Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4]C=1.[CH3:38][N:39]([CH3:49])[C:40]1[N:45]=CC(B(O)O)=C[N:41]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[N:41][C:40]([N:39]([CH3:49])[CH3:38])=[N:45][CH:6]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:35])([F:33])[F:34]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: CN(C)c1ncc(B(O)O)cn1
Product: CN(C)c1ncc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)cn1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (2-(dimethylamino)pyrimidin-5-yl)boronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=542, obsd.=542).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:5].[CH2:11](C(CC)(CC)C([O-])([O-])[O-])[CH3:12]>C(O)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[CH2:4][NH:5][C:11]([CH3:12])=[N:1]2
Reactant: NCc1c(N)cccc1F
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CCO
Product: CC1=Nc2cccc(F)c2CN1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A solution of 2-amino-6-fluorobenzylamine (1.1 g, 7.86 mmol) and triethylorthoacetate (1.58 mL, 8.64 mmol) in ethanol (30 mL) was heated at 80° C. for 14 h. The reaction mixture was allowed to cool to room temperature and evaporated in vacuo. The yellow oil was triturated with diethyl ether to give the title compound as white solid (0.74 g, 57%). Mass spectrum (API+): Found 165 (MH+). C9H9N2F requires 164.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: CC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C(C)=O
Yield: 98.6 %

Procedure:
2′-Hydroxyacetophenone (1I-3) (14.0 g, 0.103 mol), allyl bromide (20.4 g, 0.169 mol) and potassium carbonate (14.2 g, 0.103 mol) in acetone (140 ml) were refluxed for 16 h. The solvent was removed under reduced pressure and water was added. The layers were extracted with ether and the organic extracts were washed with water, dried over magnesium sulfite and concentrated under reduced pressure leaving 17.9 g of 2′-allyloxyacetophenone as a colorless oil. 8.6 g of allyl ether thus obtained was refluxed in 1,2-dichlorobenzene (40 ml) in an oil bath heated at 210° C. for 18 h. The solvent was removed under reduced pressure to give 8.9 g of 3′-allyl-2′-hydroxyacetophenone. Without purification, the product was dissolved in DMF (60 ml) and was added dropwise to a suspension of sodium hydride (60% oil dispersion, 2.4 g, 0.06 mol) in DMF (25 ml) at a rate keeping the reaction temperature between 40 to 45° C. After stirring for additional 20 min, a solution of benzyl bromide (8.6 g, 0.05 mol) in DMF (10 ml) was added dropwise. After 2 h and 4 h, each 0.7 g of additional benzyl bromide was added. After 6 h, the reaction mixture was poured into ice water and extracted with ether. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was removed to give 14.0 g of an orange oil. This was purified by 250 g of silica gel chromatography (ethyl acetate/hexane=1:4) to give compound (II-4) (9.6 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:3]=1[NH2:4].[Br:14]N1C(=O)CCC1=O>CN(C=O)C>[Br:14][C:7]1[C:6]([O:9][C:10]([F:11])([F:12])[F:13])=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(OC(F)(F)F)ccc1F
Solvent: CN(C)C=O
Product: Nc1cc(OC(F)(F)F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a mixture of 2-fluoro-5-(trifluoromethoxy)aniline (1 g, 5 mmol) dissolved in DMF (2 mL) was slowly added a solution of N-bromosuccinimide (1.1 g, 6.2 mmol) dissolved in DMF (2 mL). The reaction mixture was stirred at room temperature for 1 h, concentrated and extracted with ethyl acetate/water. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluted 0-10% ethyl acetate:hexanes) to produce the title intermediate as a red oil (818 mg, 58% yield). (m/z): [M+H]+ calcd for C7H4BrF4NO 273.94, 275.94. found 276.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:6]=[C:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1.CC(C)=[O:19]>>[C:13]([C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([C:9]([CH3:10])([CH3:12])[CH3:11])[N:6]=1)[C:2]([OH:19])=[O:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)=O
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)n1
Product: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)n1

Procedure:
Jone's reagent was added dropwise to a solution of 4-hydroxymethyl-2,6-di-t-butylpyridine (Compound B, 302 mg, 1.37 mmol) in 5 ml of acetone until the solution changed color from light yellow to orange (55 drops of Jone's reagent were consumed). After 5 minutes 2 ml of isopropanol were added to the reaction mixture, and a green precipitate of Cr3+ salt was formed. The precipitate was removed by filtration and the solution was diluted with ethyl acetate, then washed with brine, water and dried over MgSO4. After filtration, the solvent was removed to give the desired product as a white solid (227 mg). 1H NMR δ 7.71 (s, 2H), 1.34 (s, 18H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1c2ccccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 58.4 %

