Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([NH:26][C:27]1[N:32]=[C:31]([O:33][CH3:34])[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[C:31]([O:33][CH3:34])=[N:32][C:27]([NH:26][CH2:24][CH3:25])=[N:28][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCNc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Product: CCNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c(OC)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and ethyl-[4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine (Stage 235.1.1) to give the title compound as a white solid. (HPLC: tR 2.24 min (Method A); M+H=445 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.16-8.06 (m, 3H), 8.01-7.97 (m, 1H), 7.74-7.69 (m, 1H), 7.61-7.58 (m, 1H), 3.88 (s, 3H), 3.84 (s, br, 3H), 3.56 (s, 3H), 3.36-3.28 (m, 2H), 1.93 (s, 3H), 1.13 (t, 3H))
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2cccc(Br)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a mixture of 4-{[1-(3-bromo-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (6.7 g, 20.1 mmol) and ytterbium(III) triflate hydrate (1.25 g, 2.01 mmol) in dry tetrahydrofuran (15 mL) at 25° C. was added isobutyraldehyde (1.45 g, 20.1 mmol) and water (0.36 mL, 20.1 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (8.12 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H22BrNO3 M+: 404.3, observed: 404.0, 406.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[C:13]([NH2:34])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:35]1(=[O:45])[C@H:43]2[C@@H:38]([CH2:39][CH2:40][CH2:41][CH2:42]2)[C:37](=O)[O:36]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[N:34]=[C:37]([C@@H:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C@H:43]4[C:35]([OH:45])=[O:36])[N:16]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)=[CH:20][CH:19]=4)[C:14]=3[CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@@H]12
Reactant: Cc1ccc(COc2ccc(N)c(NCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)c2)nc1
Product: Cc1ccc(COc2ccc3nc([C@@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(-c5ccc(C(F)(F)F)cc5)cc4)c3c2)nc1

Procedure:
The title compound was prepared using analogous conditions described in Example 1 using 5-((5-methylpyridin-2-yl)methoxy)-N1-((4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methyl)benzene-1,2-diamine and racemic trans-hexahydroisobenzofuran-1,3-dione in Step C. MS (ESI): mass calcd. for C35H32F3N3O3, 599.2; m/z found, 600.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.27 (d, J=2.1, 1H), 7.76 (d, J=8.1, 2H), 7.69 (d, J=8.3, 2H), 7.65-7.58 (m, 2H), 7.58-7.46 (m, 2H), 7.42-7.22 (m, 3H), 6.97-6.90 (m, 2H), 5.53 (s, 2H), 5.09 (s, 2H), 3.19 (td, J=11.5, 3.6, 1H), 3.03 (td, J=11.3, 3.5, 1H), 2.23 (s, 3H), 2.21-2.17 (m, 1H), 1.89-1.79 (m, 1H), 1.77-1.59 (m, 2H), 1.58-1.19 (m, 4H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].Br[CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+]>[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.O>[C:3]([C:2]([C:1]#[N:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:7][CH2:8][CH2:9][CH3:10])#[N:4]
Reactant: N#CCC#N
Reactant: CCCCBr
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCC(C#N)(C#N)CCCC
Temperature: 50 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
Malononitrile (128 g, 1.94 moles) was added dropwise to a mixture of 500 g (3.65 moles) of 1-bromobutane, 10 g of tricaprylylmethylammonium chloride,146 g (3.63 moles) of sodium hydroxide and 450 ml of water. The addition rate was controlled such that the temperature was maintained at 45°-50° C. After the addition was complete, the mixture was stirred for two hours longer at 50° C. The organic layer was separated and washed twice with 300 ml portions of saturated aqueous sodium chloride. The product was then distilled to give 197 g of recovered1-bromobutane and 170 g of 5,5-dicyanononane (87% selectivity based on 1-bromobutane) having a boiling point of 145° C at 30 mm Hg.
Reaction SMILES: [Si:1]([O:18][C@@H:19]([CH2:22][CH2:23][CH2:24][OH:25])[CH2:20][OH:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.B(F)(F)F.[CH3:32]COCC>CCOC(C)=O>[Si:1]([O:18][C@H:19]1[CH2:22][CH2:23][CH2:24][O:25][CH2:32][O:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](O[C@H](CO)CCCO)(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: C=O
Agent: FB(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](O[C@H]1CCCOCOC1)(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 52.2 %

