Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]=1)([O:3][CH3:4])=[O:2].[Al]>O1CCCC1>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1=NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Agent: [Al]
Solvent: C1CCOC1
Product: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Yield: 62.3 %

Procedure:
A solution of 75 g of benzyl α-(3-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-α-isopropylideneacetate in 900 ml of tetrahydrofuran containing 5% water is mix with aluminium amalgam which has been prepared from 26.3 g of aluminium and 2.5% aqueous solution of mercuric chloride, and the mixture stirred under ice-cooling for 20 minutes. The reaction mixture is filtrated through Hyflo Super Cel, diluted with ethyl acetate, washed with an aqueous solution of sodium hydrogen-carbonate and water, dried on sodium sulfate, concentrated and then mixed with ether. The resulting crystals are collected by filtration to yield 47.02 g of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 62.4% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[C:8](=[O:16])[NH:7][CH2:6][CH2:5]2.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:14])([F:13])[F:15])[C:8](=[O:16])[N:7]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(Cl)c(C(F)(F)F)cc21
Reactant: FC(F)(F)c1ccncc1Br
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(C(F)(F)F)c(Cl)cc2CCN1c1cnccc1C(F)(F)F
Yield: 9.5 %

Procedure:
6-Chloro-7-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (I-85e: 100 mg, 0.4 mmol) was reacted with 3-bromo-4-(trifluoromethyl)-pyridine (117.6 mg, 0.520 mmol), 1,4-dioxane (5 mL), copper iodide (7.6 mg, 0.04 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (5.6 mg, 0.04 mmol) and potassium phosphate (255.6 mg, 1.2 mmol) to afford the crude product. Purification by preparative HPLC afforded 15 mg of the product (10% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>C(O)C>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([CH:10]3[CH2:14][CH2:13][O:12][CH2:11]3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH3:16]
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)C1CCOC1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(C3CCOC3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 19.1 %

Procedure:
To a solution of 2-phenyl-1-(tetrahydrofuran-3-yl)ethanone (Intermediate 92) (60 mg, 0.32 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (67.5 mg, 0.32 mmol) and urea (57.4 mg, 0.96 mmol) in 20 mL of ethanol was added 0.2 mL of conc. HCl, and the mixture was refluxed for 2 days. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 173 (26 mg, yield 20.0%). 1H NMR (DMSO-d6 400 MHz): δ 10.25 (s, 1H), 8.05 (m, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.28 (m, 4H), 7.08 (d, J=7.2 Hz, 2H), 6.95 (d, J=18.8, 1H), 5.08 (m, 1H), 3.98 (m, 3H), 3.62 (m, 3H), 3.01 (m, 1H), 2.13 (m, 2H), 1.31 (m, 3H); MS (ESI): m/z 426.2 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]#[N:21])=[N:14]2)[CH:7]=1)[CH3:2].[Cl-].C([NH2+]CC)C.O.[S-2:30].[Na+].[Na+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20](=[S:30])[NH2:21])=[N:14]2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(C#N)ccc2=O)c1
Reactant: [S-2]
Agent: CC[NH2+]CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cccc(Cn2nc(C(N)=S)ccc2=O)c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
200 mg (0.67 mmol) of ethyl[3-(3-cyano-6-oxo-6H-pyridazin-1-ylmethyl)-phenyl]carbamate are dissolved in 1 ml of DMF, and 219 mg (2 mmol) of diethylammonium chloride and 165 mg (2 mmol) of sodium sulfide hydrate are added. The yellow suspension is stirred at 55° C. for 2 hours. 10 ml of water are added to the reaction mixture. The precipitate is filtered off with suction, washed with water and dried in vacuo. The substance is reacted further without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5](O)=[S:6].Cl.[CH2:14]([O:16][CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][C:37]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38]2)[CH2:30][CH2:29]1)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([N:39]1[CH2:40][CH2:41][C:37]([CH2:36][CH2:35][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:20]3[N:19]([CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH2:29][CH2:30]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38]1)=[S:6]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(C)cc1C(O)=S
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=S)c4cc(C)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-methylthiobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH3:1][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)[N:17]([C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=2)[C:16]1=[O:38])([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:3].[CH:39]1(B(O)O)[CH2:41][CH2:40]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)[N:17]([C:31]2[CH:36]=[CH:35][C:34]([CH:39]3[CH2:41][CH2:40]3)=[CH:33][CH:32]=2)[C:16]1=[O:38])([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:3]
Reactant: OB(O)C1CC1
Reactant: CC(C)(N[C@@H]1C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(Br)cc2)C1=O)c1ccc(C(F)(F)F)nc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(N[C@@H]1C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C3CC3)cc2)C1=O)c1ccc(C(F)(F)F)nc1
Yield: 90.4 %

