Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][OH:34])[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:38][C@H:39]1[C@@H:44]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:43][C@H:42](Cl)[C@H:41]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@H:40]1[O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)(=[O:37])[CH3:36].CC1C=C(C)C=C(C)N=1>CCOCC.Cl([O-])(=O)(=O)=O.[Ag+]>[C:35]([O:38][C@H:39]1[C@@H:44]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:43][C@H:42]([O:34][CH2:33][C@H:14]2[O:13][C@H:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:15]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:41]([O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C@H:40]1[O:63][CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H](Cl)O[C@@H]1COCc1ccccc1
Reactant: CO[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: Cc1cc(C)nc(C)c1
Product: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Ethereal silver perchlorate (0.08M, 76.9 mL, 6.15 mmol) was added with stirring at -30° C. to a solution of methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.078 g, 4.48 mmol), 4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl chloride (2.859 g, 5.6 mmol) and 2,4,6-trimethylpyridine (0.81 mL, 6.15 mmol) in ether (20 mL). The mixture was stirred 15 min at -30° C. and silver chloride precipitated. The mixture was filtered through a celite pad, the solids were washed with ether, the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride and the organic layer was washed successively with aqueous sodium thiosulfate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a foam. Flash chromatography on silica gel and elution with a graded mixture of hexane and ethyl acetate afforded methyl 6-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl) -2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.314 g, 55%) as a foam.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[C:30]([F:36])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC>C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:32]([C:31]1[CH:34]=[CH:35][C:28]([O:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:29][C:30]=1[F:36])[OH:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1F
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1F

Procedure:
In analogy to the procedure described in example 1 a], (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C. Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10, 1353-1367) was reacted with 4-benzyloxy-2-fluoro-benzaldehyde in the presence of triethylamine and di-n-butylboron triflate to give (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one as colorless foam. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][O:11][CH2:12][C:13]([OH:15])=[O:14].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NOCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CON=Cc1ccc(Cl)cc1

Procedure:
4.2 g of 4-chlorobenzaldehyde and 3.3 g of hemihydrochloride of amino-oxyacetic acid were dissolved in 50 ml of 90% ethanol. The solution was mixed with 7.4 g of sodium acetate and then refluxed for 20 minutes. The reaction mixture was subsequently concentrated by evaporation in a vacuum. After an excess of 2 N sodium hydroxide had been added, the residue was twice extracted with ether, after which the remaining aqueous solution was acidified with 2 N hydrochloric acid and again extracted twice with ether. The latter ethereal solution was washed twice with water, then dried over anhydrous sodium sulfate and subsequently concentrated by evaporation. The residue was crystallized from a mixture of ether and petroleum ether, them from highly dilute ethanol and ultrimately twice from a mixture of benzene and petroleum ether. The substance obtained melted at 121° C.-123° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]=[CH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.Cl.[CH2:13]([NH:16][OH:17])[CH2:14][CH3:15]>CO>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([N:16]([CH2:13][CH2:14][CH3:15])[OH:17])[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: CCCNO
Reactant: Clc1ccnc2c1CCC=C2
Agent: Cl
Solvent: CO
Product: CCCN(O)C1CCc2c(Cl)ccnc2C1
Yield: 85.5 %

Procedure:
This compound was prepared from the product of Step 4 (4.35 g, 26 mmol), 1-propylhydroxylamine hydrochloride (6 g, 54 mmol), and methanol (10 ml) by the method described in Example 10. The residue was recrystallised from cyclohexane to give the product (5.35 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:35])=[C:16]([C@@:18]23[O:26][CH2:25][CH2:24][C@@H:23]2[CH2:22][S:21][C:20]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:19]3)[CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:35][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:8](=[O:10])[C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:17][C:16]=1[C@@:18]12[O:26][CH2:25][CH2:24][C@@H:23]1[CH2:22][S:21][C:20]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[N:19]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(N)ccc3F)OCC[C@@H]2CS1
Reactant: O=C(O)c1ncccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(NC(=O)c4ncccc4F)ccc3F)OCC[C@@H]2CS1
Yield: 40 %