Procedure:
To a mixture of 6a (0.55 g, 1.5 mmol) and paraformaldehyde (46 mg, 1.5 mmol) in EtOAc (30 mL), boron trifluoride etherate (195 μL, 1.5 mmol) was added and the resulting mixture was stirred at 23° C. for 4 h. The organic phase was washed with a saturated solution of NaHCO3, dried (Na2SO4) and the solvent was removed. The residue was purified by flash-chromatography (1:4 EtOAc/Hex) to afford 0.29 g (51%) of 7a as a colourless oil: [α]D20=−8.7 (c 1.9, CHCl3); 1H NMR (CDCl3) δ 7.67-7.63 (m, 4H), 7.45-7.34 (m, 6H), 4.69 (d, J=6.2 Hz, 1H), 4.45 (d, J=6.2 Hz, 1H), 4.03-3.95 (m, 1H), 3.70-3.61 (m, 1H), 3.59-3.48 (m, 3H), 1.93-1.80 (m, 1H), 1.77-1.61 (m, 2H), 1.47-1.34 (m, 1H), 1.12 (s, 9H); 13C NMR (CDCl3) δ 135.7, 134.2, 129.5, 127.5, 95.6, 72.2, 71.9, 69.0, 33.2, 27.0, 26.7, 19.2.
Reaction SMILES: CC1(C)COB([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15]3)=[CH:10][CH:9]=2)OC1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[Cl:33])[NH:29][CH:28]=[C:27]2[CH:34]=[O:35].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:19]([N:16]1[CH2:17][CH2:18][CH:14]([C:11]2[CH:10]=[CH:9][C:8]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][C:32]=3[Cl:33])[NH:29][CH:28]=[C:27]4[CH:34]=[O:35])=[CH:13][CH:12]=2)[CH2:15]1)(=[O:21])[CH3:20]
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Reactant: CC(=O)N1CCC(c2ccc(B3OCC(C)(C)CO3)cc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1CCC(c2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Temperature: 110 °C
Yield: 37.3 %

Procedure:
To a degassed mixture of crude 1-{3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]pyrrolidin-1-yl}ethanone (assume 0.38 mmol), 5-bromo-6-chloro-1H-indole-3-carbaldehyde (98.4 mg, 0.38 mmol) and 2 N aqueous potassium carbonate (0.76 mL, 1.52 mmol) in toluene (2.25 mL) and ethanol (0.75 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.8 mg, 0.038 mmol). The reaction mixture was heated to 110° C. in a microwave for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column (first EtOAc in Petroleum ether, then MeOH in CH2Cl2) to give 5-[4-(1-acetylpyrrolidin-3-yl)phenyl]-6-chloro-1H-indole-3-carbaldehyde (52 mg) as an orange solid. MS (ES+) 389.0 (M+Na)+
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([OH:24])=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].C1(C)C=CC(S(O[CH2:37][CH:38]([F:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])(=O)=O)=CC=1>C(O)CCC>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([O:24][CH2:37][CH:38]([F:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCCCC1Cc2ccc(-c3ncc(OCC(F)CCCCCC)cn3)cc2C1
Temperature: 0 °C
Yield: 63.6 %

