was stirred for 2 d. Water (50 ml) and hydrochloric acid were then added until the pH was adjusted to 4-6. The aqueous layer was extracted with dichloromethane (2×100 ml) and the organic layer was separated, washed with water until neutral and dried over sodium sulfate. The solvent was evaporated and the title compound 5,15-bis-(4-carboxyphenyl)-10,20-dihexyl-porphyrin was obtained after recrystallization from dichloromethane/aqueous methanol (26 mg, 87%).
Reaction SMILES: C(Cl)Cl.[N+:4]([C:7]1[CH:20]=[CH:19][C:10]([CH2:11][O:12][C:13]([NH:15][C:16](=[NH:18])[CH3:17])=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5].Cl.[CH3:22][O:23][C:24]1[CH:57]=[CH:56][C:27]([CH2:28][S:29][C@@H:30]2[CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[C@H:32]([C:48]([N:50]3[CH2:55][CH2:54]N[CH2:52][CH2:51]3)=[O:49])[CH2:31]2)=[CH:26][CH:25]=1>CO>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][S:29][C@@H:30]2[CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[C@H:32]([C:48]([N:50]3[CH2:55][CH2:54][N:18]([C:16](=[N:15][C:13]([O:12][CH2:11][C:10]4[CH:9]=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:20][CH:19]=4)=[O:14])[CH3:17])[CH2:52][CH2:51]3)=[O:49])[CH2:31]2)=[CH:56][CH:57]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCNCC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(C)=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 33.3 %

Procedure:
11 ml of methylene chloride, followed by 452 mg of N-(4-nitrobenzyloxycarbonyl)acetamidine, were added to a solution of 1.1 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in step (ii) above] in 22 ml of methanol, whilst heating the solution under reflux. The resulting mixture was then heated under reflux for a further 4 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and methanol as the eluent to give 466 mg of the title compound, as a powder.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([C@@H:43]2[CH2:47][CH2:46][O:45][CH2:44]2)[C:39](=[O:48])[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([C@@H:43]4[CH2:47][CH2:46][O:45][CH2:44]4)[C:39](=[O:48])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1cc(Br)ccn1[C@@H]1CCOC1
Product: C[C@@H](c1ccc(-c2ccn([C@@H]3CCOC3)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 65 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 4-bromo-1-[(R)-tetrahydro-furan-3-yl]-1H-pyridin-2-one following a procedure analogous to that described in Example 1. Yield: 65% of theory; LC (method 3): tR=2.95 min; Mass spectrum (ESI+): m/z=517 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])(C(C)(C)C)(C)C.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:30]1[CH:31]=[C:32]([O:27][C:25]2[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[CH:26]=2)[C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CO)Oc1cc(Oc2cc(F)cc(F)c2)cc(C(=O)Nc2ccn(C)n2)c1
Yield: 22.3 %

Procedure:
A solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (202 mg, 0.5 mmol), 3,5-difluorophenylboronic acid (156 mg, 1.0 mmol), copper (II) acetate (182 mg, 1.0 mmol), triethylamine (252 mg, 2.5 mmol) and freshly activated 4 Å molecular sieves (1.5 g) in DCM (10 mL) was stirred at ambient temperature and under ambient atmosphere for 64 hours. The reaction mixture was filtered, washed with DCM (2×10 mL), evaporated in vacuo and the residual oil partitioned between ethyl acetate (25 mL) and 1M hydrochloric acid (10 mL). The ethyl acetate layer was separated, washed sequentially with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), and evaporated to a residue which was chromatographed by preparative HPLC on C18 reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA) as eluant to give the title compound (45 mg).
Reaction SMILES: C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:48]1[CH:49]=[C:50]([C:55]#[N:56])[C:51]([F:54])=[CH:52][CH:53]=1.[CH2:57]([O:59]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:58]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:57]([C:48]1[CH:49]=[C:50]([C:55]#[N:56])[C:51]([F:54])=[CH:52][CH:53]=1)(=[O:59])[CH3:58]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(F)c(C#N)c1