Procedure:
A solution of 3-fluoropicolinic acid (6.34 mg, 0.045 mmol), tert-butyl ((4aS,7aS)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (11 mg, 0.030 mmol), HATU (17.07 mg, 0.045 mmol), and Hunig's Base (10.46 μL, 0.060 mmol) in DMF (299 μL) was stirred at rt for 10 h. The crude product was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 95% eater/5% MeCN/10 nM NH4OAc, B: 5% water/95% MeCN/10 mM NH4OAc) over 12 min to give tert-butyl ((4aS,7aS)-7a-(2-fluoro-5-(3-fluoropicolinamido)phenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.012 mmol, 40.9% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.91 (br. s., 1H), 8.49 (br. s., 1H), 8.11-7.97 (m, 1H), 7.71 (d, J=5.2 Hz, 1H), 7.68-7.61 (m, 1H), 7.61-7.55 (m, 1H), 7.17-7.10 (m, 1H), 4.27-4.06 (m, 2H), 3.33 (d, J=13.4 Hz, 1H), 3.03 (d, J=13.7 Hz, 1H), 2.90 (dd, J=13.0, 4.5 Hz, 1H), 2.47-2.33 (m, 1H), 2.29-2.15 (m, 1H), 1.51 (s, 9H). MS (M+H)+: 491.19.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.BrCC1CCCCO1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41]>>[S:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: BrCc1nc2ccccc2s1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2nc3ccccc3s2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)-1,3-benzothiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(1,3-benzothiazol-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (77%) as a colorless solid: mp 164-166° C.; 1H NMR (300 MHz, CDCl3) δ8.04 (d, J=8.1 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.54-7.46 (m, 1H), 7.43-7.35 (m, 1H), 7.24-7.17 (m, 2H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.41 (s, 1H), 5.53 (d, J=16.2 Hz, 1H), 5.24 (d, J=16.2 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.24-4.11 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.2, 165.9, 155.3, 152.9, 144.7, 141.2, 138.3, 135.3, 132.1, 128.9, 126.3, 125.5, 124.0, 123.9, 123.2, 121.9, 120.8, 111.8, 109.2, 99.4, 64.5, 63.9, 58.0, 42.6; MS (ES+) m/z 442.8 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](/[O-:7])\[CH3:6].[Na+].[I-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[C:5]([CH:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]([O:2][CH3:1])=[O:8])(=[O:7])[CH3:6]
Reactant: COC(=O)/C=C(\C)[O-]
Reactant: CCCCCCBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: CCCCCCC(C(C)=O)C(=O)OC

Procedure:
Analogously to Example 14A, 30 g (217 mmol) of sodium (2E)-4-methoxy-4-oxo-2-buten-2-olate (Example 13A) and 1.24 g (7.5 mmol) of potassium iodide are reacted with 37.7 g (228 mmol) of hexyl bromide to give methyl 2-acetyloctanoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([Cl:9])[C:3]=1[Cl:10].[CH3:11][O-:12].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:12][CH3:11])[CH:5]=[C:4]([Cl:9])[C:3]=1[Cl:10]
Reactant: C[O-]
Reactant: Fc1cc(Cl)c(Cl)c(Br)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(Cl)c(Br)c1