Procedure:
1.0 g (3.01 mM) of 2-octyl-5-(5-hydroxypyrimidine-2-yl)indan, 0.24 g (3.6 mM) of 85%-KOH, 0.91 g (3.01 mM) of 2-fluorooctyl p-toluenesulfonate and 20 ml of butanol was placed in a 50 ml-round bottomed flask and heat-refluxed for 7 hours under stirring. After the reaction, the reaction mixture was poured into ice water and the insoluble matter was recovered by filtration, followed by washing with methanol. The resultant insoluble matter was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene/methanol) to obtain 0.87 g of 2-octyl-5-[5-(2-fluorooctyloxy)pyrimidine-2-yl]indan (Yield: 66.4%). ##STR297##
Reaction SMILES: C([NH:4][CH2:5][CH:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][NH:9]C(=O)C)(=O)C>[OH-].[Na+]>[NH2:4][CH2:5][CH:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:7]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:8][NH2:9]
Reactant: CC(=O)NCC(c1ccccc1)C(CNC(C)=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: NCC(c1ccccc1)C(CN)c1ccccc1
Yield: 99.8 %

Procedure:
385.7 g (1.19 mols) of N,N'-diacetyl-2,3-diphenyl-1,4-diaminobutane in 715 ml of 5 N sodium hydroxide solution are heated to 200° C. in an autoclave for 16 hours. After cooling, the mixture is extracted with 1,800 ml of chloroform. Further extraction with 2 times 200 ml of chloroform and concentration of the extracts gives 285.4 g of crude product, which is recrystallised from 2.6 l of benzene. Yield: 258.5 g of 1,4-diamino-2,3-diphenylbutane; melting point: 144°-145° C. A further 15.1 g of substance having a melting point of 144°-145° C. are obtained by concentrating the mother liquor; the total yield is thus 273.6 g (95.7% of theory). For analysis, 1.0 g is recrystallised from 10 ml of benzene. Yield: 0.88 g; melting point: 144°-145° C; meso form.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:13][S:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[C:7]1([C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[C:18]2[CH:19]=[CH:20][C:15]([S:14][CH3:13])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrC1=C(c2ccccc2)CCC1
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(C2=C(c3ccccc3)CCC2)cc1
Yield: 88.3 %

Procedure:
Following a synthetic procedure which was similar to the one outlined in Step 3 of Example 1, 750 mg (3.4 mmol) of 1-bromo-2-phenylcyclopentene (Step 1) was reacted with 1.2 g (6.8 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 1). Purification by silica gel chromatography (MPLC) with hexane gave 800 mg (89%) of 1-(2-phenylcyclopenten-1-yl)-4-(methylthio)benzene as an oil: NMR (CDCl3) δ 2.00-2.17 (m, 2H), 2.46 (s, 3H), 2.86-3.01 (m, 4H), 7.08-7.19 (m, 4H), 7.19-7.32 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:9][CH:10]=[CH2:11])[CH2:4][CH2:5][CH2:6][C:7]#[N:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][CH:3]([CH2:9][CH:10]=[CH2:11])[CH2:4][CH2:5][CH2:6][C:7]#[N:8])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCC(CO)CCCC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC(CCCC#N)COS(C)(=O)=O
Reaction time: 3 h

Procedure:
To a solution of 2679 g of 6-hydroxy-5-(2-propenyl)-hexanenitrile in 25 l of methylene chloride is added 2681 ml of triethylamine. The mixture is cooled to -10° in an ice salt bath and a solution of 2103 g of methanesulfonyl chloride in 2 l of methylene chloride is added dropwise over 3 h keeping the temperature at -5°. After addition is complete, the mixture is stirred for 3 h in an ice salt bath and then overnight at 10°. The mixture is washed with water, saturated sodium bicarbonate solution, water and then brine, dried over sodium sulfate, evaporated to dryness, and dried at 45°/3 mm Hg (=4.00 mbar) to yield 6-methylsulfonyloxy-5-(2-propenyl)-hexanenitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[CH:6]=[CH:5]2.[C:13]([Cu])#[N:14].CN(C=O)C>C(Cl)Cl>[Cl:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:13]#[N:14])[CH:3]=2)[N:8]=1
Reactant: N#C[Cu]
Reactant: Clc1ccc2cc(Br)ccc2n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc2nc(Cl)ccc2c1
Temperature: 150 °C

