Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[C:8]([N+:20]([O-])=O)=[N:9][C:10]([CH:15]2[O:19][CH2:18][CH2:17][O:16]2)=[C:11]([O:13][CH3:14])[CH:12]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[C:8]([NH2:20])=[N:9][C:10]([CH:15]2[O:19][CH2:18][CH2:17][O:16]2)=[C:11]([O:13][CH3:14])[CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(OC)c(C2OCCO2)nc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cc(OC)c(C2OCCO2)nc1N
Reaction time: 1.5 h

Procedure:
The oil isolated in step 5 was dissolved in 30 ml of ethanol and hydrogenated for 90 minutes at 50 PSI using 10% Pd/C as the catalyst. The reaction mixture was filtered and evaporated to yield the intermediate 3-(2-amino-6-[1,3]dioxolan-2-yl-5-methoxy-pyridin-3-yl)-propionic acid ethyl ester as a dark oil. Mass Spectrum: m/e=297.1 (p+1). This material was dissolved in 10 ml of toluene and heated to reflux for 4 hours. The solution was cooled to room temperature and evaporated to yield 0.1 g of 7-[1,3]dioxolan-2-yl-6-methoxy-3,4-dihydro-1H-[1,8]naphthyridin-2-one as a dark oil. Mass spectrum: m/e=251 (p+1). 1H NMR (CDCl3) δ 7.10 (s, 1H), 6.10 (s, 1H), 4.30 (m, 2H), 4.10 (m, 2H), 3.90 (s, 3H), 2.90 (m, 2H), 2.75 (m, 2H). This material was used without further purification in step 7.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[F:19])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:10]=2[CH3:27])[CH:5]=[N:6][CH:7]=1.[F:28][C:29]1[C:30](B(O)O)=[CH:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=1.C1(P(C2CCCCC2)C2(OC)CC=CC(OC)=C2C2C=CC=CC=2)CCCCC1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][C:17]1[CH:16]=[C:15]([F:20])[CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:4]1[CH:3]=[C:2]([C:30]3[C:29]([F:28])=[CH:34][N:33]=[C:32]([O:35][CH3:36])[CH:31]=3)[CH:7]=[N:6][CH:5]=1)=[C:10]([CH3:27])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:12]2
Reactant: COc1cc(B(O)O)c(F)cn1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC1=C(c2ccccc2)C(OC)(P(C2CCCCC2)C2CCCCC2)CC=C1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2cncc(Nc3c(C)c(-c4ccccn4)nc4cc(F)cc(F)c34)c2)c(F)cn1
Temperature: 90 °C
Reaction time: 21.5 h

Procedure:
A mixture of N-(5-bromo-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine (28.1 mg, 0.066 mmol), 5-fluoro-2-methoxypyridin-4-ylboronic acid (commercially available from Asymchem) (17.7 mg, 0.104 mmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl, (S-Phos) (5.9 mg, 0.014 mmol), palladium(II) acetate (5.1 mg, 7.57 μmol), and potassium phosphate tribasic (45.1 mg, 0.21 mmol) in DMF (1.0 mL) and water (0.05 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organic layers were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-35% EtOAc in hexanes) to afford an impure yellow residue. The light yellow film was further purified by HPLC (10-60% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concentrated then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a white solid as N-(5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-5′-fluoro-2′-methoxy-3,4′-bipyridin-5-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.77 (1H, ddd, J=4.8, 1.8, 0.9 Hz), 8.43 (1H, t, J=1.7 Hz), 8.36 (1H, d, J=2.7 Hz), 8.09 (1H, d, J=2.2 Hz), 7.94 (2H, m), 7.66 (1H, ddd, J=9.6, 2.5, 1.4 Hz), 7.40 (1H, ddd, J=7.4, 4.8, 1.5 Hz), 7.11 (2H, m), 6.86 (1H, d, J=5.3 Hz), 3.95 (3H, s), 2.24 (3H, s). Mass Spectrum (pos.) m/e: 474.1 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.C[N+]1([O-])CCOCC1.CCOCC>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCc1ccc2[nH]cnc2c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc2[nH]cnc2c1

