Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]([C@@H:14]([CH2:18][CH3:19])[C:15](O)=[O:16])[C:10]2=[O:13])=[CH:5][CH:4]=1.C([O:26][C:27](=[O:45])[CH2:28][C@H:29]([NH2:44])[CH:30]([OH:43])[CH2:31][O:32][C:33]1[C:38]([F:39])=[C:37]([F:40])[CH:36]=[C:35]([F:41])[C:34]=1[F:42])(C)(C)C>>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]([C@@H:14]([CH2:18][CH3:19])[C:15]([NH:44][C@H:29]([C:30](=[O:43])[CH2:31][O:32][C:33]3[C:38]([F:39])=[C:37]([F:40])[CH:36]=[C:35]([F:41])[C:34]=3[F:42])[CH2:28][C:27]([OH:45])=[O:26])=[O:16])[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Reactant: CC[C@@H](C(=O)O)n1ccc2ccc(C(F)(F)F)cc2c1=O
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)COc1c(F)c(F)cc(F)c1F)n1ccc2ccc(C(F)(F)F)cc2c1=O

Procedure:
This compound was prepared using (S)-2-(7-trifluoromethyl-1-oxo-1H-isoquinolin-2-yl)-butyric acid (prepared as described in methods A-E, see example 2) and (3S)-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (prepared as described in methods N-P) using procedures similar to those described in methods F, G and E. The product was isolated as a white solid (90% last step). IR (solid) 1791.6, 1649.5, 1516.8, 1493.1, 1322.5 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.85 (3H, t), 1.90-2.20 (2H, 2×m), 2.50-2.90 (2H, 2×m), 4.70 (1H, m), 5.25 (2H, dd), 5.45 (1H, m), 6.80 (1H, d), 7.65 (1H, m), 7.70 (1H, d), 7.95 (1H, d), 8.05 (1H, d), 8.45 (1H, s), 9.00 (1H, d) ppm; 19F NMR (376 MHz, d6-DMSO) (proton decoupled) δ −56.60, −70.15, −136.38, −152.08.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37]I>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH3:37])[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: CC(C)c1ccc(N(Cc2cnn(C)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) and methyl iodide (0.073 mL) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-methylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.49 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 17, 5-hydroxy-N-(4-isopropylphenyl)-N-[(1-methylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) was obtained. melting point: 215° C.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:23]1[CH2:34][CH2:33][CH2:32][C@@H:24]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C1C=CC2N(O)N=NC=2C=1.O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:23]1[CH2:34][CH2:33][CH2:32][C@@H:24]1[C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 62 %

Procedure:
Z-L-Phe-OH (2.25 g, 7.5 mmol) and H-D-Pro-OtBu (0.862 g, 5.0 mmol) were dissolved in DMF (10 ml), mixed with HOBt H2O (766 mg, 5.0 mmol), BOP (3.3 g, 7.5 mmol) and triethylamine (1.75 ml, 12.5 mmol) under ice cooling, and then stirred for 2 hours. After the reaction mixture was concentrated, it was re-dissolved in ethyl acetate and washed sequentially with 10% citric acid, 4% NaHCO3 and brine. After drying over anhydrous MgSO4 and concentrating, the oily residue was purified by flash chromatography on silica gel (CHCl3/MeOH=99/1) to yield 1.403 g (62%) of the titled compound as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([Cl:6])=[O:5].[Cl-].[C:8]([O:11][CH:12]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[C:24]([I:25])=[C:23]([NH2:26])[C:22]([I:27])=[C:18]([C:19]([OH:21])=[O:20])[C:17]=1[I:28])(=[O:10])[CH3:9]>O1CCOCC1>[Cl-:6].[C:8]([O:11][CH:12]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[C:24]([I:25])=[C:23]([NH:26][C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:22]([I:27])=[C:18]([C:19]([OH:21])=[O:20])[C:17]=1[I:28])(=[O:10])[CH3:9]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I)OC(C)=O
Reactant: COCC(=O)Cl
Agent: [Cl-]
Solvent: C1COCCO1
Product: COCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I

