Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:27][CH2:28]Br>CN(C=O)C>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:28][CH2:27][N:17]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:16]2=[O:25])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(NC(=O)NCCC(=O)OCC)cc1
Reactant: BrCCBr
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(N2CCN(CCC(=O)OCC)C2=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
To a solution of the product of Example 11, Step A (0.05 g; 0.143 mmol) in anhydrous DMF (2 ml) 60% NaH in mineral oil (0.014 g; 0.344 mmol) was added at room temperature. After stirring for 1 h, to it 1,2-dibromoethane (0.172 ml; 0.2 mmol) was added. This was stirred at ˜50° C. for 1 h under N2, cooled to room and solvents were removed in vacuo. The residue was diluted to 15 ml with Et2O, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 9.5:0.5) to give the title compound (0.02 g; 37%) as a colourless solid. 1H-NMR (CDCl3) 7.4 (d, 2H, J=8.5 Hz); 7.1 (d, 2H, J=8.5 Hz); 4.13 (q, 2H, J=7.1 Hz); 3.76 (m, 2H); 3.57 (t, 2H, J=6.7 Hz); 3.5 (m, 2H); 2.6 (t, 2H, J=6.7 Hz); 2.53 (t, 2H, J=7.9 Hz); 1.55 (m, 2H); 1.24 (m, 13H); 0.85 (t, 3H, J=6.9 Hz).
Reaction SMILES: COC(=O)NC(C(N1CCC(C2NC(C3C=CC(C4C=CC([C:33]5[NH:34][C:35]([CH:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=[N:36][CH:37]=5)=CC=4)=CC=3)=CN=2)C1)=O)C(C)C.C(OC(N1CCCC1C1NC([C:72]2[CH:84]=[CH:83][C:82]3[C:81]4[C:76](=[CH:77][C:78]([C:85]5[NH:86][C:87]([CH:90]6[CH2:94][CH2:93][CH2:92][N:91]6[C:95](OC(C)(C)C)=[O:96])=[N:88][CH:89]=5)=[CH:79][CH:80]=4)[CH2:75][C:74]=3[CH:73]=2)=CN=1)=O)(C)(C)C>>[CH3:52][O:51][C:49](=[O:50])[NH:48][CH:44]([C:95]([N:91]1[CH2:92][CH2:93][CH2:94][CH:90]1[C:87]1[NH:86][C:85]([C:78]2[CH:77]=[CH:76][C:75]3[C:74]4[C:82](=[CH:83][C:84]([C:33]5[NH:34][C:35]([CH:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=[N:36][CH:37]=5)=[CH:72][CH:73]=4)[CH2:81][C:80]=3[CH:79]=2)=[CH:89][N:88]=1)=[O:96])[CH:45]([CH3:47])[CH3:46]
Reactant: COC(=O)NC(C(=O)N1CCC(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)C1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)Cc2cc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)ccc2-3)[nH]1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)Cc2cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc2-3)[nH]1)C(C)C

Procedure:
Followed the procedure used to prepare compound (1-{3-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl -propyl)-carbamic acid methyl ester, except that 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9H-fluoren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester was used instead of 2-(5-{4′-[2-(1-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H-NMR (300 MHz, CD3OD) δ 8.03 (d, 2H), 7.96 (s, 2H), 7.88 (s, 2H), 7.77 (d, 2H), 5.26 (t, 2H), 4.24 (d, 2H), 4.20-4.05 (m, 4H), 3.95-3.80 (m, 2H), 3.75-3.60 (m, 6H), 2.65-2.50 (m, 2H), 2.40-2.00 (m, 8H), 1.05-0.90 (m, 12H); m/z 751.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.COC1C=CC2N=C(C3C=CC(N[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=NC=3)OC=2C=1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[N:14][C:13]([NH:16][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[N:12][CH:11]=3)[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3cnc(N)nc3)oc2c1
Reactant: COc1ccc2nc(-c3ccc(NC(=O)OC(C)(C)C)nc3)oc2c1
Product: COc1ccc2nc(-c3cnc(NC(=O)OC(C)(C)C)nc3)oc2c1

