Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[C:19](=[O:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[CH3:18][O:17][C:15]1[CH:16]=[C:11]2[C:12](=[CH:13][CH:14]=1)[C:19]([OH:27])=[C:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:1]2
Reactant: CCCCCCCCC#Cc1cc(OC)ccc1C(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCCCCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Yield: 74.9 %

Procedure:
A solution of 1-[2-(1-decyn-1-yl)-4-(methyloxy)phenyl]-2-phenylethanone (192) (0.80 g, 2.21 mmol) in toluene was treated with a KHMDS solution in toluene to give 0.60 g (75%) of the title compound (193) as a light brown oil. 1H NMR (400 MHz, CDCl3): δ 0.85 (t, J=7.1 Hz, 3H), 1.10-1.30 (m, 10H), 1.35-1.50 (m, 2H), 2.46 (t, J=7.3 Hz, 2H), 3.93 (s, 3H), 5.16 (s, 1H), 7.06-7.10 (m, 2H), 7.22 (s, 1H), 7.32-7.37 (m, 2H), 7.42-7.48 (m, 1H), 7.50-7.56 (m, 2H), 8.08 (d, J=9.8 Hz, 1H). LCMS (ESI): m/z 363 (M+H)+, m/z 361 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[NH3:33]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([C:26]([NH2:33])=[O:28])[CH2:22][CH2:21]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)O)CC4)nc23)c1
Reactant: N
Solvent: O=S(Cl)Cl
Product: Cc1cccc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(N)=O)CC4)nc23)c1

Procedure:
Prepared from compound 134 of Example 1 by reaction with thionyl chloride and ammonia.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:21])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3]\[CH2:4][NH2:5].[CH2:22]([O:24][P:25]([CH2:30][C:31](O)=[O:32])([O:27][CH2:28][CH3:29])=[O:26])[CH3:23].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[O:32]=[C:31]([NH:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:21])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:30][P:25](=[O:26])([O:24][CH2:22][CH3:23])[O:27][CH2:28][CH3:29]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)NC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of compound 35 (0.360 g, 1.24 mmol), diethylphosphonoacetic acid (0.266 g, 1.36 mmol, prepared as disclosed by M. P. Cooke, K. B. Bicunas, Synthesis, 283, 1981, and 1-hydroxybenzotriazole (0.251 g, 1.86 mmol) in anhydrous THF (15 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.285 g, 1.49 mmol). The mixture was stirred at rt for 24 h, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on 230-400 mesh silica gel (Macherey-Nagel Silica Gel 60 Art. Nr. 81538) eluting with CH2Cl2-hexane-MeOH (98:70:4) and collecting 4 mL fractions. The appropriate fractions were combined, evaporated, and pump-dried to give intermediate 36 (0.464 g, 80%) as an oil: 1H-NMR (CDCl3, 80 Mhz) δ 1.33 (t, 6H, J=7.1 Hz, 2×CH3CH2), 1.60 (s, 9H, 3×CH3), 1.67 (s, 6H, 2×CH3), 2.02 (m, 12H, 6×CH2), 2.83 (d, 2H, J=20 Hz, CH2P), 3.86 (d, 2H, J=7.1 Hz, CH2), 4.14 (q, 4H, J=7.1 Hz, 2×CH3CH2), 5.10 (br, 3H, 3×CH), 5.20 (t, 1H, J=7.1 Hz, CH); MS (FAB+) m/e 468 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[C:12](=[O:16])[CH2:13][CH2:14][O:15][C:10]=2[C:9]=1[CH2:19][CH2:20][CH3:21].C([O:24][C:25]([C:27]1[O:28][C:29]2[C:35]([OH:36])=[CH:34][CH:33]=[CH:32][C:30]=2[CH:31]=1)=[O:26])C.C(=O)([O-])[O-].[K+].[K+].O.[OH-].[Li+].S(=O)(=O)(O)O>C1COCC1.O.C(OCC)(=O)C.CCOCC.CC(=O)CC>[O:16]=[C:12]1[C:11]2[CH:17]=[CH:18][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:36][C:35]3[C:29]4[O:28][C:27]([C:25]([OH:26])=[O:24])=[CH:31][C:30]=4[CH:32]=[CH:33][CH:34]=3)=[C:9]([CH2:19][CH2:20][CH3:21])[C:10]=2[O:15][CH2:14][CH2:13]1
Reactant: CCCc1c(OCCCCCBr)ccc2c1OCCC2=O
Reactant: CCOC(=O)c1cc2cccc(O)c2o1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCOc2cccc3cc(C(=O)O)oc23)ccc2c1OCCC2=O
Yield: 26 %

