Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:12](=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:8][NH:7]1)=[O:5])[CH3:2].[C:33]([C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]=1[O:46][CH3:47])[C:40](O)=[O:41])([CH3:36])([CH3:35])[CH3:34].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:12](=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:8][N:7]1[C:40](=[O:41])[C:39]1[CH:43]=[C:44]([C:48]([CH3:49])([CH3:50])[CH3:51])[C:45]([O:46][CH3:47])=[C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:38]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](NC(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CN1
Reactant: COc1c(C(C)(C)C)cc(C(=O)O)cc1C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CN1C(=O)c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To the solution of (2S,4S)-4-[6,6-Bis-(4-fluoro-phenyl)-hexanoylamino]-pyrrolidine-2-carboxylic acid ethyl ester (32) (0.39 g, 0.88 mmol) in dry CH2Cl2 (20 ml) was added 3,5-di-tert-butyl-4-methoxy benzoic acid (0.23 g, 0.88 mmol). To the reaction was added EDC (0.34 g, 1.76 mmol) and DMAP (cat), and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (10 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using pet ether: EtOAc (1:1) to give 0.46 g of desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc(Sc2ccccc2)s1
Yield: 48 %

Procedure:
A suspension of 2-bromo-1,3-thiazole-5-carboxylic acid ethyl ester (1.5 g, 6.15 mmol, 1 eq) and K2CO3 (1.7 g, 12.3 mmol, 2 eq) in EtOH (60 mL) is cooled in an ice bath, and thiophenol (0.631 mL, 6.15 mmol, 1 eq) is added. The reaction is monitored by HPLC until the starting material is consumed. The reaction mixture is filtered (to remove a solid by-product), and the solvent is removed in vacuo. The crude mixture is purified by silica gel chromatography using a Biotage Flash 40S column using 2% EtOAc in hexanes to afford the product as an oil (0.784 g, 46%). MS (ESI) for C12H11NO2S2 m/z 266.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2/[CH:26]=[CH:27]/[CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].[BH4-].[Na+].[OH-].[Na+]>CO.O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]2/[CH:26]=[CH:27]/[CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: CC/C=C/c1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC/C=C/c1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 0.26 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-(1-trans-butenyl)-4-chloroimidazole-5-carboxaldehyde in 10 mL of methanol at 0° C. was added 0.24 g of sodium borohydride portionwise over 0.5 hours. The mixture was stirred for an additional 0.5 hours at 0° C. and then poured into a solution at 10% sodium hydroxide in water. The resulting mixture was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (elution: ethyl acetate/benzene) provided 0.23 g of 1-[2'-carbomethoxybiphenyl-4-yl)methyl-2-(1-transbutenyl)-4-chloro-5-hydroxymethylimidazole. NMR (200 MHz, CDCl3) δ7.84 (d, 1H); 7.53 (t, 1H); 7.40 (t, 1H); 7.29 (m, 3H); 7.08 (d, 2H); 6.86 (d of t, 1H); 6.17 (d, 1H); 5.30 (s, 2H); 4.54 (br s, 2H); 3.63 (s, 3H); 2.23 (quint., 2H); 1.04 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3](O)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.C1COCC1>[OH:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(CCCCOc1ccccc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CO)CCCCOc1ccccc1

Procedure:
A solution of 129 g of 2-methyl-6-phenoxy-hexanoic acid in 200 ml of absolute ether and 100 ml of absolute THF was added dropwise, under exclusion of humidity, to 32 g (0.84 mol) of LiAlH4 in 1.2 l of absolute ether. After reflux and stirring for 5 hours the LiAlH4 in excess was destroyed with acetic acid and then destroyed by dropwise addition of water and a 10% sulfuric acid. The organic layer was washed with saturated NaHCO3 -solution, dried and evaporated. The crude product was immediately further reacted.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22]([CH3:25])(=[O:24])=[O:23])[NH:11][C:10]=2[CH:9]=1.[OH-].[K+]>C(C(C)=O)C>[CH3:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22]([CH3:25])(=[O:24])=[O:23])[N:11]([CH2:2][CH2:3][CH2:4][Cl:5])[C:10]=2[CH:9]=1
Reactant: ClCCCBr
Reactant: COc1ccc2c(c1)Nc1cccc(S(C)(=O)=O)c1S2
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: COc1ccc2c(c1)N(CCCCl)c1cccc(S(C)(=O)=O)c1S2
Yield: 75.5 %