Procedure:
The title intermediate was synthesized from 5-(6-methoxy-1,3-benzoxazol-2-yl)pyrimidin-2-amine according to the procedure described for tert-butyl [5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-yl]carbamate to give 115 mg. 1H NMR 400 MHz, Chloroform-d) δ ppm 9.33 (s, 2H) 8.17 (s, 1H) 7.65 (d, 1H) 7.14 (d, 1H) 7.00 (dd, 1 H) 3.90 (s, 3H) 1.60 (s, 9H). MS m/z 343 (M+H).
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:11][C:12]([CH3:14])=[O:13].O>O1CCCC1>[Cl:10][C:2]1([O:13][C:12]1([CH3:14])[CH3:11])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Reactant: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Cl)OC1(C)C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of 70.8 g of potassium tert.-butylate in 500 ml of tetrahydrofuran was added over 30 minutes under an inert atmosphere to 111 g of tert.-butyl dichloroacetate and 35.5 g of acetone at 0°C and after letting the mixture return to room temperature, the mixture was stirred for 1 hour and poured into iced water. The mixture was extracted with petroleum ether and the extract was washed twice with water and dried over sodium sulfate. 40 g of alumina were added thereto and after stirring, the mixture was filtered to remove mineral products. The solvent was removed from the filtrate by distillation under reduced pressure to obtain 116.5 g of tert.-butyl 2-chloro-2,3-epoxy-3-methyl-butanoate in the form of a colorless liquid soluble in the usual organic solvents and insoluble in water.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[NH:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[NH:8][C:7](=[O:15])[C:6]=2[CH:16]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2

Procedure:
3,4-Dihydro-6-hydroxy-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (prepared as described in Example 3--5.0 g.) and acetic anhydride (250 ml.) were stirred for 40 hours at room temperature, the mixture was filtered, and the solid product was washed with acetic anhydride, then diethyl ether, to give 6-acetoxy-3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one, m.p. 201°-203° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([C:17]#[N:18])=[C:6]([Cl:16])[NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.CN(C)P(N(C)C)(N(C)C)=O.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.O.C(OCC)C>[C:30]([N:7]1[C:8]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[C:4]([Br:3])[C:5]([C:17]#[N:18])=[C:6]1[Cl:16])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1c(Cl)[nH]c(-c2ccc(Cl)cc2)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1c(Br)c(-c2ccc(Cl)cc2)n(C(=O)c2ccccc2)c1Cl
Reaction time: 0.33 h
Yield: 75 %

Procedure:
To a suspension of sodium hydride (0.21 g of a 60% dispersion, 5.3 mmol) in 50 mL of dry tetrahydrofuran in a 100 mL single neck round bottom flask fitted with a condenser and a nitrogen inlet is added portionwise 4-bromo-2-chloro-5-(p-chlorophenyl)pyrrole-3-carbonitrile (1.0 g, 3.2 mmol). The reaction is stirred for 15 minutes at room temperature before the pipette addition of hexamethylphosphoramide (HMPA) (3 mL) followed immediately by benzoyl chloride (0.75 g, 5.4 mmol). Thereafter the reaction mixture is heated to reflux for 17 hours and allowed to cool. Rotary evaporation yields a crude semi-solid to which is added 15 mL of diethyl ether and 15 mL of water. Vigorous stirring over a period of 20 minutes followed by vacuum filtration results in the isolation of the product as a yellow solid (1.0 g, 2.4 mmol, 75%), mp 179°-181° C.
Reaction SMILES: [CH:1](=[O:6])[CH:2]=[CH:3][CH2:4][CH3:5].[CH3:7][CH:8]([CH3:12])[CH2:9][CH:10]=O>>[CH:1](=[O:6])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:10][CH2:9][CH:8]([CH3:12])[CH3:7]
Reactant: CC(C)CC=O
Reactant: CCC=CC=O
Product: CC(C)CCCCC=CC=O