Procedure:
A mixture of 0.556 g (1.57 mmol) of 7-[(5-bromopentyl)oxy]-2,3-dihydro-8-propyl-4H-1-benzopyran-4-one, 0.323 g (1.57 mmol) of 7-hydroxy-2-benzofurancarboxylic acid ethyl ester, 0.866 g (6.26 mmol) of anhydrous granular potassium carbonate and 16 mL of 2-butanone was stirred and refluxed for 16.5 hrs. The resulting slurry was filtered with suction and the solids were washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the residue was purified by flash chromatography on 70 g of silica gel, eluting with 4:1 hexane-ethyl acetate giving 0.527 g (70%) of 7-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid ethyl ester as a white solid, mp 79.5°-81° C. A mixture of 0.262 g (0.55 mmol) of this ester in 3.5 mL of THF and 3.5 mL of water was treated with 35.1 mg (0.84 mmol) of lithium hydroxide monohydrate and the mixture was stirred for 17.5 hr. After being acidified with 16 mL of 3N aqueous sulfuric acid, the resulting mixture was worked-up with ether and ethyl acetate in the usual manner. The crude product was recrystallized from hexane-ethyl acetate to give 0.185 g (74.9%) of the title compound as a white solid, mp 152°-153.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[Cl:27][C:28]1[C:38]([Cl:39])=[CH:37][C:31]2[C:32](=O)[O:33][C:34](=[O:35])[C:30]=2[CH:29]=1>>[Cl:27][C:28]1[CH:29]=[C:30]2[C:31](=[CH:37][C:38]=1[Cl:39])[C:32](=[O:33])[N:23]([C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=1)[C:34]2=[O:35]
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C(=O)c6cc(Cl)c(Cl)cc6C5=O)c4)CC3)cccc2n1

Procedure:
Prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 5,6-dichloro-2-benzofuran-1,3-dione according to Method I.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[F:12].[CH2:13](C([SnH3])=C(CCCC)CCCC)[CH2:14]CC>O1CCOCC1.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>[F:12][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([F:8])[C:2]=1[CH:13]=[CH2:14]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1c(F)ccc([N+](=O)[O-])c1F
Yield: 76.5 %