Procedure:
2-Methoxy-6-methylsulphonyl-10-(3-chloropropyl)phenothiazine (m.p. 122°-124°C.; 15.0 g.) is prepared by reacting 1-bromo-3-chloropropane (30.4 g.) with 2-methoxy-6-methylsulphonylphenothiazine (15.9 g.) in the presence of 85% pure ground potassium hydroxide (5.6 g.) dissolved in methyl ethyl ketone (75 cc.).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:26][CH2:25][C:8]2([C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li]CCCC.[CH:32]1([CH:35]=[O:36])[CH2:34][CH2:33]1>C1COCC1>[CH:32]1([CH:35]([OH:36])[CH2:1][S:2]([N:5]2[CH2:6][CH2:7][C:8]3([C:12](=[O:13])[N:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=4)[CH2:10][CH2:9]3)[CH2:25][CH2:26]2)(=[O:4])=[O:3])[CH2:34][CH2:33]1
Reactant: CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Reactant: O=CC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)CC(O)C1CC1)CC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.8 %

Procedure:
To a solution of 8-methanesulfonyl-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (76 mg, 0.19 mmol) in THF at −78° C. was added n-BuLi (1.6M, 145 uL, 0.23 mmol) dropwise. The reaction mixture was stirred for 5 min followed by the addition of a solution of cyclopropanecarbaldehyde (54 mg, 0.78 mmol) in THF (500 uL) at −78° C. The dry ice bath was removed and the reaction mixture was warmed to 0° C. and stirring was continued for a further 30 min. The reaction mixture was quenched with AcOH (20 uL) and was then concentrated to dryness under reduced pressure. The crude residue was partitioned between ethyl acetate and water and the organic layer was then washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography to afford 8-(2-cyclopropyl-2-hydroxy-ethanesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (42 mg, 47%) as a white solid. MS (ESI): 463.2 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[C:25](B(O)O)=[CH:24][CH:23]=[C:22]([CH3:29])[N:21]=1>>[CH2:16]([NH:15][C:13]([C:3]1[N:4]=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:25]1[C:20]([F:19])=[N:21][C:22]([CH3:29])=[CH:23][CH:24]=1)=[O:14])[CH2:17][CH3:18]
Reactant: Cc1ccc(B(O)O)c(F)n1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(C)nc3F)cccc2c1N

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (300.0 mg, 0.97 mmol) and 2-fluoro-6-methylpyridine-3-boronic acid (426.7 mg, 2.75 mmol) according to Method A to afford a white solid (124.2 mg, 38%). 1H NMR (300.132 MHz, CDCl3) δ 8.53 (bs, 1H), 7.94 (t, J=1.4 Hz, 1H), 7.92 (dt, J=8.6, 1.4 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.83 (dt, J=7.1, 1.2 Hz, 1H), 7.74 (dd, J=8.8, 7.3 Hz, 1H), 7.19 (dd, J=7.4, 1.3 Hz, 1H), 3.46 (q, J=6.7 Hz, 2H), 2.59 (s, 3H), 1.66 (sextet, J=7.3 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=340 (M+H). HPLC 2.28 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH:5]=[CH:6][C:7]([OH:9])=O.O=S(Cl)Cl.Cl.[NH2:19][N:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH:5]=[CH:6][C:7]([NH:19][N:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22])=[O:9]
Reactant: Cc1ccc(C=CC(=O)O)cc1Cl
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(C=CC(=O)NN2CC(=O)NC2=O)cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 3-chloro-4-methylcinnamic acid (50 g, 0.25 mole) was added dropwise SOCl2 (140 ml). The mixture was heated under reflux for 45 min. after the addition was complete. After stirring at room temperature for 1 hour the SOCl2 was removed in vacuo. Dry benzene was added and then removed in vacuo. The acid chloride residue was treated with 1 -aminohydantoin hydrochloride (42 g, 0.275 mole) in 350 ml of pyridine, then heated under reflux for 2 hr. After cooling slightly, the reaction mixture was poured into a mixture of 200 ml of con HCl and 1500 ml of ice. After standing overnight the product was removed by filtration and washed with H2O. Recrystallization from CH3NO2 provided analytical material which melted at 271°-273° (28 g, 38%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([F:31])[CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH3:38])[N:34]=1>>[CH3:38][N:35]1[CH:36]=[CH:37][C:33]([NH:32][C:6]([C:8]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([F:31])[CH:22]=3)[C:11]3[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:34]1
Reactant: Cn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)c(F)c2)c2c(c1)OC(C)(CO)C2
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)c(F)c3)c3c(c2)OC(C)(CO)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (232a) and 3-amino-1-methyl-pyrazole. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1 H) 7.80-7.99 (m, 1H) 7.26-7.32 (m, 1 H) 7.11 (dd, J=17.05, 1.39 Hz, 2 H) 6.73-6.92 (m, 3 H) 3.82 (s, 3 H) 3.75 (d, J=5.56 Hz, 1 H) 3.63 (d, J=7.58 Hz, 1 H) 3.23 (s, 3 H) 2.81 (d, J=16.17 Hz, 1 H) 2.04 (d, J=1.77 Hz, 1 H) 1.47 (s, 3 H); LCMS for C22H22FN3O6S m/z 476.00 (M+H+).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[BrH:12]>C1(C)C=CC=CC=1>[Br:12][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1ccncc1[N+](=O)[O-]
Reactant: Br
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnccc1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 4-methoxy-3-nitropyridine (3.5 g) was added 48% hydrobromic acid (30 ml), and the solution was stirred overnight at 80° C. Toluene was added thereto followed by stirring. The solvent was evaporated in vacuo. To the total amount of the resulting 3-nitropyridin-4-ol (crude product) were added phosphorous oxybromide (20 g) and chloroform (30 ml), and the solution was stirred for 2 hours at 110° C. To the reaction mixture was added an ice, the solution was neutralized with aqueous ammonia, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then filtered through silica gel, and the solvent was evaporated in vacuo to provide the title compound (2.6 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH:10]3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:23])[O:4][N:3]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(c2ccccc2)C(=O)Nc2ccc(-c3c(C)noc3C)cc21
Temperature: 60 °C
Yield: 60.3 %