Procedure:
This example describes the process of the invention for the co-aldol condensation of n-pentenal and 3-methylbutanal (3-MBA) to give an isodecenal consisting of the isomers 2-propyl-5-methylhexenal and 2-isopropylheptenal (1+3) and also 2-propylheptenal (1+1). 400 kg/h of catalyst were passed through the reactor (as described in Example 3) at a temperature of 110° C. at the autogenous pressure of the reactants.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C[O-].[Na+].Cl[C:15]1[C:16]2[N:24]=[N:23][N:22]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:17]=2[N:18]=[C:19]([CH3:21])[N:20]=1>C(#N)C>[CH2:26]([CH:25]([N:22]1[C:17]2[N:18]=[C:19]([CH3:21])[N:20]=[C:15]([O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:16]=2[N:24]=[N:23]1)[CH2:28][CH3:29])[CH3:27]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: CCC(CC)n1nnc2c(Cl)nc(C)nc21
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(CC)n1nnc2c(Oc3c(C)cc(C)cc3C)nc(C)nc21
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
2,4,6-Trimethylphenol (0.114) was added to a solution of sodium methoxide (0.334 g) methanol (10 mL) and the resulting solution was evaporated to dryness under reduced pressure. The salt thus obtained was taken up in 10 mL of acetonitrile and added dropwise by to a cold solution (0-5° C.) of 7-chloro-3-(1-ethylpropyl)-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidine in 35 mL of acetonitrile, such that the temperature did not rise above 5° C. The mixture was stirred at 0-5° C. for 3 hours. The solvent was then removed from the mixture under reduced pressure and the residue treated with water and extracted three times with methylene chloride. The combined extracts were dried over MgSO4 and stripped of the solvent under reduced pressure. The material was purified on silica gel using a solution of 1% methanol in methylene chloride to yield the title compound as a colorless powder, mp 92° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.[CH3:17][C:18]([CH3:23])=[CH:19][C:20](Cl)=[O:21].O>C1COCC1>[CH3:17][C:18]([CH3:23])=[CH:19][C:20]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=1)=[O:21]
Reactant: CC(C)=CC(=O)Cl
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 g, 0.00456 mol) in THF (5 mL) at 0° C., were added TEA (0.552 g, 0.000547 mol) and dimethylacryloyl chloride (0.648 g, 0.00456 mol) and stirred for 15 mins at 0° C. The reaction was poured into water (200 mL) and extracted with EtOAc (300 mL×2). The combined extracts was washed with brine (200 mL), dried over sodium sulphate, and concentrated under vacuum to afford 3-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide (0.7 g, Yield: 51%).
Reaction SMILES: [CH:1]([CH:3]=O)=O.Br.[NH2:6][CH:7]([CH2:11][CH3:12])[C:8]([NH2:10])=[O:9].[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[CH2:11]([C:7]1[C:8]([OH:9])=[N:10][CH:1]=[CH:3][N:6]=1)[CH3:12]
Reactant: O=CC=O
Reactant: CCC(N)C(N)=O
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CCc1nccnc1O
Temperature: 25 °C

Procedure:
Aqueous glyoxal (50 ml), was added over one minute to a stirred solution of 2-aminobutanamide hydrobromide (61.9 g), in aqueous methanol (650 ml methanol, 70 ml water) at -40° C. 10.8M Aqueous sodium hydroxide solution (76.6 ml) was then added over one hour, keeping the temperature at -40° C. The reaction was then allowed to warm to ambient temperature over 18 hours and concentrated hydrochloric acid (41 ml) was added, followed by solid sodium hydrogen carbonate (33 g). The reaction mixture was filtered and the filtrate concentrated to a volume of approximately 100 ml. The concentrated solution was extracted with dichioromethane (3×250 ml), and the combined organic extracts were dried (MgSO4). Solvent was removed by evaporation to give 3-ethyl-2-hydroxypyrazine as a yellow solid, (30.3 g, 74%); 1H NHR (d6 -DMSO, 200 MHz): 1.15 (t,3H), 2.67 (q,2H), 7.15-7.25 (m,2H), 12.00 (s,1H); mass spectrum (+ve CI): 125 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:14])[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>O1CCOCC1>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:14])[CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(C)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(CC(=O)O)(c1ccccc1)c1ccccc1
Temperature: 65 °C
Reaction time: 6 h