Procedure:
(1H-benzo[d]imidazole-5-yl)methanol (2.8 mmol, 1 eq.) was dissolved in 30 mL dichloromethane and a molecular sieve (4 A) was added. To the solution were added Tetrapropylammonium perruthenate (0.28 mmol, 0.1 eq.) and N-Methylmorpholine-N-Oxide (9.8 mmol, 3.5 eq.). After stirring the mixture for 72 hours at room temperature 50 mL of ether was added and filtrated. The solvent was removed under reduced pressure and the product was purified by means of flash-chromatography using silica gel and a ethyl acetate/MeOH-gradient.
Reaction SMILES: Br.BrC[C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:21][NH2:22].C(=O)(O)[O-]>CN(C)C(=O)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:21][NH:22][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15]
Reactant: COc1ccc(CN)cc1OC
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: COc1ccc(CNc2cnc3nc(N)nc(N)c3n2)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (59 mg, 0.176 mmol) in anhydrous N,N dimethylacetamide was added 3,4-dimethoxy-benzylamine (51.15 ul, 0.3512 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 20.3 mg product was obtained. Yield: 34%; 1H NMR (500 MHz, DMSO-d6): δ 3.67534(s, 3H), 3.70494(s, 3H), 4.05412 (b, 4H), 6.78852–6.80460 (d, J=8.04 Hz, 1H), 6.83624 (s, 1H), 6.83624–6.85393 (d, J=8.195 Hz, 1H); 8.96623(s, 1H), 9.00584(s, 2H), 9.5577(s, 2H); ESI-MS: 342 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([O:15]C)=[CH:13][CH:12]=[CH:11][C:10]=1[F:17]>Br>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:17]
Reactant: COc1cccc(F)c1-c1ccc(Cl)cc1Cl
Agent: Br
Product: Oc1cccc(F)c1-c1ccc(Cl)cc1Cl
Yield: 88.8 %

Procedure:
Treatment of 2,4-dichloro-2′-fluoro-6′-methoxybiphenyl (5.0 g, 18.4 mmol) with hydrogen bromide (33% in acetic acid, 100 mL) according to the procedure described for Example 69, Step 2 provided 4.2 g (89%) of 2′,4′-dichloro-6-fluorobiphenyl-2-ol as a light brown oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:14]=1)[C:9]([OH:11])=O)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:30]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl.C(Cl)(Cl)Cl.CN(C)C=O>[CH2:16]([O:15][C:13]1[CH:12]=[C:8]([CH:7]=[C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH:14]=1)[C:9]([C:38]1[CH:39]=[CH:40][C:35]([O:34][CH2:30][CH:31]([CH3:32])[CH3:33])=[C:36]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:37]=1)=[O:11])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)COc1cc(OCC(C)C)cc(C(=O)O)c1
Reactant: CCOC(=O)CCc1ccccc1OCC(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(C(=O)c2cc(OCC(C)C)cc(OCC(C)C)c2)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
In 11 ml of methylene chloride is dissolved 1.11 g of 3,5-diisobutoxybenzoic acid. To the solution thus obtained, 0.44 ml of oxalyl chloride is added at ambient temperature, and then 20 μl of N,N-dimethylformamide is added and stirred at ambient temperature for 2 hours. Then, at −20° C., 1.67 g of aluminum chloride is added and thereafter 1.15 g of ethyl 3-(2-isobutoxyphenyl)propanoate is added, and the mixture thus obtained is stirred at 5-10° C. for 10 minutes. The reaction mixture is added to a mixture of chloroform and ice water, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 1.75 g of ethyl 3-[5-(3,5-diisobutoxybenzoyl)-2-isobutoxyphenyl]propanoate as a yellow-colored oily product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:9]=1[C:26](OCC)=O.O>O1CCCC1>[CH3:26][C:9]1[C:10]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[N:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:13][C:8]=1[CH3:7]
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)nc(-c2ccncc2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 1.8 %

Procedure:
To a suspension of lithium aluminum hydride (0.24 g) in dry tetrahydrofuran (40 ml) was dropwise added a solution of ethyl 6-methyl-2-phenyl-4-(4-pyridyl)-5-pyrimidinecarboxylate (2.0 g) in the same solvent (20 ml) under cooling at 7°-9° C. After the addition was completed, the mixture was stirred for 2 hours at room temperature. The excess lithium aluminum hydride was decomposed by a careful addition of water and the dried solution was concentrated in vacuo to an oil. The oil was column chromatographed on silica gel eluting with chloroform and the fractions containing a produce were collected and concentrated in vacuo. The residual crystals were recrystallized from n-hexane to give 5,6-dimethyl-2-phenyl-4-(4-pyridyl)pyrimidine (0.03 g), mp 152°-153° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH3:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14].CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[CH3:7])=[O:6]
Reactant: O=C=NCCCl
Reactant: Cc1ccncc1N
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccncc1NC(=O)NCCCl
Temperature: 25 °C
Yield: 86.1 %

