Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:20][CH:19]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2].[C:37](OC(=O)C)(=[O:39])[CH3:38].C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>O>[CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:22][CH:23]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([C:37](=[O:39])[CH3:38])[CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1c2c(nc(CC)n2Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)CCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (2.26 g), acetic anhydride (0.94 g), sodium hydrogen carbonate (2.33 g), chloroform (18 ml) and water (18 ml) is stirred overnight at room temperature. The organic layer is separated, washed with brine, dried, and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-5-acetyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo [4,5-c]pyridine-4-carboxylate (2.10 9) as a white foam.
Reaction SMILES: [Na].C(O)C.[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][C:18]=1[N+:31]([O-:33])=[O:32]>C(Cl)Cl>[N+:31]([C:18]1[CH:19]=[C:20]([C:21](=[O:22])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:29]=[CH:30][C:17]=1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])([O-:33])=[O:32]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium ethoxide, formed by reacting 4.6 g. (0.2 mole) of sodium metal with 200 ml. of ethanol, at 0° C. was added 32 g. (0.2 mole) of diethyl malonate followed by 26.1 g. (0.1 mole) of 4-chloro-3-nitrobenzophenone. The mixture was allowed to stir at room temperature for 2 hours and was then poured into 400 ml. of ice cold 2N hydrochloric acid and 300 ml. of methylene chloride. The organic layer was separated, dried over magnesium sulfate and concentrated to an oil. The residual oil was induced to crystallize by trituration with hexane containing trace amounts of diisopropyl ether, 34.75 g., m.p. 68°-70° C. The sample was further purified by trituration with hot hexane-diisopropyl ether, 30.84 g. (80% yield).
Reaction SMILES: [CH3:1][C:2]1([C:14](=[O:41])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:31][CH:30]=4)[N:23]=3)=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.Cl.O1CCOCC1>C(OCC)(=O)C.CO>[CH3:1][C@@:2]1([C:14]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:31][CH:30]=4)[N:23]=3)=[CH:20][CH:21]=2)=[O:41])[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)C(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@]1(C(=O)Nc2ccc(-c3ccnc(Nc4ccc(N5CCOCC5)cc4)n3)cc2)CCCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
tert-Butyl 2-methyl-2-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl-carbamoyl)pyrrolidine-1-carboxylate (0.140 g, 0.250 mmoles), was dissolved in an ethyl acetate (5 ml) and methanol (1 ml) mixture. 4 M hydrogen chloride in 1,4-dioxane (0.625 ml, 2.5 mmoles, 10 equivalents, purchased from Sigma-Aldrich) was then added in a drop wise fashion over 5-10 minutes. Upon completion of addition, the reaction mixture was stirred at room temperature, and the progress of the reaction monitored by LC/MS. After 16 hours, additional 4M hydrogen chloride in 1,4-dioxane (0.312 ml, 1.25 mmoles, 5 equivalents) was added. After a total of 48 hours the reaction was complete and the resulting slurry was filtered off. The reaction flask was rinsed with ethyl acetate to ensure complete transfer of product. The resulting solid was washed with ethyl acetate (3×10 ml) and diethyl ether (2×25 ml) and dried under reduced pressure to give of 0.061 mg 2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)prolinamide 367 as its hydrochloride salt (53% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][CH:64]1[O:69][CH2:68][CH2:67][NH:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][O:69][CH:64]([CH3:63])[CH2:65]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC1CNCCO1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC1CN(C(=O)c2cc3ncnc(NC(C)c4nc5cc(Cl)ccc5[nH]4)c3cc2Cl)CCO1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-methyl-morpholine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH2:15]O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:15][C:14]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2ncccc2CO)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(-c2ncccc2CCl)cc1
Reaction time: 2 h
Yield: 55 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of [2-(4-methoxyphenyl)pyridin-3-yl]methanol (1 g, 4.65 mmol, 1.00 equiv) in thionyl chloride (20 mL). The resulting solution was stirred for 2 h at reflux. The resulting mixture was concentrated under vacuum to yield 600 mg (55%) of 3-(chloromethyl)-2-(4-methoxyphenyl)pyridine as a white solid.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:22])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2([CH3:13])[C:3](=[O:23])[C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:11]2=[O:22])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccccc1NC(=O)C(C)c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C2(C)C(=O)Nc3ccccc3C2=O)cc1
Yield: 56.8 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 2-[2-(4-methoxy-phenyl)-propionyl amino]-benzoic acid methyl ester (1.00 g, 3.19 mmol) and LiHMDS (9.57 mmol, 1M solution in THF). After normal workup, the objective compound (0.51 g, 57%) was obtained as yellow solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3) δ 1.83 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 6.77 d, J=8.9 Hz, 2H, ArH), 6.89-7.07 (m, 2H, ArH), 7.21 (d, J=8.9 Hz, 2H, ArH), 7.44-7.89 (m, 2H, ArH), 9.08 (br s, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.CCN(C(C)C)C(C)C.[CH3:21][N:22]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][CH:24]=[C:23]1[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.C(Cl)Cl>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[C@@H:4]([NH:3][C:33]([C:23]1[N:22]([CH3:21])[C:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:24]=1)=[O:34])[CH2:5]2
Reactant: Cn1c(C(=O)O)ccc1-c1ccccc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1c(C(=O)N[C@H]2CN3CCC2CC3)ccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
To a solution of (R)-(+)-3-aminoquinuclidine dihydrochloride (0.831 g, 4.17 mmol) in 55 mL of dry THF is added DIEA (2.08 mL, 11.9 mmol). After allowing the mixture to stir under nitrogen for 15 min, the product from Step 152c (0.800 g, X 3.98 mmol) is added. The mixture is allowed to stir for another 15 min, cooled in an A ice bath, and HATU (1.59 g, 4.17 mmol) is added. The reaction mixture is stirred on >an ice bath for 0.5 h, then at rt for an additional 2 h. The mixture is diluted with 60 mL CH2Cl2, washed with 50 mL of 1N NaOH and 50 mL of satd NaHCO3 solution, dried over MgSO4, filtered, and concentrated in vacuo. The crude product is purified by flash column chromatography (10% EtOAc, 1% NH4OH in CH2Cl2) to give 0.383 grams of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-methyl-5-phenyl-1H-pyrrole-2-carboxamide (31%) as a white solid. MS for C19H23N3O (ESI) (M+H)+ m/z 310.3.
Reaction SMILES: [CH3:1][C:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([CH3:16])[O:4][N:3]=1.[CH2:17]([C:20]1([CH3:44])[C:29]2[C:24](=[C:25]3[CH2:33][CH2:32][CH2:31][C:26]3=[C:27](Br)[CH:28]=2)[N:23](C(OC(C)(C)C)=O)[C:22]([CH3:42])([CH3:41])[C:21]1=[O:43])[CH:18]=[CH2:19].ClC1C=C(O)C=CC=1C1C=C2C(=C3CCCC=13)NC(C)(C)C(=O)C2(C)C>>[CH2:17]([C:20]1([CH3:44])[C:29]2[C:24](=[C:25]3[CH2:33][CH2:32][CH2:31][C:26]3=[C:27]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:16])[CH:28]=2)[NH:23][C:22]([CH3:42])([CH3:41])[C:21]1=[O:43])[CH:18]=[CH2:19]
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: C=CCC1(C)C(=O)C(C)(C)N(C(=O)OC(C)(C)C)c2c1cc(Br)c1c2CCC1
Agent: CC1(C)Nc2c(cc(-c3ccc(O)cc3Cl)c3c2CCC3)C(C)(C)C1=O
Product: C=CCC1(C)C(=O)C(C)(C)Nc2c1cc(-c1c(C)noc1C)c1c2CCC1
Yield: 31 %