Procedure:
A solution of 28 mg (0.12 mmol) of 6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid, 19 mg (0.13 mmol) of 1-methyl-1,2,3,4-tetrahydro-isoquinoline, 23 mg (0.12 mmol) of EDC and 19 mg (0.12 mmol) of HOBt in 2 mL of DMF is stirred at room temperature for 24 h. The mixture is concentrated in vacuo and the solid residue is partitioned between methylene chloride (3 mL) and saturated aqueous sodium hydrocarbonate solution (3 mL). The organic layer is separated, washed with 0.5 N HCl, water and brine and concentrated in vacuo. Purification of the residue by flash column chromatography (chloroform:methanol 99:1) gives 26 mg (58%) of title compound as a crystalline solid.
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(C)(=O)=O)[N:3]=1.[C:19]1([CH2:25][CH2:26][CH2:27][OH:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[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]([O:28][CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCCCc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 3-phenyl-1-propanol and DBU in DME. ES-MS m/e (%): 359 (M+K+, 20), 343 (M+Na+, 21), 321 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].CO.C[O-].[Na+].Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>C1C=CC=CC=1>[CH3:20][O:19][C:17](=[O:18])[CH:16]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: N#Cc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(Oc1ccc(C#N)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 41.2 %

Procedure:
To a mixture of 2.98 g of p-cyanophenol and 40 ml of methanol is added 1.19 g of sodium methoxide. To the mixture is added 8.22 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate and 10 ml of benzene. The mixture is refluxed for 22 hours and the solvent removed under reduced pressure. The residue is chromatographed over silica gel with dichloromethane as the solvent. The product is obtained as an oil which is crystallized from methylcyclohexane-methanol and a small amount of hexane. Crystals are obtained and washed with hexane-methanol to give 3.7 g of white crystals, mp 102°-104° C.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=1)[CH2:2]2.C(=O)([O-])O.[Na+].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C(Cl)Cl.CCOC(C)=O>[C:31]1([O:30][C:28](=[O:29])[NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([N:3]4[CH2:4][CH:5]5[O:8][CH:1]([CH2:7][CH2:6]5)[CH2:2]4)[N:14]=3)=[CH:16][CH:17]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(-c2ccnc(N3CC4CCC(C3)O4)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2ccnc(N3CC4CCC(C3)O4)n2)cc1)Oc1ccccc1

Procedure:
4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)aniline (intermediate 26) (471 mg, 1.51 mmol) was stirred with sodium hydrogen carbonate (190 mg, 2.26 mmol) and phenyl chloroformate (285 μl, 2.26 mmol) in DCM (5 ml) at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with brine and the organics were concentrated in vacuo. The resulting yellow solid was purified by flash chromatography (0-100% EtOAc:Petroleum Ether 40-60) to afford the title compound. (60 mg, 10%)
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][CH2:9][CH3:10].[OH:11][C:12]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[C:24]([CH3:27])([CH3:26])[CH3:25]>C(O)C>[OH:11][C:12]1[C:19]([C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:18][C:15]([CH:16]=[N:2][N:3]2[CH:7]=[CH:6][N:5]=[C:4]2[CH2:8][CH2:9][CH3:10])=[CH:14][C:13]=1[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CCCc1nccn1N
Agent: Cl
Solvent: CCO
Product: CCCc1nccn1N=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.47 g of 1-amino-2-propylimidazole hydrochloride are dissolved in 300 ml of ethanol, and 3.5 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde are added. The mixture is stirred at room temperature for 3 hours and the solution obtained is evaporated. The residue is treated with 150 ml of water and 150 ml of methylene chloride, and saturated sodium bicarbonate solution is added while stirring up to a neutral reaction (pH=7). The methylene chloride phase is separated. The aqueous phase is extracted once with 50 ml of methylene chloride. The methylene chloride solutions are combined, dried and evaporated. The residue is triturated with ether, and the solid is removed by filtration and dried at 60° in a vacuum. There is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-propylimidazole of m.p. 160°-161°.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([N:35]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1Cl
Solvent: O
Product: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1N=Cc1ccccc1