Procedure:
Under an argon atmosphere, 449 mg (0.490 mmol) of tris(dibenzylideneacetone)dipalladium and 671 mg (1.078 mmol) of rac-1,1′-binaphthalene-2,2′diylbis(diphenylphosphane) are added to 4.90 g (24.5 mmol) of 3-bromo-6-fluorobenzenecarbonitrile in 180 ml of toluene. After the addition of 10.6 g (29.4 mmol) of (1-ethoxyvinyl)tributylstannane, the mixture is stirred under reflux overnight. The reaction mixture is subsequently concentrated and the residue is taken up in 200 ml of THF. After the addition of an aqueous 2N hydrogen chloride solution (50 ml), the mixture is stirred at room temperature for 4 h. The reaction mixture is subsequently neutralized using a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10:1→3:1). 3.50 g (88% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][C:18]=3[F:31])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].O1CCC[CH2:35]1.S(C1C=CC(C)=CC=1)(OC)(=O)=O>O.CN(C)C=O>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][O:29][CH3:35])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][C:18]=3[F:31])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@@H]4CO)cc3F)CC2)c(C)c1
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H]1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (138 mg) and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 1, (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-hydroxymethylpyrrolidin-2-one (330 mg) was obtained. To a mixture of the obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-hydroxymethylpyrrolidin-2-one (330 mg) and sodium hydride (37 mg) were added tetrahydrofuran and N,N-dimethylformamide, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added methyl tosylate (117 μL), and the mixture was further stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-methoxymethylpyrrolidin-2-one. The obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-methoxymethylpyrrolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate was added and the mixture was stirred. The reaction mixture was concentrated under reduced pressure, diethyl ether was added, and the precipitate was collected by filtration to give the title compound (48 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]([CH3:18])(=O)=O)[N:3]=1.[CH2:19](S)C.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:15][CH2:18][CH3:19])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCS
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCSc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, ethanethiol and DBU in DME. EI-MS m/e (%): 246 (M+, 49), 245 ([M—H]+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>COCCCOCCCO>[CH3:1][C:2]1[CH:11]=[C:10]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:9]2[C:4](=[CH:5][C:6]([C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(Cl)c2ccc(C(F)(F)F)cc2n1
Reactant: C1CNCCN1
Agent: COCCCOCCCO
Product: Cc1cc(N2CCNCC2)c2ccc(C(F)(F)F)cc2n1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
2-Methyl-4-chloro-7-(trifluoromethyl)quinoline (1.1 g, 4.4 mmol) was dissolved in dipropyleneglycolmonomethylether, piperazine was added (12 g, 14 mmol) and the mixture was stirred at 140° C. overnight. The solvent was removed under reduced pressure and the residue purified by column chromatography (prepacked silica column, gradient ethyl acetate/methanol with the addition of 1% ammonia) to yield 1.07 g of a solid. (3.6 mmol, 82%) MS (APCI): m/z=295.8 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:10][CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.O>C1COCC1>[CH3:27][C:26]1([CH3:28])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:10][CH2:11][CH2:12][O:13]1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCO)C(=O)OCc1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](C(=O)OCc2ccccc2)CCCOC1(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
To the solution of benzyl N-(tert-butoxycarbonyl)-5-hydroxy-D-norvalinate (Preparation 50, 3 g, 9.28 mmol) in THF (20 mL) was added 2,2-dimethoxypropane (12.07 mL, 92.8 mmol) and PPTS (catalytic amount), and the reaction was stirred for 5 hours at 60° C. The reaction mixture was poured into cold water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (2.5 g, 74%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])=[O:4].[OH-].[Li+]>C1COCC1.O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:10]([N:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[C:3]([OH:4])=[O:2])=[O:11])[CH:13]=1
Reactant: COC(=O)C1CCCN1C(=O)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCCN1C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of 1-(pyridine-3-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester (1.3 g, 5.4 mmol), in THF (13 mL) was added lithium hydroxide (0.34 g, 8.1 mmol) in water (1.3 mL) at room temperature (25° C.). The mixture was allowed to stir at room temperature (25° C.) over a period of 2 h. THF was evaporated from the reaction mixture, dissolve the residue in methanol acidified to pH=4, filtered and evaporated the sticky liquid on evaporation was triturated with diethyl ether, to obtain required compound as off-white solid (1.0 g, 83%).