Procedure:
1-Bromo-2,3-dichloro-5-fluorobenzene (5.1453 g, 21.10 mmol) was dissolved in THF (25 mL) at room temperature and cooled to 0° C. Then, 5.1 g of sodium hydride (60%, 128 mmol) was added and 2.0 mL of methanol was added slowly. Additional THF (5 mL) was added. The mixture was stirred at room temperature for 10 minutes, then heated at 75° C. for four hours and cooled to room temperature. The mixture was poured into ice with some aq. sat. NH4Cl solution and extracted with EtOAc (3×100 mL). The organic solution was washed with brine, dried over Na2SO4, concentrated to dryness. The residue was purified with flash column chromatography on silica gel using hexane as solvent to afford the product (4.6727 g) as a white solid in 87% yield. 1H-NMR (CDCl3): δ 7.109 (d, J=3.0 Hz, 1 H), 6.988 (d, J=3.0 Hz, 1 H), 3.786 (s, 3 H). The product was also synthesized from 1-bromo-2,3-dichloro-5-fluorobenzene and sodium methoxide in THF. The final product was purified by recrystallization from hexane.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH:18]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:19][C:20]([O-])=[O:21])=[N:6][O:7][C:8]=2[CH:9]2[CH2:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10]2)[CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[NH2:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>O.C(N(CC)CC)C.CN(C=O)C>[Cl:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[NH:37][C:20]([CH2:19][CH:18]([C:5]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:8]([CH:9]2[CH2:10][CH:11]([CH2:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:12]2)[O:7][N:6]=1)[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:21]
Reactant: COC(=O)CCC(CC(=O)[O-])c1noc(C2CC(CC(C)(C)C)C2)c1C1CC1
Reactant: Cc1ccc(N)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCC(CC(=O)Nc1ccc(C)cc1Cl)c1noc(C2CC(CC(C)(C)C)C2)c1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methyl 3-[4-Cyclopropyl-5-[3-(2,2-dimethylpropyl)cyclobutyl]isoxazol-3-yl]adipate (100 mg), 2-chloro-4-methylphenylamine (0.0377 mL) and DMF (1 mL) were mixed. To the mixture were added triethylamine (0.0354 mL), HOBt.H2O (47 mg) and WSC.HCl (58.8 mg) at ice temperature. The mixture was stirred at RT overnight. To the reaction mixture was added saturated aqueous sodium bicarbonate at ice temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with water, 1 N hydrochloric acid and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: ethyl acetate/hexane=1/8) to give the title compound (63.3 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:33]=[CH:32][C:26]2[O:27][C:28]([F:31])([F:30])[O:29][C:25]=2[CH:24]=1>>[F:31][C:28]1([F:30])[O:27][C:26]2[CH:32]=[CH:33][C:23]([N:18]3[CH2:19][CH2:20][N:15]([C:5]4[C:4]([CH3:21])=[C:3]([O:2][CH3:1])[C:11]5[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=5[C:6]=4[CH3:14])[CH2:16][CH2:17]3)=[CH:24][C:25]=2[O:29]1
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Product: COc1c(C)c(N2CCN(c3ccc4c(c3)OC(F)(F)O4)CC2)c(C)c2c1OC(C)(C)C2
Yield: 47.9 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (436 mg, 1.50 mmol) synthesized in Reference Example 96 and 5-bromo-2,2-difluoro-1,3-benzodioxole (614 mg, 2.25 mmol), the reaction was carried out in the same manner as Reference Example 59 to synthesize 321 mg of the title compound (yield 48%). Melting point was 149 to 151° C. (hexane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCCCC.C([O:16][C:17](=O)[CH2:18][C:19]1[N:20]=[C:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)=[C:27]([O:37][CH3:38])[CH:26]=2)[S:22][CH:23]=1)C.O>O1CCOCC1>[CH3:38][O:37][C:27]1[CH:26]=[C:25]([NH:24][C:21]2[S:22][CH:23]=[C:19]([CH2:18][C:17]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:16])[N:20]=2)[CH:30]=[CH:29][C:28]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1
Reactant: CCOC(=O)Cc1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: C1CCNCC1
Solvent: O
Solvent: CCCCCCC
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(CC(=O)N3CCCCC3)cs2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 80 mg (0.94 mmol) piperidine in dioxane (1 ml) 2M trimethylaluminium solution in heptane (0.94 mmol, 0.47 ml) was carefully added. The solution was stirred at room temperature for 1 hour. A suspension of 100 mg (0.27 mmol) ({2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-acetic acid ethyl ester in dioxane (3 ml) was added and the reaction was refluxed over night. Water was added carefully and the reaction was extracted twice with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure to yield 110 mg (99%) 2-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-1-piperidin-1-yl-ethanone as a brown foam. MS ISP (m/e): 410.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.35 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.23 (d, 1H), 7.17 (d, 1H), 7.03 (s, 1H), 6.64 (s, 1H), 3.79 (s, 3H), 3.67 (s, 2H), 3.49 (br t, 2H), 3.42 (br t, 2H), 2.14 (s, 3H), 1.58-1.32 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][NH:67][CH:68]4[CH2:72][CH2:71][CH2:70][CH2:69]4)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][NH:67][CH:68]4[CH2:72][CH2:71][CH2:70][CH2:69]4)[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNC2CCCC2)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNC2CCCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-cyclopentylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=561, obsd.=561).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([OH:21])=O)=[CH:13]3)[CH2:5]1)([CH3:3])[CH3:2].Cl.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:21])=[CH:13]3)[CH2:5]1)([CH3:2])[CH3:3]
Reactant: C1CCNC1
Reactant: CC(C)N1CC[C@H](Oc2ccc3[nH]c(C(=O)O)cc3c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CC[C@H](Oc2ccc3[nH]c(C(=O)N4CCCC4)cc3c2)C1