Procedure:
A solution of 2-bromo-1,3-difluoro-4-nitrobenzene (0.20 g, 0.84 mmol), tributylvinylstannane (0.27 mL, 0.924 mmol) and Pd(PPh3)4 (48.6 mg, 0.042 mmol) in dioxane (4 mL) was heated at 150° C. for 1 h using microwave irradiation. The cooled reaction mixture was concentrated in vacuo, the resulting residue was purified by column chromatography (Si—PCC, eluant 2-10% EtOAc in cyclohexane) affording the title compound as a pale orange oil (0.119 g, 77%). 1H NMR (CDCl3, 300 MHz): 8.01-7.93 (1H, m), 7.03 (1H, dt, J=9.2, 1.9 Hz), 6.71 (1H, dd, J=18.0, 12.0 Hz), 6.15 (1H, d, J=18.0 Hz), 5.77 (1H, d, J=12.0 Hz)
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26].N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[ClH:37]>O.Cl[Cu]>[Cl:37][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26]
Reactant: Nc1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Reactant: Cl
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: O=C(Nc1ccncc1)c1cccn(C2CCc3c(Cl)cccc32)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a mixture of 1-(4-amino-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (600 mg, 1.0 eq) in H2O (4 mL) and conc. HCl (2 mL) was added dropwise NaNO2 (1.1 eq) in H2O (1 mL) at 0° C., the mixture was stirred at room temperature for 30 minutes. Then this mixture was added to another flask containing CuCl (1.5 eq), 2 mL H2O and 1 mL aqueous HCl at 0° C., the mixture was stirred for 5 h. At the end of reaction, saturated Na2CO3 aqueous was added to adjust to pH 12. The aqueous solution was extracted with ethyl acetate three times. The combined organic layer was washed with brine and dried over MgSO4, evaporated the filtrate to give the crude product, which was purified by Flash Column (DCM:MeOH=30:1) to afford 1-(4-chloro-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (350 mg, 55%). MS (ESI) 366.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 12.31 (s, 1H), 8.61 (bd, 1H), 8.53 (bs, 2H), 7.69 (bs, 2H), 7.38 (bd, 1H), 7.26 (bm, 2H), 7.03 (d, J=6.0 Hz, 2H), 6.69 (bs, 1H), 6.46 (bs, 1H), 3.05-3.25 (bm, 2H), 2.91 (bd, 1H), 2.08 (bd, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:24])[C@@H:12]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]([N:11]([CH3:24])[C@H:12]([CH2:13][OH:14])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C(=O)OCc1ccccc1)[C@H](CO)CC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a mixture of (S)-2-((benzyloxycarbonyl)(methyl)amino)-4-tert-butoxy-4-oxobutanoic acid dicyclohexylamimonium salt (20 g, 0.0386 mol) and Et3N (7.90 mL, 0.0579 mol) in THF (500 mL) was added isobutyl chloroformate (6.05 mL, 0.0463 mol) at 0° C. The reaction mixture was stirred for 1 h, and filtered to remove TEA salt. To the filtrate was added a solution of NaBH4 (2.19 g, 0.0579 mol) in THF (50 mL) and water (100 mL) at 0-5° C. The reaction mixture was stirred at RT for 1 h and quenched with saturated NH4Cl solution. The reaction mixture was concentrated to remove most of THF and extracted with EtOAc (700 mL×3). The organic layers were washed with water, NaHCO3 and brine, dried over Na2SO4, and concentrated to give (S)-tert-butyl 3-((benzyloxycarbonyl)(methyl)amino)-4-hydroxybutanoate (10 g), which was used without further purification. LRMS (M+Na+) m/z 346.1.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[CH2:34][C@@:32]2([CH3:33])[C@@H:28]([CH2:29][CH2:30][C@@H:31]2[OH:35])[C@@:27]2([CH:36]=[CH2:37])[C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([OH:38])=[CH:23][C:24]=1[CH2:25][CH2:26]2>>[CH3:1][N:2]([CH3:3])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[CH2:34][C@@:32]2([CH3:33])[C@@H:28]([CH2:29][CH2:30][C@@H:31]2[OH:35])[C@@:27]2([CH:36]=[CH2:37])[C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([OH:38])=[CH:23][C:24]=1[CH2:25][CH2:26]2
Reactant: CNC
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCCl)C[C@@]1(C)[C@H]2CC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCN(C)C)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with dimethylamine (2 M in tetrahydrofuran, 10 equivalents) with the addition of sodium carbonate analogously to instructions 17.2, 33 mg of mixture 30b yields 30 mg of amine 32b as a colorless foam (GC-MS: m/z theor.: 425, pract.: 425).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1.[N:31]([O-])=O.[Na+].O>C(O)(=O)C>[NH2:31][C:12]1[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:8][C:9]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[N:10][C:11]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: c1ccc(N2CCN(c3nc(N4CCOCC4)cc(N4CCOCC4)n3)CC2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. 4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine (3.0 g, 7.31 mmol) was dissolved in acetic acid (20 ml), an aqueous solution (1 ml) of sodium nitrite (605 mg, 8.78 mmol) was dripped in under water cooling, and agitation was done for 30 minutes at room temperature. After adjusting the pH to approximately 4.0 with a 2N NaOH aqueous solution, extraction was carried out 2 times using dichloromethane. After washing with water, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. The residue was dissolved in a methanol (40 ml)-ethyl acetate (40 ml) mixture solvent, 300 mg of Pd/C was added, and catalytic hydrogenation was done for 2 hours under atmospheric pressure. The Pd/C was filtered using celite, and the filtered liquid was distilled away under reduced pressure. The residue was washed with ether, and 1.63 g (52% yield) of 5-amino-4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained. The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 63 are shown below.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[Cl:13][C:14]1[CH:29]=[CH:28][C:17]2[N:18]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:19](=[S:21])[NH:20][C:16]=2[CH:15]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:25]1[CH2:24][CH2:23][CH:22]([N:18]2[C:17]3[CH:28]=[CH:29][C:14]([Cl:13])=[CH:15][C:16]=3[NH:20][C:19]2=[S:21])[CH2:27][CH2:26]1
Reactant: S=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: BrCC1COc2ccccc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: S=c1[nH]c2cc(Cl)ccc2n1C1CCN(CC2COc3ccccc3O2)CC1