Procedure:
1-Chloro-2-isocyanato-ethane (5.91 ml, 69.35 mmol) was added dropwise to a stirred solution of 4-methyl-pyridin-3-ylamine (5 g, 46.23 mmol) in toluene (180 mL) at 0° C. The reaction temperature was maintained at room temperature for 5 hours. The reaction was monitored by TLC (5% MeOH in chloroform). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 8.5 g (86% yield) of 1-(2-chloro-ethyl)-3-(4-methyl-pyridin-3-yl)-urea.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:16]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:17][CH2:18][C:10]=3[C:9]=2[CH:8]=1.[OH-].[Na+]>O1CCOCC1.O>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][CH2:18][C:10]=3[C:9]=2[CH:8]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)cc21
Temperature: 25 °C
Yield: 11.1 %

Procedure:
To a solution of ethyl 2-(7-(2,4-bis(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.191 g, 0.393 mmol) in dioxane (1.312 mL) and water (0.656 mL) was added NaOH (0.826 mL, 0.826 mmol). The mixture was heated under reflux for 2 h, cooled to room temperature and diluted with water. After washing with DCM, the aqueous layer was acidified with 1 M HCl and extracted with EtOAc (thrice). The combined extracts were washed with brine, dried over MgSO4 and concentrated to give the title compound as a magenta solid (19.9 mg). LCMS m/z=458.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03-2.13 (m, 1H), 2.35 (dd, J=15.98, 9.03 Hz, 1H), 2.58-2.78 (m, 4H), 3.41-3.52 (m, 1H), 5.31 (s, 2H), 6.72 (dd, J=8.78, 2.46 Hz, 1H), 6.92 (d, J=2.40 Hz, 1H), 7.23 (d, J=8.72 Hz, 1H), 7.99-8.19 (m, 3H), 10.52 (s, 1H), 12.19 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH2:22]I)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH:40]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:44][CH:43]=2)[OH:41])=[C:37]([OH:39])[CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH:40]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:44][CH:43]=2)[OH:41])=[C:37]([CH:38]=1)[O:39][CH2:22][C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:16][CH:17]=1)=[O:24])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(CI)c1ccc(OCc2ccccc2)cc1
Reactant: Oc1cc(OCc2ccccc2)ccc1C(O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1cc(OCc2ccccc2)ccc1C(O)c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Yield: 59.8 %

Procedure:
Potassium carbonate (0.165 g, 1.2 mmol) was added to a solution of 1-(4-benzyloxy-phenyl)-2-iodo-ethanone (P4) (0.352 g, 1 mmol) and 5-benzyloxy-2-[(4-benzyloxy-phenyl)-hydroxy-methyl]-phenol (P3) (0.412 g, 1 mmol) were in 40 mL of dry acetone and the mixture was refluxed for 6 hr. After completion of reaction (TLC), the solvent was evaporated and the residue extracted with EtOAc:water (3×40 mL). The organic layers were combined, dried over sodium sulfate and evaporated. The residue was dissolved in EtOAc and chromatographed over silica using hexanes: EtOAc (4:1) to give (0.381 g, 60%) yellowish solid product T3. 1H NMR (400 MHz, CDCl3) δ, 7.88 (d, 2H , J=8.8 Hz, Ar—H2/6), 7.41-7.29 (m, 17H, 2×Ar—H, 3×C6H5), 7.07(d, 1H, J=8.8 Hz, 8.4 Hz), 7.02(d, 2H, J=8.8 Hz, Ar—H3/5), 6.92(d, 2H, J=8.8 Hz, 2×Ar—H), 6.54(dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H4′), 6.5 (d, 1H, J=2.4 Hz, Ar—H6′), 6.04 (d, 1H, J=5.6 Hz, CH—OH), 5.24(m, 2H2O—CH2), 5.13 (s, 2H, PhCH2), 5.04 (s, 2H, PhCH2), 5.0 (s, 2H, PhCH2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][S:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>C1(C)C=CC=CC=1.O.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:27][S:28]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[N:12]=3)=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: CS(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccc(S(C)=O)cc3)cc2)nc1CCN1CCCC1
Yield: 30.3 %