Procedure:
24.7 g (150 mmol) of methoxyacetyl chloride is added at room temperature to a suspension of 73.4 g (100 mmol) of 5-amino-2,4,6-triiodisophthalic acid-N-(2,3-diacetoxypropyl)-amide-chloride (EP 0308364) in 500 ml of anhydrous dioxane, stirred with exclusion of moisture. The batch is refluxed for several hours, until no more feedstock can be detected according to thin-layer chromatography, then it is concentrated by evaporation, the residue is taken up in dichloromethane and shaken out with saturated aqueous sodium bicarbonate solution. After drying on anhydrous magnesium sulfate, the organic phase is concentrated by evaporation and the residue is recrystallized from ethyl acetate/tert-butyl methyl ether.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][NH2:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CN(Cc2ccccc2)CCO1
Solvent: CCO
Product: NC[C@@H]1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
(4-Benzylmorpholin-2-yl)methanamine 2d (1.35 g, 6.50 mmol) was dissolved in 30 mL of ethanol followed by the addition of L-(−)-dibenzoyltartaric acid (2.34 g, 6.50 mmol). The reaction solution was heated to reflux for 10 minutes, then cooled down to room temperature, placed for 16 hours resulting in the formation of crystal and filtered. The filter cake was dissolved in 10 mL of water, added with 1 M aqueous sodium hydroxide solution to adjust pH to 9 and extracted with dichloromethane (30 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound [(2R)-4-benzylmorpholin-2-yl]methanamine 15a (0.28 g, yield: 28.0%) as a light yellow oil liquid.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]2[CH:8]=[CH:9][CH:10]=[C:3]12.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>C1COCC1>[CH3:1][CH:2]1[N:7]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:6][CH2:5][N:4]2[CH:8]=[CH:9][CH:10]=[C:3]12
Reactant: O=C1CCC(=O)O1
Reactant: CC1NCCn2cccc21
Solvent: C1CCOC1
Product: CC1c2cccn2CCN1C(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A solution of (190 mg, 1.4 mmol) of 1-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (A21) in THF (10 ml) was added dropwise in the course of 30 min to a suspension of (558 mg, 5.6 mmol) of succinic anhydride in THF (10 ml). The mixture was then stirred for 2 h at RT and concentrated in vacuo. The residue was taken up in chloroform, washed with water and brine, dried over MgSO4 and concentrated in vacuo. 257 mg (0.92 mmol, 54%) of 4-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-4-oxobutanoic acid (S4) were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([N:41]([CH2:48][CH3:49])[CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:48]([N:41]([C:38]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:40][CH:39]=1)[CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])[CH3:49]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOCCN(CC)c1ccc(OB([O-])[O-])cc1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (200 mg), 4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl borate (290 mg) and potassium carbonate (266 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (40 mg), and the mixture was refluxed for 8 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give pale yellow crystals of 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 71) (89 mg).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([F:12])[C:7](Br)=[C:6]([CH3:14])[C:3]=1[C:4]#[N:5].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[NH2:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([F:12])[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([CH3:14])[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1ccccc1
Reactant: COc1c(N)c(C#N)c(C)c(Br)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(N)c(C#N)c(C)c(-c2ccccc2)c1F
Temperature: 110 °C
Reaction time: 15 h

Procedure:
Under nitrogen atmosphere, 2-amino-5-bromo-4-fluoro-3-methoxy-6-methylbenzonitrile (I-45) (20.0 g, 77.20 mmol), phenylboronic acid (11.3 g, 92.64 mmol), potassium phosphate (34.4 g, 162.11 mmol) were dissolved in a mixed liquid of 1,4-dioxane (400 ml) and water (20 ml), tetrakis(triphenylphosphine)palladium (2.6 g, 2.32 mmol) was added, followed by stirring at 110° C. for 15 hours. After cooling, the insoluble matter was separated by filtration through Celite, the reaction solvent was evaporated away under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluted wrath a mixed solvent of n-hexane/ethyl acetate (3:1, v/v) to obtain the entitled compound (20.12 g, quant) as a yellow white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([CH3:7])[CH:6]=1.[N+](=[CH2:21])=[N-].CN(N=O)C(N)=O.[OH-].[K+]>C(OCC)C>[CH3:21][O:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([CH3:7])[CH:6]=1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(O)cn1C
Reactant: C=[N+]=[N-]
Agent: CN(N=O)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCOC(=O)Cc1c(C(=O)OCC)c(OC)cn1C
Reaction time: 0.5 h

Procedure:
Ethyl 4-hydroxy-3-ethoxycarbonyl-1-methylpyrrole-2-acetate (20 mmole) is dissolved in 10 μl of diethyl ether containing diazomethane freshly prepared from N-methyl-N-nitrosourea and potassium hydroxide. After the reaction is allowed to stand at room temperature for about 0.5 hour, the ether is evaporated under reduced pressure at mild temperature and the residue, i.e., crude ethyl-4-methoxy-3-ethoxycarbonyl-1-methylpyrrole-2-acetate, is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: C1COCCN1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 96 h
Yield: 70 %