Procedure:
2.3 g of 2-bromomethyl-1,4-benzodioxane, 2.35 g of 4-(5-chlorobenzimidazole-2-thion-1-yl)-piperidine, 1.4 ml of triethylamine and 0.3 g of sodium iodide were warmed at 60° C. in 25 ml of anhydrous dimethylformamide for 60 hours, and the mixture was then poured onto ice-water. The precipitate which had separated out was filtered off with suction, washed with water and dried.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][N:7]([CH3:18])[C:8]([C:10]1[C:15](Br)=[CH:14][N:13]=[C:12]([CH3:17])[N:11]=1)=[O:9].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][N:7]([CH3:18])[C:8]([C:10]1[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:14][N:13]=[C:12]([CH3:17])[N:11]=1)=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ncc(Br)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ncc(-c2ccccc2)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Yield: 56.9 %

Procedure:
To a suspension of 0.456 g (1 mmol) 5-bromo-2-methyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, 0.034 g (0.2 mmol) tetrakis-(triphenylphosphin)palladium and 0.121 g (1 mmol) phenylboronic acid in 20 ml 1,2-dimethoxyethane a solution of 0.105 g (1 mmol) Na2CO3 in 8 ml H2O was added. The resulting reaction mixture was heated at reflux for 16 hrs. After evaporation of the 1,2-dimethoxyethan, the aqueous phase was extracted twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 40:1) and crystallised (Ethanol) to give 0.258 g (57%) 2-methyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as off-white crystalls, m.p. 149-152°.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH2:5]([C:7]1([CH2:16][CH3:17])[C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9][C:8]1=[O:15])[CH3:6]>C([N+](CC)(CC)CC)C.CN(C)C=O>[OH:4][CH:2]([CH3:3])[CH2:1][N:11]1[C:12](=[O:13])[C:7]([CH2:5][CH3:6])([CH2:16][CH3:17])[C:8](=[O:15])[N:9]([CH2:1][CH:2]([OH:4])[CH3:3])[C:10]1=[O:14]
Reactant: CCC1(CC)C(=O)NC(=O)NC1=O
Reactant: CC1CO1
Agent: CC[N+](CC)(CC)CC
Solvent: CN(C)C=O
Product: CCC1(CC)C(=O)N(CC(C)O)C(=O)N(CC(C)O)C1=O
Temperature: 100 °C
Yield: 102.7 %