Procedure:
Dissolve (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-1-(4-bromo-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-2-one (1.25 mmoles; 750 mg), cyclopropylboronic acid (1.62 mmoles; 139 mg), tribasic potassium phosphate N-hydrate (4.36 mmoles; 925 mg), and tricyclohexylphosphine (124.51 μmoles; 34 mg) in toluene (5 mL) and water (275 μL) and degas the solution for 5 minutes then place under a nitrogen atmosphere. Add Pd(OAc)2 (62 μmoles; 14 mg) and heat the mixture at 90° C. overnight. Dilute with ethyl acetate (50 mL) and filter through celite. Wash the filtrate with water, 1N HCl, saturated aqueous sodium bicarbonate, brine, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to a brown residue. Purify the residue by flash chromatography on silica with gradient 0->50% ethyl acetate in hexane to afford the title compound (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1-(4-cyclopropyl-phenyl)-pyrrolidin-2-one (1.13 mmoles; 639.00 mg; 91.07% yield). LC/MS m/z 564.2 (M+1), Tr=4.87 min (Method 3).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccccc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 160.3 %

Procedure:
To a solution of 2-fluorobenzoic acid (25.3 g, 181 mmol) in tetrahydrofuran (300 ml) was added 1,1′-carbonylbis-1H-imidazole (32.2 g, 198 mmol) and the mixture was stirred at room temperature for 30 min. To the reaction solution was added monoethyl malonate magnesium salt (27.1 g, 94.7 mmol) and the mixture was heated under reflux for 30 min. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution, and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(2-fluorophenyl)-3-oxopropionate (31.9 g, 84%) as a colorless oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11](OS(C(F)(F)F)(=O)=O)=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1([CH2:28][C:29]2N=CC(O)=[CH:31][CH:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(NS(C(F)(F)F)(=O)=O)C=CC=CC=1>C(Cl)Cl>[NH3:1].[N:22]1([CH2:28][CH2:29][C:30]#[C:31][C:11]2[CH:10]=[CH:9][C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:13][N:12]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Oc1ccc(CN2CCCCC2)nc1
Reactant: O=S(=O)(Oc1ccc(CN2CCCCC2)cn1)C(F)(F)F
Agent: O=S(=O)(Nc1ccccc1)C(F)(F)F
Solvent: ClCCl
Product: C(#Cc1ccc(CN2CCCCC2)cn1)CCN1CCCCC1
Product: N
Yield: 0 %
Yield: 95 %