Procedure:
Using 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole instead of tert-butyl 2,2,4,4-tetramethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate of Example 1, 10), using tert-butyl 4-allyl-6-bromo-2,2,4-trimethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate obtained in Example 50, 1) instead of 4-bromo-3-chlorophenol of Example 1, 10) and according to a similar method, the title compound (25 mg, 31%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[NH4+:12].[OH-]>[Cu].C(O)(C)C>[NH2:12][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Clc1cnc2c(n1)CCCC2
Reactant: [NH4+]
Agent: [Cu]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1cnc2c(n1)CCCC2
Temperature: 133 °C

Procedure:
A seated tube containing 2-chloro-5,6,7,8-tetrahydroquinoxaline (1.51 g, 0.009 mol), concentrated NH4OH (10 mL), isopropyl alcohol (30 mL), and copper powder (300 mg) was heated in an oil bath at 133° C. for 20 hours. The cooled mixture was filtered through celite and washed through the filter agent with H2O and hexanes. The layers were separated and the aqueous portion was washed (2×) with hexanes in order to remove unreacted starting material and then extracted with EtOAc (4×). The combined EtOAc extracts were dried over sodium sulfate and concentrated under reduced pressure to yield 2-amino-5,6,7,8-tetrahydroquinoxaline as a yellow-green solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][C:8]1[N:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Cl[C:18]1[C:23]([Cl:24])=[CH:22][C:21]([CH:25]=[CH2:26])=[CH:20][N:19]=1>COCCOC.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>[Cl:24][C:23]1[C:18]([C:11]2[CH:12]=[N:13][C:8]([CH3:7])=[CH:9][CH:10]=2)=[N:19][CH:20]=[C:21]([CH:25]=[CH2:26])[CH:22]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: C=Cc1cnc(Cl)c(Cl)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1cnc(-c2ccc(C)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.2 %