Procedure:
According to the procedure described for the synthesis of Example 1 the title compound was synthesized from 5-((S)-1-isopropyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid 1:1 hydrochloride and pyrrolidine under coupling conditions employing TBTU and DIPEA in DMF. The crude product was purified over silica eluting with a gradient formed from DCM/MeOH(2 N NH3) 98/2 to 94/6. The product fractions were evaporated to yield the title compound as off-white solid. (m/e): 342.3 (MH+, 100%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1)(=O)=O.[CH3:20][N:21](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[O:17]=[C:13]1[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][C:7]([C:20]#[N:21])=[CH:8][CH:9]=2)[NH:14]1
Reactant: CN(C)C=O
Reactant: O=C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)NC(=O)CC2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Step R1-2: The mixture of 2-oxo-1,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate (338 g), Zn(CN)2 (134 g) and Pd(PPh3)4 (33.5 g) in DMF (3.0 L) was heated at 100° C. for 4 hours and cooled to room temperature. To the mixture, Zn(CN)2 (134 g) and Pd(PPh3)4 (12.7 g) were added and the mixture was stirred at 100° C. for 2 hours. After cooling to 60° C., the reaction mixture was filtrated through a pad of Celite. The filtrate was concentrated to obtain a solid. The solid was washed with EtOAc twice to obtain 2-oxo-1,2,3,4-tetrahydroquinoline-7-carbonitrile as a pale yellow solid (165 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:32]=[N:33][C:34]([Cl:37])=[CH:35][CH:36]=3)=[O:29])=[C:23]([Br:38])[CH:22]=2)[CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>O.C(#N)C>[Br:38][C:23]1[CH:22]=[C:21]([CH:17]2[O:18][CH2:19][CH2:20][NH:15][CH2:16]2)[CH:26]=[CH:25][C:24]=1[NH:27][C:28]([NH:30][C:31]1[CH:32]=[N:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(NC(=O)Nc3ccc(Cl)nc3)c(Br)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1ccc(Cl)nc1)Nc1ccc(C2CNCCO2)cc1Br
Temperature: 80 °C
Reaction time: 5 h
Yield: 67.6 %

Procedure:
To a stirred solution of trifluoroacetic acid (90 μl) in water (6 ml) was added a solution of (RS)-2-{3-bromo-4-[3-(6-chloro-pyridin-3-yl)-ureido]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (46 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 5 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: heptane/EtOAc/MeOH) to afford (RS)-1-(2-bromo-4-(morpholin-2-yl)phenyl)-3-(6-chloropyridin-3-yl)urea (25 mg, 68%) as an off-white solid. MS (ISP): 415.0 ([{37Cl81Br}M+H]+), 413.0 ([{37Cl79Br or 35Cl81Br}M+H]+), 411.0 ([{35Cl79Br}M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17].[C:20]1(=O)[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:20]2[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH:21]=2)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)CNc1c(Br)ccc(C(=O)O)c1[N+](=O)[O-]
Reactant: O=C1CCCC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)CNc1c(Br)ccc(C(=O)OC2=CC(=O)CCC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
190 mg (0.574 mmol) of 4-bromo-3-[(2,2-dimethylpropyl)amino]-2-nitrobenzoic acid, 198 mg (1.713 mmol) of cyclohexane-1,3-dione, 145 mg (0.741 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 7 mg (0.057 mmol) of 4-(dimethylamino)pyridine were dissolved in 5 ml of methylene dichloride and stirred at RT for 24 h. The solution was then washed with water and saturated NaHCO3 solution, the organic phase was dried over MgSO4, and then the whole was filtered with suction through a glass frit, filled with 1 cm of silica gel, and the filter product was washed with heptane/ethyl acetate 1:2. The filtrate was concentrated.