Procedure:
Trifluoro-methanesulfonic acid 5-piperidin-1-ylmethyl-pyridin-2-yl ester. A solution of 6-piperidin-1-ylmethyl-pyridin-3-ol (0.225 g, 1.17 mmol), N-phenyltrifluoromethanesulfonamide (0.50 g, 1.41 mmol), and TEA (0.50 mL, 3.50 mmol) in DCM (20 mL) was heated at reflux for 18 h. The solvent was removed and chromatography of the residue (SiO2: 0-3% 2 M NH3 in MeOH/DCM) gave the title compound as a solid (0.036 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:20][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH3:10])=[CH:13][CH:14]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: CCc1ccc(C(C)=O)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: CCc1ccc(C(=O)C=Cc2ccc(Cl)cc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and 4-ethylacetophenone, 3-(4-chlorophenyl)-1-(4-ethylphenyl)prop-2-en-1-one was obtained as pale yellowish solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([C@:14]1([CH2:28][OH:29])[CH2:18][N:17]([C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1)[CH:12]=[CH2:13].CN(C)C=O>O1CCCC1.CO>[CH2:11]([C@:14]1([CH2:28][O:29][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18][N:17]([C@@H:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1)[CH:12]=[CH2:13]
Reactant: BrCc1ccccc1
Reactant: C=CC[C@@]1(CO)CC(=O)N([C@H](C)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: C=CC[C@@]1(COCc2ccccc2)CC(=O)N([C@H](C)c2ccccc2)C1
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
Benzyl bromide (17.1 mL, 0.144 mol) and sodium hydride (55% in liquid paraffin, 6.27 g, 0.144 mol) were sequentially added to a solution of (4R)-4-allyl-4-hydroxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (31.1 g, 0.120 mol) in tetrahydrofuran (300 mL)-dimethylformamide (75 mL) in a nitrogen atmosphere at 0° C. The mixture was stirred at the same temperature for 30 minutes. Methanol (5 mL) was carefully added and stirred until gas was not generated. Then, the reaction was quenched with a saturated ammonium chloride solution (50 mL). The reaction solution was poured into a mixture of ethyl acetate (1000 mL) and water (150 mL), followed by extraction with ethyl acetate (1500 mL). The organic layer was sequentially washed with water (200 mL) and brine (200 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→2:1→1:1) to give 41.3 g (99%) of the title compound as a pale yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([NH2:21])[C:14]=2[N:22]=1)[CH3:8]>ClCCl.C(Cl)(Cl)Cl>[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:23][CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH2:29][CH2:30]2)[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([NH2:21])[C:14]=2[N:22]=1)[CH3:8]
Reactant: CC(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)C(C)C)CC1
Reaction time: 8 h
Yield: 50.2 %

Procedure:
Isobutyryl chloride (96 μL, 0.917 mmol) was added drop wise to a chilled (0° C.) solution of 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine (304 mg, 0.917 mmol) in dichloromethane (10 mL). The reaction mixture was allowed to stir overnight then it was diluted with chloroform and washed with 5% sodium hydroxide, water and brine. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from acetonitrile to provide 185 mg of 2-(ethoxymethyl)-1-[2-(1-isobutyrylpiperidin-4-yl)ethyl]-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine as a yellowish solid, m.p. 167.5–169.2° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:32]=[CH:31][C:25]([O:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:59](OC(=O)C)(=[O:61])[CH3:60].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:32]=[CH:31][C:25]([O:26][CH2:27][CH2:28][CH2:29][NH:30][C:59](=[O:61])[CH3:60])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:33]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: NCCCOc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NCCCOc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Reaction time: 1 h

Procedure:
While 5 mL solution of 37 mg 3-(4-{6-[3-(4-Fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}phenoxy)-propylamine obtained in Example 16 and 20 mg triethylamine in dichloromethane was stirred under ice-coolingd water in a stream of nitrogen, 9 μL acetic anhydride was added thereto and stirred for 1 hour. An aqueous saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give 30 mg of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C1C=CC=CC=1>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)=[O:35])=[CH:32][CH:31]=1
Reactant: CCOC(=O)CCCCNc1ccc2c(c1)CCC2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCCN(C(=O)c1ccc(Cl)cc1)c1ccc2c(c1)CCC2
Yield: 88.5 %