Procedure:
8.1 g of Na2CO3 (76 mmol), 3.5 g of 6-methylpyridin-3-ylboronic acid (11) (25 mmol), and 0.97 g of Pd(PPh3)4 were added to 4.9 g of compound (8) (28 mmol) prepared in Example 5 dissolved in 100 mL of 1,2-dimethoxyethane and 100 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated about 50% under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate, concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: ethyl acetate/hexane=1/4) to obtain 5.2 g of 3-chloro-6′-methyl-5-vinyl-2,3′-bipyridine (yield 90%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH2:25][OH:26])[C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][C:17]([N:22]([CH3:24])[CH3:23])=[CH:16][CH:15]=3)C1C=CC=CC=1.[C:27](O)(=O)C>CO.[Pd]>[CH3:23][N:22]([CH3:24])[C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:25][O:26][CH3:27])[C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:21][C:20]2=1
Reactant: CN(C)c1ccc2c(c1)c1cc(OCc3ccccc3)ccc1n2CO
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CO
Product: COCn1c2ccc(O)cc2c2cc(N(C)C)ccc21
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of [3-(benzyloxy)-6-(dimethylamino)-9H-carbazol-9-yl]methanol 7 (120 mg), Pd/C (100 mg) and acetic acid (cat. amount) in MeOH (15 mL) was hydrogenated at room temperature for 4 hrs. It was filtered through a short Celite pad. The filtrate was concentrated in vacuo to give the desired product (94 mg, 100%). NMR (acetone-d6, 400 MHz) δ: 7.38-7.50 (m, 4H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 6.97 (dd, J=8.4, 2.4 Hz, 1H), 5.62 (s, 2H), 3.20 (s, 3H), 2.94 (s, 6H). MS: m/z=271 (M+H+)+.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH2:11][C@H:10]2[N:7]([C:8](=[O:15])[C@@H:9]2[C@H:12]([OH:14])[CH3:13])[C:6]=1[C:16]([OH:18])=[O:17])[CH2:3][NH2:4].Cl.[C:20](=N)(OCC)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1>[OH:14][C@@H:12]([C@H:9]1[C:8](=[O:15])[N:7]2[C@@H:10]1[CH2:11][C:5]([C@H:2]1[CH2:3][NH:4][C:20]([CH3:21])=[N:1]1)=[C:6]2[C:16]([OH:18])=[O:17])[CH3:13]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C([C@H](N)CN)C[C@H]12
Reactant: CCOC(C)=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1=N[C@@H](C2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)CN1
Yield: 7.3 %

Procedure:
To a solution of (5R,6S)-3-[(1S)-1,2-diaminoethyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1.00 g) in a mixture of water (100 ml) and tetrahydrofuran (100 ml) was added portionwise ethyl acetimidate hydrochloride (1.00 g) under ice-cooling with stirring, keeping the pH between 8.0 and 8.5 with saturated aqueous potassium carbonate. After stirring for 2 hours, the mixture was concentrated under reduced pressure to be about 10 ml-volume. The aqueous solution was subjected to a column chromatography on silica gel (100 g) and eluted with a mixture of water and acetonitrile (6:4, V/V). The fractions containing the object compound were collected, concentrated under reduced pressure, and lyophilized to give a solid. A solution of the solid in water (10 ml) was subjected to a column chromatography on "Diaion HP-20" and eluted with water. The fractions containing the objected compound were collected, concentrated under reduced pressure, and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(4S)-2-methyl-2-imidazolin-4-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.08 g) as a solid.
Reaction SMILES: C(OC([N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])=O)C.[OH-:12].[Na+].C[CH2:15][OH:16]>>[O:11]=[C:7]1[CH:8]([C:15]([OH:16])=[O:12])[CH2:9][CH2:10][NH:6]1
Reactant: CCOC(=O)N1CCCC1=O
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)C1CCNC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.50 g (3.18 mmol) 2-oxo-pyrollidine-carboxylic acid ethyl ester in 10 mL EtOH are added 5 mL aq. NaOH (1M) solution. The reaction mixture is stirred at r.t. for 3 h. The EtOH is removed in vacuo and the residue is diluted with water and acidified with aq. HCl (2M) solution. The resulting precipitate is filtered and dried.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>[Pd].C(O)C>[NH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:20]
Reactant: O=C(NCCCn1ccnc1)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)NCCCn2ccnc2)c1