Procedure:
A mixture of 5-(3,5-dimethylisoxazol-4-yl)-3-phenyl indolin-2-one (260 mg, 0.85 mmol), ethyl bromoacetate (172 mg, 1.0 mmol), potassium iodide (171 mg, 1.0 mmol) and potassium carbonate (260 mg, 1.88 mmol) in acetone (10 mL) was heated at 60° C. for 15 hours in a capped pressure tube. The mixture was then cooled to room temperature and diluted with ethyl acetate (30 mL) and extracted with water (2×30 mL) and brine (20 mL). Aqueous layers were back washed with ethyl acetate (30 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give product (200 mg, 59.9%). 1H NMR (400 MHz, DMSO-d6): δH 10.61 (s, 1H), 7.21-7.39 (m, 7H), 6.97 (d, J=8.0 Hz, 1H), 3.82-3.85 (m, 2H), 3.41 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H), 0.90 (t, J=6.8 Hz, 1H). MS (ESI) m/e [M+1]+ 391.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]1[S:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[CH3:10][C:11]1[S:12][CH:13]=[C:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[N:15]=1
Reactant: O=Cc1ccccc1Br
Reactant: Cc1nc(B2OC(C)(C)C(C)(C)O2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccccc2C=O)cs1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
To a solution of 2-bromobenzaldehyde (0.063 mL, 0.54 mmol) in DMF (5 mL) and H2O (1 mL) are added 2-methylthiazole-4-boronic acid pinacol ester (122 mg, 0.54 mmol), Pd(PPh3)4 (63 mg, 0.054 mmol) and K2CO3 (112 mg, 0.81 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The reaction is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and is filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel flash chromatography eluting with 50% EtOAc in heptane to afford 2-(2-methyl-thiazol-4-yl)-benzaldehyde (58 mg, 53%) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17]O)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH:27]1[CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH2:17][CH2:16][C@@:13]2([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[CH3:9])[CH2:15][CH2:14]2)[CH2:30][CH2:29][CH2:28]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: C1CNC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CCC2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and azetidine following procedures analogous to those described in Example 178. LC-MS Method 2 tR=1.15 min, m/z=463; 1H NMR (CDCl3) 1.43 (d, 4H), 2.05-2.27 (m, 7H), 2.56-2.74 (m, 2H), 2.86 (m, 1H), 3.20 (m, 1H), 3.50 (m, 1H), 3.71 (m, 1H), 4.17-4.39 (d, 2H), 5.52 (m, 1H), 6.80 (d, 2H), 6.95-7.02 (m, 2H), 7.13-7.24 (m, 4H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:48])[C:29]2[CH:34]=[CH:33][C:32]([CH:35]([O:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:22]=1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[NH4+:53].[OH-].[Na+]>O>[NH2:53][C:9]1[C:8]2[N:22]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:48])[C:29]3[CH:34]=[CH:33][C:32]([CH:35]([O:42][CH2:43][CH2:44][N:45]([CH3:46])[CH3:47])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:31][CH:30]=3)[C:7]=2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=1
Reactant: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Temperature: 150 °C
Yield: 15.3 %