Procedure:
4-Bromo-2-nitroanisol (8.5 g, 36 mmol), morpholine (3.8 ml, 44 mmol), potassium phosphate (11 g, 51 mmol), 2-biphenyl-dicyclohexyl phosphine (960 mg, 2.7 mmol) and palladium(II)acetate (411 mg, 1.8 mmol) are dissolved in dimethoxyethane (80 ml) and stirred at 80° C. for 96 hours. The mixture is then cooled to room temperature, diluted with ethyl acetate (50 ml) and filtrated through dicalite. Flash chromatography on silica (eluent dichloromethane/methanol 99: 1) affords the product as red solid (6.0 g, 69%). MS: m/e=238 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH2:18][CH2:19][N+:20]([O-])=O)[C:7]=2[N:23]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4>[Ni].CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH2:18][CH2:19][NH2:20])[C:7]=2[N:23]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: COc1ccc2c(n1)c(CC[N+](=O)[O-])c1n2Cc2ccccc2-1
Agent: [Ni]
Solvent: CO
Product: COc1ccc2c(n1)c(CCN)c1n2Cc2ccccc2-1

Procedure:
Under a hydrogen pressure of 55 psi, 530 mg (1.71 mmol) of the compound obtained in Step G and 210 mg of Raney nickel are stirred in 20 ml of methanol at 60° C. for 15 hours. After returning to room temperature, the reaction mixture is filtered using a Büchner funnel and then evaporated to yield the title amine in the form of a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:16]=3[N:15]=[C:14](Cl)[C:13]=2[CH2:12][CH2:11]1.[NH2:30][CH2:31][CH2:32][CH2:33][OH:34]>>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:16]=3[N:15]=[C:14]([NH:30][CH2:31][CH2:32][CH2:33][OH:34])[C:13]=2[CH2:12][CH2:11]1
Reactant: NCCCO
Reactant: COc1ccc(N2CCc3c(Cl)nc4c(OCC(F)(F)F)cccc4c32)c(C)c1
Product: COc1ccc(N2CCc3c(NCCCO)nc4c(OCC(F)(F)F)cccc4c32)c(C)c1

Procedure:
1-(2-Methyl-4-methoxyphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(700 mg, 1.7 mmol) was dissolved in 3-amino-1-propanol(5.0 ml), and reacted at the same condition of Step 3 in the Example 49 to obtain 470 mg of desired compound as solid in 60% of yield.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([CH3:35])([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CC(C)(C)CC(=O)O
Agent: Cl
Product: CC(C)(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (87 mg, 81%), MS (ISP) m/z=429.4 [(M+H)+], mp 192.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 3,3-dimethyl-butyric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Cl:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]1([OH:62])[CH2:61][CH2:60][NH:59][CH2:58]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:59]3[CH2:60][CH2:61][C:57]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=4[Cl:50])([OH:62])[CH2:58]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Reactant: OC1(c2ccccc2Cl)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccccc3Cl)C2)cc1Cl
Yield: 34.6 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(2-chlorophenyl)pyrrolidin-3-ol hydrochloride (9 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (6 mg). MS (ESI, pos. ion) m/z: calcd for C21H18Cl2N2O4: 432.0644, found 432.0645.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([OH:20])=[C:15]([F:21])[CH:14]=2)[CH:3]=1.C[Si]([C:26]#[C:27][Sn](CCCC)(CCCC)CCCC)(C)C>>[F:21][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:26]#[CH:27])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[C:17]([F:19])[C:16]=1[OH:20]
Reactant: Oc1ccc2nc(-c3cc(F)c(O)c(F)c3)cc(Br)c2c1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Product: C#Cc1cc(-c2cc(F)c(O)c(F)c2)nc2ccc(O)cc12
Yield: 87 %