Procedure:
A mixture of 2.35 g. of N-[3-(1H-imidazol-1-yl)propyl]-3-nitrobenzamide, 0.5 g. of 10% palladium on carbon catalyst and 150 ml. of ethanol was shaken under 45 lbs. of hydrogen in a Parr hydrogenator until the reaction was complete. The catalyst was removed by filtration and the mother liquor concentrated. The crystalline residue was washed onto a filter with ether, giving the desired product, m.p. 88°-90° C.
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH:30]=[CH:29][C:28]=3[CH:32]=2)[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]>C(O)(=O)C.[Pd]>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3occc3c2)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3c(c2)CCO3)C1
Reaction time: 6 h

Procedure:
10% Palladium-on-carbon (10 mg) was added to a solution of 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(benzofuran-5-yl)ethyl]pyrrolidine (0.1 g--see Example 7) in acetic acid (2 ml) and the mixture was hydrogenated at 40° C. and atmospheric pressure for 6 hours. The catalyst was filtered off and washed with water (20 ml). The combined filtrate and washings were transferred to a separating funnel, dichloromethane (20 ml) was added, and the mixture was basified by the addition of 10% aqueous sodium hydroxide. The layers were separated and the aqueous layer was further extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a colourless solid which was purified by column chromatography on silica eluting with dichloromethane containing methanol (4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless glass, yield 0.048 g, which was characterised spectroscopically to be identical to the product of Example 1(B).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[OH:14])=[CH:6][CH:5]=1.[N:15]([O-])=[O:16].[Na+].S(=O)(=O)(O)O>O>[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([N:15]=[O:16])=[C:11]2[OH:14])=[CH:6][CH:5]=1
Reactant: O=N[O-]
Reactant: Oc1cccc2ccc(Cl)cc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Nc1ccc2ccc(Cl)cc2c1O
Temperature: 0 °C

Procedure:
To a solution of sodium hydroxide, 22.4 g in 1.0 liter of water, is added 100 g (0.56 mole) of the chloronaphthol (V). The mixture is stirred with slight heating until solution is complete. The solution is then cooled to -5° to 0° and treated with sodium nitrite, 40.0 g, (0.6 mole) followed by the addition of concentrated sulfuric acid (176 ml) over a 90-minute period. Ice-water (600 ml) is added periodically to prevent clumping of the solid which forms. When addition of the acid is complete, the reaction mixture is stirred for another hour at -5° to 0°. The product is filtered, washed with 4.0 liters of cold water, air-dried overnight and then dried in vacuum oven at 60° for 2.5 days. Yield: 108.6 g (93.4%) light yellow-green solid.
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].[C:5]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl-].[NH4+]>C1COCC1>[C:5]([N:12]1[CH2:17][CH2:16][C:15]([OH:18])([C:1]#[CH:2])[CH2:14][CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C#C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of ethynylmagnesium chloride in THF (100 mL, 50 mmol) was diluted with THF (50 mL) and cooled in an ice—water bath. A solution of Boc-4-piperidone (5.06 g, 25.4 mmol) (Aldrich) in THF (50 mL) was added dropwise over 15 min. The mixture was stirred with cooling for 3 h. Aqueous ammonium chloride solution (100 mL, 15% W/V) was then added and the resulting mixture extracted with ether (2×200 mL). The ether layers were washed with saturated aqueous sodium chloride solution (200 mL), then combined, dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (Biotage 40M, ethyl acetate—hexanes 1:3, V/V as solvent) to give N-Boc-4-hydroxy-4-ethynyl-piperidine as a colorless oil that solidified on standing. (Yield 5.39 g, 94.2%).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:13]=1)[CH3:4].[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([C:39](O)=[O:40])[N:32]=1>>[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:39]([C:33]2[CH:34]=[C:35]([O:37][CH3:38])[N:36]=[C:31]([O:30][CH3:29])[N:32]=2)=[O:40])[CH2:26][CH3:27])[CH:13]=1)[CH3:4]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Reactant: COc1cc(C(=O)O)nc(OC)n1
Agent: Cl
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)c2cc(OC)nc(OC)n2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester, dihydrochloride and 2,4-dimethoxypyrimidine-6-carboxylic acid were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-(2,6-dimethoxy-pyrimidine-4-carbonyl)-N-ethyl-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 8, Step 7.