Procedure:
6.3 g of ethyl 5-(indan-5-ylamino)valerate and 3.1 g of ethyl diisopropylamine are reacted in 50 ml of benzene with 4.2 g of p-chlorobenzoyl chloride. The resulting residue (left after filtering off the precipitate and concentrating the filtrate by evaporation) is saponified as described in Example 77b. Recrystallization of the crude product from ethyl acetate/petrol ether (1:2) yields 7.9 g (88.1% of theory) of 5-{p-chloro-[N-(indan-5-yl)]benzamido}valeric acid, MP 132° to 134°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7](=[O:9])[CH3:8])=[CH:3]1.ClS([N:14]=[C:15]=O)(=O)=O.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[C:7]([C:4]1[CH:5]=[C:6]([C:15]#[N:14])[N:2]([CH3:1])[CH:3]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)c1ccn(C)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(C#N)n(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a solution of 1-methyl-3-acetylpyrrole (4.0 g, 32.5 mmol) in dry dichloromethane (40 mL), under nitrogen at −78° C., was added chlorosulfonyl isocyanate (2.8 mL, 32.5 mmol) dropwise. The reaction warmed to room temperature over 2 h, and was then treated with dimethylformamide (8 mL). After 30 min, the reaction was poured into water, treated with a 1 N sodium carbonate solution (10 mL) and extracted with methylene chloride (2×50 mL). The combined organic layers were washed with water, dried (anhydrous sodium sulfate) and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexanes, 3:1 to 1:1) to afford 4-acetyl-1-methyl-1H-pyrrole-2-carbonitrile (2.5 g, 16.87 mmol), which was used without further characterization.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C:14](=O)/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.O.[NH2:26][NH2:27]>CCO>[CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH2:15][CH:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[OH:23])[NH:27][N:26]=3)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: NN
Reactant: Cc1ccc(C)n1-c1ccc(C(=O)/C=C/c2ccccc2O)cn1
Solvent: CCO
Solvent: O
Product: Cc1ccc(C)n1-c1ccc(C2=NNC(c3ccccc3O)C2)cn1
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
To a suspension of (2E)-1-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]-3-(2-hydroxyphenyl)prop-2-en-1-one (0.31 g, 0.97 mmol) in EtOH (8.5 mL) was added hydrazine hydrate (65% solution, 0.146 mL, 1.95 mmol). After stirring for 15 min, the reaction mixture was concentrated to give 2-{3-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]-4,5-dihydro-1H-pyrazol-5-yl}phenol as a yellow solid (0.32 g, 99%). LCMS: (FA) ES+ 333.2 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O-:20])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3].[Na+].[C:24]([O:27][CH2:28]Br)(=[O:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O:20][CH2:28][O:27][C:24](=[O:26])[CH3:25])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3csc4cncn34)C[C@H]12
Reactant: CC(=O)OCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCOC(=O)C1=C(c2csc3cncn23)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: -10 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a solution-of 60.2 mg of sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate in 1.4 ml of DMF was added 67.7 mg of acetoxymethyl bromide under the atmosphere of argon at a temperature of −30° C., and the mixture was stirred for 3 hours during which the temperature was raised up to −10° C. The reaction mixture was diluted twice with 20 ml of ethy acetate, and washed twice with 10 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 2 ml. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=15:1) and Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give 22.1 mg of the title compound.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4].[CH2:8]([N:11]=[C:12]=[O:13])[CH2:9][CH3:10]>C(N(CC)CC)C.C(Cl)Cl>[CH2:8]([NH:11][C:12]([N:2]([O:1][C:12]([NH:11][CH2:8][CH2:9][CH3:10])=[O:13])[C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4])=[O:13])[CH2:9][CH3:10]
Reactant: CCCN=C=O
Reactant: O=C(NO)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)ON(C(=O)NCCC)C(=O)C1CC1

Procedure:
N-hydroxycyclopropanecarboxamide (5.0 grams), n-propyl isocyanate (9.3 grams) and 5 drops of triethylamine were stirred at room temperature in about 100 ml of methylene chloride for about 12 hours. The reaction mixture was then concentrated leaving an oily residue which crystallized upon scratching. This solid was then recrystallized from a mixture of cyclohexane and isopropanol and dried. Upon drying, the desired N-((propylamino)carbonyl)-N-(((propylamino)carbonyl)-oxy)cyclopropanecarboxamide was obtained as a white solid, m.p. 76°-78° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.[F-].[Cs+]>C(COC)OC.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1[C:30]1[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Reactant: OB(O)c1cccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)CCc1ccc(-c2cccnc2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (1.0 g, 2.4 mmol) was dissolved in dimethoxyethane (15 mL) and ethanol (1.5 mL). Pyridin-3-ylboronic acid (0.33 g, 2.65 mmol) was added and argon was bubbled in the mixture for 15 minutes. Cesium fluoride (0.8 g, 5.3 mmol) and tetrakistriphenylphosphine palladium (0.14 g, 0.1 mmol) were added and the mixture was brought to reflux under an argon atmosphere for 4 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate/water (15 mL/15 mL). The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 9/1) to yield 0.45 g (55%) of the desired product as a yellow oil.