Procedure:
To a stirred solution of 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (50 mg, 0.149 mmol), sodium carbonate (47.5 mg, 0.448 mmol) and 4-Methylsulfinylbenzene boronic acid (137.3 mg, 0.75 mmol) in toluene (2.5 mL), water (0.75 mL) and ethanol (1 mL) under nitrogen was added Tetrakis(triphenylphosphine) palladium (0) (17. 2 mg, 0.015 mmol). The reaction was then heated to reflux for 48 h. The reaction was allowed to cool and bound to a SCX-2 cartridge (5 g). The cartridge was washed with one cartridge volume of dimethylformamide and two volumes of methanol. The product was eluted using 2M ammonia in methanol. The ammonia/methanol solution was evaporated on a Genevac® HT4. The sample was further purified by prep-LCMS. The resulting acetonitrile/water fractions were combined and evaporated using a Genevac® HT4 to give 17.8 mg of a colourless oil (30%). MS (m/e): 395.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C(O)(=[O:25])C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:25]
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CC(=O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(C(F)(F)F)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
2-Chloro-4-(trifluoromethyl)benzonitrile (500 mg, 2.43 mmol) was diluted with toluene (3 mL), placed under nitrogen and cooled to −78° C. DIBAL-H (4865 μL, 4.86 mmol) was added dropwise and the reaction was stirred for 1 hour. The reaction was warmed to 0° C. and acetic acid (2 mL) was added followed by 10 mL of water. After stirring for 2 hours, the reaction was extracted twice with ethyl acetate, washed with Rochelle's salt, dried over MgSO4, filtered and concentrated. The material was purified using a biotage 25 cartridge running a gradient, 100% hexanes to 20% DCM/hexanes to yield 2-chloro-4-(trifluoromethyl)benzaldehyde (400 mg, 1.92 mmol, 78.8% yield) as a clear oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][S:28]1(=[O:37])=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.ClCCl.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH2:29][S:28]3(=[O:36])=[O:37])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: O=S1(=O)Cc2ccccc2N1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4ccccc4CS3(=O)=O)[C@H](C)[C@H]12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (25.5 mg, 0.07 mmol), 1,3-dihydro-benzo[c]isothiazole 2,2-dioxide (13 mg, 0.077 mmol), and triphenylphosphine (28 mg, 0.105 mmol) in anhydrous tetrahydrofuran (0.4 mL) was cooled in an ice bath and treated with diethyl azodicarboxylate (0.017 mL, 0.105 mmol). The mixture was stirred at 0-5° C. for 30 minutes, then streaked onto a 1 mm×20 cm×20 cm silica gel GF plates. The plates were developed with 5% ethyl acetate in dichloromethane. The product band was removed and eluted with ethyl acetate to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-(2,2-dioxo-2,3-dihydro-benzo [c]isothiazol-1-yl-methyl)-1-methyl-carbapen-2-em-3-carboxylate (15 mg) as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:29][O:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:34]2[CH2:35][CH2:36][CH:31]([O:30][CH3:29])[CH2:32][CH2:33]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: COC1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1CCN(S(=O)(=O)c2cc(-c3sc(NC(C)=O)nc3C)c(Br)s2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and 4-methoxy-piperidine hydrochloride (314.3 mg; 3.61 mmol; 5 eq) are added successively and the reaction mixture is stirred for 30 minutes at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (250 mg; 60%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:23]([C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=1)(=[O:24])=[O:25]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cc(Br)c2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)n2ccc3c(Br)cc(F)cc32)cc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 4-bromo-6-fluoro-1H-indole (2 g) in DMF (5 ml) was added sodium hydride (60% in mineral oil) (0.448 g). The reaction was stirred at 20° C. for 10 min. 4-Nitrobenzenesulfonyl chloride (2.278 g) was added and the reaction was stirred at 20° C. for 1 h. The mixture was poured onto water (100 ml), and extracted with DCM (50 ml) which was separated by hydrophobic frit. Purification by silica (2×100 g) on Flashmaster II using a gradient of DCM and cyclohexane gave the title compound as a pale yellow solid, 1.54 g.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=1)=[O:19])C>>[Cl:30][C:25]1[CH:24]=[C:23]([CH:21]2[CH2:22][CH:20]2[C:18]([OH:19])=[O:17])[CH:28]=[CH:27][C:26]=1[O:29][CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Reactant: ClCc1cccnc1SC1CCCC1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SC2CCCC2)c(Cl)c1
Yield: 70 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (49 mg, 0.23 mmol) obtained in Step C of Preparation Example 8 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (62 mg, 0.25 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (65 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:3]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[Cl:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])[N:7]=[CH:6][N:5]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:23])[F:25]
Reactant: CCC(=O)Cl
Reactant: CC(NC(=O)c1cc(N)ncn1)c1cnc(OCC(F)(F)F)c(Cl)c1
Product: CCC(=O)Nc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)ncn1

Procedure:
The title compound is prepared from 6-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (30 mg, 0.08 mmol, Step-1, single enantiomer) and propionyl chloride (11 mg, 0.12 mmol) according to the procedure similar to that described in Step-2 of Example 8.