Procedure:
N-[4-(2-Butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide (101 mg, 0.16 mmol) and ammonium acetate (1.1 g) were placed into a pressure tube along with a stir bar. The tube was sealed and heated at 150° C. for 16 hours. The reaction was cooled to room temperature and diluted with water. The resulting cloudy aqueous mixture was made basic with 10% aqueous sodium hydroxide and extracted with chloroform (3×25 mL). The combined organic fractions were washed with water followed by brine, dried (Na2SO4), decanted and evaporated to provide a yellow oil. Purification by flash column chromatography (silica gel, 95:5 dichloromethane/methanol gradient to 9:1 dichloromethane/methanol and finally 94:5:1 dichloromethane/methanol/triethylamine) provided 14 mg of N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide as a yellow oil. 1H-NMR (500 MHz, DMSO-d6) δ8.41 (t, J=5.5 Hz, 1H), 7.76 (d, J=8.3 Hz, 2H); 7.43 (d, J=8.3, 2H), 7.37-7.31 (m, 4H), 7.26-7.22 (m, 1H), 5.84 (bs, 2H), 5.52 (s, 1H), 4.22 (t, J=7.7 Hz, 2H), 3.49 (t, J=5.8 Hz, 2H), 3.29 (dd, J=6.4, 12.4 Hz, 2H), 2.76 (t, J=7.7 Hz, 2H), 2.58 (t, J=5.7 Hz, 2H), 2.32 (s, 3H), 2.27 (s, 3H), 2.22 (s, 6H), 1.73-1.65 (m, 4H), 1.61-1.55 (m, 2H), 1.35 (sextet, J=7.4 Hz, 2H), 0.86 (t, J=7.4 Hz, 3H); 13C-NMR (125 MHz, DMSO-d6) δ165.9, 153.0, 148.1, 145.4, 142.0, 138.6, 133.5, 128.23, 127.4, 127.3, 127.1, 126.4, 126.1, 124.5, 103.0, 82.0, 66.3, 58.0, 45.2, 43.6, 38.4, 29.3, 28.8, 26.1, 26.0, 21.7, 21.0, 13.6, 12.2.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[C:22]([CH3:30])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:30][C:22]1[CH:21]=[C:20]([NH:19][CH:2]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][C:8]=2[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:29]=[CH:28][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1ccc(N)cc1C
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.1 g), methyl 4-amino-2-methylbenzoate (1.1 g), sodium carbonate (0.6 g) and sodium iodide (2.4 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.5 g, 33%) as an oil.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:53][CH:52]([N:54](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH:55]=[NH:56])[CH2:51]2)=[O:49])[CH2:43]1>>[CH:55]([NH:54][CH:52]1[CH2:51][N:50]([C:48]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][N:45]2[CH3:47])=[O:49])[CH2:53]1)=[NH:56]
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC(N(C=N)C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CC(NC=N)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 7.2 %

Procedure:
A procedure similar to that described in Example 125 was repeated, but using 0.35 g of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and 0.22 g of (2S,4S)-4-mercapto-1-methyl-2-{3-[N-(4-nitrobenzyloxycarbonyl)-N-formimidoylamino]azetidin-1-ylcarbonyl}pyrrolidine (prepared as described in Preparation 118), to give 17 mg of the title compound as a powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1
Temperature: 60 °C
Yield: 112.9 %

Procedure:
A solution of ethyl 5-{(1R)-1 -[2-(tert-butoxy)2-oxoethyl]4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated dropwise with pyrrolidine (0.63 ml, 7.60 mmol) and the resulting solution was heated at 60° C. for 9 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1) to afford the title compound as a pale yellow oil (360 mg).