Procedure:
4.9 g of ethyl 3,3-diphenylbutanoate (18.3 mmol) were dissolved in 30 ml of dioxane, 36 ml of 1M KOH were added, and the mixture was stirred at 60-70° C. for 6 h.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Brc1cnc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3ncc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a solution of 6-bromo-1H-imidazo[4,5-b]pyridine (500 mg, 2.52 mmol) and 1-chloromethyl-4-methoxy-benzene (394.6 mg, 2.52 mmol) in DMF (10 mL) was added Cs2CO3 (902 mg, 2.77 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then partitioned between EtOAc and water. The organic layer was dried over MgSO4, and concentrated. The residue was purified on a silica gel column eluting with EtOAc-Hexane to provide 6-bromo-1-(4-methoxy-benzyl)-1H-imidazo[4,5-b]pyridine (450 mg).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([CH2:19][C:20]([N:22]2[CH2:42][CH2:41][C:25]3[C:26]4[C:27]([N:32]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=5)[C:24]=3[CH2:23]2)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:21])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])C1C=CC=CC=1.[H][H]>[C].[Pd].CO.C1COCC1>[F:40][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][N:32]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C:25]2[CH2:41][CH2:42][N:22]([C:20](=[O:21])[CH2:19][C:17]3[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:8])[CH:18]=3)[CH2:23][C:24]1=2
Reactant: COC(=O)c1ccc(CC(=O)N2CCc3c(n(Cc4cccc(F)c4)c4ncccc34)C2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(=O)N2CCc3c(n(Cc4cccc(F)c4)c4ncccc34)C2)cc1O
Yield: 93.9 %

Procedure:
To 1.24 mL of a methanol/THF (1:1) solution of the compound (70 mg) produced in Example 63 was added 5% palladium carbon (7 mg, 10 wt %), and the mixture was stirred at room temperature for 3 hours under the hydrogen atmosphere. After the reaction solution was filtered with Celite, the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column (hexane/ethyl acetate=70:30-40:60) to obtain the title compound (55.2 mg) having the following physical property values.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[C:7](=[O:16])[N:6]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])=[O:4].[OH-].[Li+]>>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:9][N:8]([S:10]([CH:13]([CH3:14])[CH3:15])(=[O:12])=[O:11])[C:7]1=[O:16]
Reactant: COC(=O)C1CN(S(=O)(=O)C(C)C)C(=O)N1c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Product: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccc(F)cc2F)C1=O

Procedure:
In analogy to example 1, (RS)-3-(2,4-difluoro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid methyl ester was hydrolyzed using lithium hydroxide solution to give (RS)-3-(2,4-difluoro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28](=[O:30])[CH3:29])=[CH:27][C:22]4=[N:21][CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.[BH4-].[Na+].Cl>CO>[OH:30][CH:28]([C:26]1[CH:25]=[CH:24][N:23]2[C:19]([CH2:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)=[CH:20][N:21]=[C:22]2[CH:27]=1)[CH3:29]
Reactant: CC(=O)c1ccn2c(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cnc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccn2c(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cnc2c1
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To a stirred solution of 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone (40 mg, 0.095 mmol) from Example 200 in MeOH at rt was added NaBH4. After 30 min, 3N HCl was added and the mixture was purified by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-2-((6-((7-(1-hydroxyethyl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (23 mg, 58%) as white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.11 (d, J=7.4 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 6.84 (d, J=7.4 Hz, 1H), 5.30 (br s, 1H), 4.72 (q, J=6.4 Hz, 2H), 4.26 (s, 2H), 3.50 (br s, 1H), 2.03 (d, J=11.8 Hz, 1H), 1.82-1.87 (m, 1H), 1.55-1.69 (m, 2H), 1.32 (d, J=6.9 Hz, 3H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 423 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:28])[C@@H:15]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][NH:22][C:21](=[N:25][OH:26])[CH:20]=3)[C@H:12]2[S:11][CH2:10][C:9]=1[CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:36][CH3:37])=[N-]>O1CCCC1.CCOCC>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:28])[C@@H:15]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][NH:22][C:21](=[N:25][O:26][CH2:36][CH3:37])[CH:20]=3)[C@H:12]2[S:11][CH2:10][C:9]=1[CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3cc[nH]c(=NO)c3)[C@H]2SC1
Reactant: CC=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCON=c1cc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@H]23)cc[nH]1