Procedure:
40.7 g (0.7 mol) of propene oxide are added dropwise over the course of 1 hour to a mixture of 55.3 g of 5,5-diethylbarbituric acid (0.3 mol), 2.77 g of tetraethylammonium chloridde (5 mol percent) and 400 ml of dimethylformamide at 35° C. whilst stirring. Thereafter the mixture is gradually heated to 100° C. After 7 hours' stirring at 100° C. the mixture is worked-up in accordance with example 4. 92.5 g of crude 1,3-di(β-hydroxy-n-propyl)-5,5-diethylbarbituric acid (99.5% of theory) are obtained. The product boils at 138°-148° C. under 0.08 mm Hg; 75.2 g or pure product (80% of theory) are obtained.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([CH2:8][OH:9])[O:6][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4]1.[OH-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:9][CH2:8][C@H:7]1[C@H:3]([CH2:2][O:1][CH2:5][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC[C@@H]1OC(c2ccccc2)O[C@H]1CO
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: c1ccc(COC[C@@H]2OC(c3ccccc3)O[C@H]2COCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
15 g (71.4 mMol) (4S,5S)-4,5-dihydroxymethyl-2-phenyl-1,3-dioxolan are rendered completely anhydrous by evaporating 2× with 300 ml toluene and the oil remaining in the reaction vessel is dissolved in 150 ml toluene. 30 g powdered KOH (535 mMol) and 71.5 g (418 mMol) benzyl bromide are added and the reaction mixture stirred for 15 hours at 80° C. The mixture is cooled, the remaining toluene-phase decanted, and the inorganic component removed from the residual phase by stirring 2× with 200 ml toluene and decanting. The combined toluene phases are filtered through talc, evaporated and the remaining oil filtered fraction-wise through 2 kg silica gel 60 using methylene chloride as solvent. Fractions containing benzyl bromide are disposed of. The title compound is obtained as a light yellow fluid with a rotation of [α]D20 =+10.1 (±1)° (c=1.4 in chloroform).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:31])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)=[O:31])=[CH:13][CH:14]=1
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
The compound (545 mg) obtained in Example 15-3 was dissolved in anhydrous methanol (10 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (10.0 ml), and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and subjected to extraction with chloroform, followed by washing with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off, thereby obtaining the subject compound (389 mg) as a colorless crystal.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[NH:11]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: O=C(CNc1ccccc1)c1ccccc1

Procedure:
100 g of ω-bromoacetophenone are dissolved in 600 ml of absolute ethanol, followed by the dropwise addition at 20° C. of 100 g of aniline. On completion of the addition, the ω-anilinoacetophenone formed precipitates in crystalline form. Yield: 62 g=59%; m.p: 97°-99° C.
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH:28]=2)[N:14]=1)[CH3:4]>CN(C=O)C.[Pd]>[NH2:1][C:2](=[O:42])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[N:26][N:27]([CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[CH2:33][CH2:34]3)[CH:28]=2)[N:14]=1)[CH3:4]
Reactant: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F

Procedure:
A solution of tert-butyl 4-(4-((4-((2-(1-amino-1-oxopropan-2-yl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate A65 (3.30 g, 5.66 mmol) in DMF (50 mL) and TEA (5 mL) was stirred with 10% Pd/C (wetted with ca. 53% water, 3.00 g) under an atmosphere of H2 for 20 hours at 35° C. The mixture was filtered through Celite and the solvent was removed in vacuo. Purification by column chromatography (Biotage Isolera, 120 g SiO2 cartridge, 20-100% EtOAc in petroleum benzine 40-60° C.) gave the title compound A66 as a yellow solid (3.32 g, 99%). LCMS-D: rt 3.54 min; m/z 588 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:13])[CH:10]=[N:9]1.S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[CH2:24]([O:16][C:15](=[O:17])[CH:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH:12]=[C:11]([Cl:13])[CH:10]=[N:9]2)=[C:2]([Cl:1])[CH:3]=1)[CH3:18])[CH3:25]
Reactant: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Yield: 83 %

Procedure:
14.25 g (50 mmoles) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid, 150 ml of ethanol and 7 g of concentrated sulfuric acid are heated to the boil for 10 hours. Concentration is effected, followed by pouring onto ice water, extracting with diethyl ether, washing of the organic solution with sodium hydrogen carbonate solution, drying the organic solution and distilling it to obtain 12.4 g (83% of theory) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid ethyl ester (b.p. 134° C./3·10-2 mm Hg).