Procedure:
14 g of 2-amino-3-cyano-4-chloro-6-(4-benzylpiperazin-1-yl)quinoline and 28 mL of benzylamine are stirred at 125° C. for 4 hours. The reaction mixture is poured onto 100 mL of water. The precipitated material is filtered off, washed with 2×50 mL of water. After drying 8 g of the title compound is obtained, m.p.: 202° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[CH:21][C:20]=3[F:33])=[O:17])=[CH:13][C:12]([C:34]([CH3:37])([CH3:36])[CH3:35])=[N:11]2)=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[C:34]([C:12]1[CH:13]=[C:14]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)=[CH:21][C:20]=2[F:33])=[O:17])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=2)[N:11]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(CO)cc3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a solution of 4-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoic acid methyl ester (700 mg, 1.35 mmol) in anhydrous THF at 0° C. was slowly added a 1N solution of lithium aluminum hydride in THF (0.95 mL, 0.95 mmol). The mixture was stirred at room temperature for 15 minutes, and then water was added dropwise to quench the reaction. The mixture was extracted with EtOAc, and the combined organic phases were dried over MgSO4 and evaporated at reduced pressure. The residue was purified by HPLC (10% to 90% aq acetonitrile) to afford 600 mg (90%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 8.97 (s, 1H), 8.79 (s, 1H), 8.29 (d, J=5.7 Hz, 1H), 8.13 (t, J=9.0 Hz, 1H), 7.46 (m, 4H), 7.18 (d, J=14.7 Hz, 1H), 6.95 (d, J=10.2 Hz, 1H), 6.76 (d, J=2.1 Hz, 1H), 6.71 (d, J=5.4 Hz, 1H), 6.36 (s, 1H), 5.30 (t, J=5.7 Hz, 2H), 2.38 (s, 3H), 1.25 (s, 9H); MS LC-MS [M+H]+=490.2, RT=2.41 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O(C)[Na].[NH2:20][OH:21].Cl>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([C:15](=[N:20][OH:21])[NH2:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ccc(-c2ccc(C#N)o2)cc1
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: CC(=O)c1ccc(-c2ccc(C(N)=NO)o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 17.0 g (0.080) mole of 5-(4-acetylphenyl)-2-furonitrile, 4.24 g (0.080 mole) of NaOCH3 and 300 ml of anhydrous CH3OH was refluxed for 1 hour and then cooled to room temperature. After adding 5.16 g (0.080 mole) of NH2OH.HCl, the reaction was stirred at room temperature for 2 hours at near reflux for 15 minutes and then cooled in an ice bath. The resulting solid was filtered, air dried, and recrystallized from ethyl acetate/Darco to yield 4.5 g (23%). An analytical sample was prepared by drying a sample in the vacuum pistol at the temperature of refluxing CHCl3, m.p. 197°-199°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:42](=[O:44])[CH3:43])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (70 mg, 0.13 mmol, example 2) and triethylamine (92 uL, 0.65 mmol) in methylene chloride (3 mL) was added acetyl chloride (59 uL, Aldrich). The reaction mixture was stirred at room temperature overnight then concentrated. Purification of the crude residue by flash chromatography (12 g of silica gel, eluting with 5-30% ethyl acetate in hexane) gave the title compound (56.1 mg, 80%). HR-MS (ES, m/z) calculated for C31H34N2O2Cl2 [(M+H)+] 537.2070, observed 537.2068.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].C(Cl)Cl>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2cc[nH]c2cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)NCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5,6-dimethoxyindole (2.00 g, 11.29 mmol) in acetic acid (120 mL), sodium cyanoborohydride (2.13 g, 33.86 mmol) was added in portions (slightly exothermic). After stirring at rt for 1 h, DCM was added and the org. layer was washed with sat. NaHCO3-solution and brine. The org. layer was dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 5,6-dimethoxyindoline as a brown solid, which was stored in the freezer until it was used in step 4. LC-MS conditions B: tR=0.28 min, [M+H]+=180.23.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19](OCC)=[O:20].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:19]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=3)=[O:20])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cnc2ccc(CC3CCOCC3)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CC3CCOCC3)cc2c1O
Temperature: 65 °C

Procedure:
A solution of ethyl 4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxylate (0.315 g) from Preparation No. 51 and 4-chlorobenzylamine (0.61 nL) is heated to 180° C. for 1 h. The reaction mixture is cooled to 65° C. and diluted with CH2Cl2. Hexanes are added to initiate precipitation of the product. The resulting solid is collected and dried to yield 0.33 g of N-(4-chlorobenzyl)-4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxamide as an off-white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29]O>>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29][NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Reactant: O=C1Nc2ccc(F)cc2C1=CO
Product: O=C1Nc2ccc(F)cc2C1=CNc1ccc(OCCCN2CCCCC2)cc1
Yield: 47.9 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-piperidin-1-yl-propoxy)-phenylamine (0.57 g, 1.3 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.363 g, 2 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (379 mg, 47%).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][C:65](=[O:67])[N:64]([CH3:68])[C:63]2=[O:69])[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][C:65](=[O:67])[N:64]([CH3:68])[C:63]4=[O:69])[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: CN1C(=O)CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N(C)C4=O)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 89.4 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (220 mg, 0.37 mmol) and (2S,4S)-4-mercapto-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer B (140 mg, 0.36 mmol) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate diastereomer B (244 mg, yield: 89.4%).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][NH:21][C:22]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:27]>CN(C=O)C.ClCCl>[F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][N:21]([CH3:27])[C:22]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(CN2CCc3c(c4cccc(F)c4n3C)C2=O)ncn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
A stirred solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol -4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (347 mg) in dry DMF was treated with sodium hydride (73% dispersion in oil; 49 mg) and stirred under nitrogen for 30 min. The reaction mixture was then cooled to 0° and iodomethane (217 mg) was added dropwise. The reaction mixture was then allowed to warm to room temperature, with stirring being continued for 2 h. DMF was removed in vacuo and the residue was dissolved in dichloromethane (75 ml) and washed with water (3×75 ml) and brine (2×50 ml). The combined aqueous washings were extracted with dichloromethane (2×50 ml) and the combined organic extracts were dried and concentrated in vacuo to give an oil. This was dissolved in dichloromethane and adsorbed onto silica. Purification by FCC eluting with System A (200:10:1) gave a solid which was triturated with ether and then dried in vacuo to give the title compound (62 mg), m.p. 174°-175°.