Procedure:
This compound was prepared from 6c following a combination of method J using (trimethylsilylethynyl)tributyltin and method L. Yellow solid; Yield: 87%; mp 220° C. (dec.); 1H-NMR (300 MHz, acetone-d6) δ 4.39 (s, 1H), 7.45 (dd, J=9.1, 2.7 Hz, 1H), 7.60 (d, J=2.7 Hz, 1H), 7.95 (d, J=10.1 Hz, 1H), 7.96 (d, J=7.1 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H), 8.14 (s, 1H), 9.18 (s, 1H), 9.31 (s, 1H); MS (ESI) m/z 296 ([M−H]−), 298 ([M+H]+).
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[NH2:18][C:19]1([O:28][CH3:29])[CH2:22][N:21]([S:23]([O-:26])(=[O:25])=[O:24])[C:20]1=[O:27].N1C=CC=CC=1.[N:36]([CH:39]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:40](Cl)=[O:41])=[N+:37]=[N-:38].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[N:36]([CH:39]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:40]([NH:18][C:19]1([O:28][CH3:29])[CH2:22][N:21]([S:23]([O-:26])(=[O:24])=[O:25])[C:20]1=[O:27])=[O:41])=[N+:37]=[N-:38]
Reactant: COC1(N)CN(S(=O)(=O)[O-])C1=O
Reactant: [N-]=[N+]=NC(C(=O)Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC#N
Product: COC1(NC(=O)C(N=[N+]=[N-])c2ccccc2)CN(S(=O)(=O)[O-])C1=O
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
3-Amino-3-methoxy-2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt (202 mgs; see Example 74A) is dissolved in 20 ml of dry acetonitrile. To the well stirred solution at -20° C. under dry nitrogen are added dry pyridine (167 μl) and α-azidophenylacetyl chloride (96 μl). After 20 minutes, 0.5M pH 5.5 monobasic potassium phosphate buffer (12 ml) is added and the acetonitrile removed in vacuo. The aqueous residue is extracted three times with methylene chloride. The extract is dried over anhydrous sodium sulfate and evaporated in vacuo to give 281 mg of crude product as a gum. This is purified by chromatography through a column of silica gel (30 g) using methylene chloride and mixtures of methylene chloride-methanol up to 6% methanol, and yielding 231 mg of the title compound.
Reaction SMILES: B(F)(F)F.CC[O:7]CC.[CH2:10]([C:17]1[CH:22]=[C:21]([CH2:23][C:24](Cl)=[O:25])[CH:20]=[CH:19][C:18]=1[CH2:27][C:28](Cl)=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClC(Cl)C>[O:29]=[C:28]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][C:17]2[CH:22]=[C:21]([CH2:23][C:24]([OH:7])=[O:25])[CH:20]=[CH:19][C:18]=2[CH2:27]1
Reactant: CCOCC
Reactant: O=C(Cl)Cc1ccc(CC(=O)Cl)c(Cc2ccccc2)c1
Agent: FB(F)F
Solvent: CC(Cl)Cl
Product: O=C(O)Cc1ccc2c(c1)Cc1ccccc1C(=O)C2
Temperature: 25 °C

Procedure:
In 50 ml of dichloroethane was dissolved in 3.0 g of 2-benzyl-4-chlorocarbonylmethylphenylacetyl chloride. With stirring at room temperature, 5.0 g of a solution of boron trifluoride etherate was added to the solution. The mixture was stirred for 2 hours, and worked up in the same way as in Example 6 to afford 1.42 g of 10,11-dihydro-10-oxo-5H-dibenzo[a,d]cycloheptene-3-acetic acid as a colorless crystalline powder (recrystallized from a mixture of methanol and n-hexane) having a melting point of 186° to 188° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][N:16]=1)[CH2:9][C:10]#[CH:11]>>[C:17]1([C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1ncc(-c2ccccc2)o1
Product: C(#Cc1ccccn1)CCc1ncc(-c2ccccc2)o1
Yield: 9.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (25 mg, 0.16 mmol) and 2-(but-3-ynyl)-5-phenyloxazole (31 mg, 0.16 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM/MeOH 95:5, DCM/MeOH/NH4OH 90:5:0.1 to 90:9:1) to yield 4.0 mg (15 μmol, 9%) of 2-(4-(5-phenyloxazol-2-yl)but-1-ynyl)pyridine as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18]/[C:17](=[N:19]\[OH:20])/[C@H:16]([CH2:21][NH:22]C(=O)OCC3C=CC=CC=3)[CH2:15]1)=[N:9][C:8]([O:33][CH3:34])=[CH:7][CH:6]=2>[Pd].CO.C1COCC1>[NH2:22][CH2:21][C@@H:16]1[CH2:15][N:14]([CH2:13][CH2:12][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:33][CH3:34])[N:9]=3)[N:4]=[CH:3][C:2]=2[F:1])[CH2:18]/[C:17]/1=[N:19]\[OH:20]
Reactant: COc1ccc2ncc(F)c(CCN3C/C(=N\O)[C@H](CNC(=O)OCc4ccccc4)C3)c2n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2ncc(F)c(CCN3C/C(=N\O)[C@H](CN)C3)c2n1
Reaction time: 6 h

Procedure:
Phenylmethyl {[(3R,4Z)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-4-(hydroxyimino)-3-pyrrolidinyl]methyl}carbamate (0.180 g, 0.39 mmol) was dissolved in 1:1 (MeOH/THF) (10 mL). Catalytic 10% Palladium on carbon was added and the solution subjected to H at 55 PSI on a Parr shaker for 6 hours. The solution was filtered through a pad of celite and concentrated under reduced pressure. (0.174 g, quant.) LCMS: m/z 334.4 (MH+).