Procedure:
A solution of t-butyl-3-acetoxymethyl-7β-(2-hydroxyiminopyrid-4-ylacetamido)-ceph-3-em-4-carboxylate (synisomer) (1.15 g) in tetrahydrofuran (20 ml) was treated with an excess of diazoethane at 20° for 40 minutes. The mixture was diluted with ether, washed with water and extracted with 2N-hydrochloric acid. The aqueous extract was neutralised with saturated sodium bicarbonate solution and extracted with ethyl acetate. Evaporation of the dried organic extract offered the title ester as a foam (0.84 g, 69%), [α]D + 47° (c 0.84, DMSO), λmax. (EtOH) 259 nm (ε 15,450), βmax. (Nujol) 3300 (NH), 1788 (β-lactam), 1740 (OAc), 1724 (CO2R), 1678 and 1540 cm.-1 (CONH), τ (d6 -DMSO) values include 0.12 (d, J 8Hz; NH), 1.26 and 2.42 (multiplets; aromatic protons), 5.69 (q, J 7Hz, OCH2CH 3), 7.93 (s; OCOCH3), 8.50 (s; (CH3)3) and 8.69 (t, J 7Hz; OCH2CH3).
Reaction SMILES: [C:1]([C:6]1[C:10]([O:11][C:12]([F:17])([F:16])[CH:13]([Cl:15])[F:14])=[CH:9][N:8]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[Cl:29])[N:7]=1)([O:3]CC)=[O:2].[OH-].[Na+].CO.Cl>O>[C:1]([C:6]1[C:10]([O:11][C:12]([F:16])([F:17])[CH:13]([Cl:15])[F:14])=[CH:9][N:8]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:26])([F:28])[F:27])=[CH:20][C:19]=2[Cl:29])[N:7]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1OC(F)(F)C(F)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1OC(F)(F)C(F)Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.2 %

Procedure:
A mixture of (RS)-3-carboethoxy-4-(2-chloro-1,1,2-trifluoroethoxy)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole 5 (0.95 g), aqueous sodium hydroxide solution (2M; 20 ml) and methanol (20 ml) was stirred at room temperature for 20 hours. The solution was acidified with hydrochloric acid (2M), diluted with water (50 ml) and extracted with ether (2×30 ml). The combined extracts were dried over magnesium sulfate and evaporated to give (RS)-3-carboxy-4-(2-chloro-1,1,2-trifluoroethoxy)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.7 g) as a yellow solid, m.p. 149°-159° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:18][CH2:17]2)=[O:15])[CH2:3]1.[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:32]=1[C:33](Cl)=[O:34]>>[CH2:7]([N:5]1[C@H:4]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:20][CH2:21]2)=[O:15])[CH2:3][C@H:2]([NH:1][C:33](=[O:34])[C:32]2[C:31]([Cl:30])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:40])[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](NC(=O)c3c(Cl)cccc3Cl)CN2Cc2ccccc2)CC1
Yield: 20 %

Procedure:
As described for Example 89e, 2-[4-(4-amino-1-benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (50.0 mg, 0.128 mmol) was converted, using 2,6-dichloro-benzoyl chloride instead of 2-chloro-benzoyl chloride, to the title compound (15 mg, 20%) as light yellow oil. MS m/e=562.2 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][C:12]2[N:13]=[CH:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)=[CH:2]1.[OH-].[Na+]>C(O)(=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[CH:2]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(CCc3coc4ccccc34)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc2c(CCc3c[nH]cn3)coc2c1
Temperature: 25 °C

Procedure:
4-(1-Benzofuran-3-yl-ethyl)-1-trityl-1H-imidazole (Intermediate I4) (0.52 g) in acetic acid (10 mL) and water (5 mL) was heated to reflux for 1 h. The mixture was cooled to rt and the pH was adjusted with 2M NaOH until basic. The aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO4 and filtered through paper. The solvent was removed under a vacuum. The residue was purified by chromatography on silical gel with 2.5% NH3-MeOH: CH2Cl2 to give 4-(1-benzofuran-3-yl-ethyl)-1H-imidazole Intermediate I5) 0.29 g.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=2[F:14])[N:6]=1.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])[S:3][CH:4]=2)=[C:8]([F:14])[CH:9]=1
Reactant: Fc1cc(Br)ccc1-c1csc(Br)n1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)Nc1nc(-c2ccc(Br)cc2F)cs1
Temperature: 175 °C
Yield: 19.7 %

Procedure:
2-Bromo-4-(4-bromo-2-fluorophenyl)-1,3-thiazole (1.5 g, 4.4 mmol), prepared in the previous step, and 2-amino-2-methyl-1-propanol (2.5 mL, 26.7 mmol) were placed in a sealed tube and heated to 175° C. overnight. The reaction was concentrated under reduced pressure. The residue was purified on silica gel using a stepwise gradient of 5-40% ethyl acetate:hexane to give 2-{[4-(4-bromo-2-fluorophenyl)-1,3-thiazol-2-yl]amino}-2-methylpropan-1-ol (0.3 g, 22%), MS (ES) m/z 346 [M+H]+.