Procedure:
To a flask containing a stir bar was added 6-bromo-2-chloroquinoline (0.90 g, 3.7 mmol), CuCN (0.50 g, 5.6 mmol) followed by addition of DMF (10 mL). The resulting mixture was then refluxed at 150° C. overnight. When the reaction appeared complete by LC analysis, the reaction flask was taken out of the oil bath and cooled to room temperature. To the reaction mixture was then poured DCM (20 mL) and a precipitate formed immediately, which was filtered, redissolved in DCM, absorbed onto silica gel, and purified by flash chromatography to provide the title product.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Cl:27])[N:25]=3)[CH:20]=[CH:19][C:18]2=[O:28])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.[O:38]1[C:47]2[CH:46]=[C:45]([CH:48]=O)[N:44]=[CH:43][C:42]=2[O:41][CH2:40][CH2:39]1.C([BH3-])#N.[Na+]>ClCCl.C(#N)C.O.CO>[Cl:27][C:24]1[N:25]=[C:26]2[C:21]([CH:20]=[CH:19][C:18](=[O:28])[N:17]2[CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([NH:8][CH2:48][C:45]3[N:44]=[CH:43][C:42]4[O:41][CH2:40][CH2:39][O:38][C:47]=4[CH:46]=3)[CH2:14][CH2:13]2)=[CH:22][CH:23]=1
Reactant: NC1CCN(CCn2c(=O)ccc3ccc(Cl)nc32)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: O=c1ccc2ccc(Cl)nc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Yield: 11.3 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-chloro-1,8-naphthyridin-2(1H)-one trifluoroacetate (Intermediate 138, crude, 405 mg, 0.76 mmol), di-isopropyl ethylamine (0.38 mL, 2.27 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde [WO 2004/058144](180 mg, 1.1 mmol) and sodium cyanoborohydride (100 mg, 1.56 mmol) were reacted as described for Example 21. Chromatography on silica gel using methanol in dichloromethane (0-20% with 1% aqueous ammonium hydroxide) followed by reverse phase chromatography with 20-75% acetonitrile/water/10 mM NH4OAc Buffer) gave the title compound (39 mg, 11%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-c2cnccn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2cnccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-pyrazinylbenzaldehyde (prepared as described in Reference Example 17) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:5][CH:4]=1)=O.[CH3:15][C:16]([S@@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>ClCCl.O.C(O[Ti](OCC)(OCC)OCC)C>[C:16]([S@@:19](/[N:21]=[CH:1]/[C:3]1[S:7][C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:5][CH:4]=1)=[O:20])([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(/C=N/[S@@](=O)C(C)(C)C)s1
Temperature: 25 °C

Procedure:
tert-Butyl 5-formylthiophene-2-carboxylate (2 g, 9.42 mmol) and (S)-2-methylpropane-2-sulfinamide (1.370 g, 11.31 mmol) were dissolved in dichloromethane (100 ml). The mixture was chilled in an ice bath to which was added tetraethoxytitanium (8.7 ml, 41.5 mmol). The mixture was allowed to warm to room temperature overnight with stirring. The mixture was poured into a large Erlenmeyer flask with 200 mL dichloromethane and was diluted with 18 mL H2O. After vigorous stirring for 30 minutes the suspension was filtered through diatomaceous earth and the filtrate was concentrated. Purification using normal phase chromatography provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[CH3:21][C:17]1[C:15]2[N:16]=[C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])[O:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2c(C)cccc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2c(C)cccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-4-methylbenzoxazole (112 mg, 0.4 mmol) and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) the title compound was obtained (110 mg, 60%). 1H NMR (DMSO) δ 8.46(t, 1H), 8.41(dd, 1H), 8.03(s, 1H), 8.06(m, 2H), 7.61(m, 2H), 7.44(dd, 1H), 7.22(d, 1H), 7.00(d, 1H), 3.34(m, 2H), 2.44(s, 3H), 1.74(m, 2H), 1.06(t, 3H). MS 453.9 m/z (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Br:10])C=O.C(Cl)(=O)C.[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>CCO>[Br:10][C:9]1[CH:8]=[CH:7][C:4]([CH:15]([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Solvent: CC(=O)Cl
Product: CCOC(OCC)c1ccc(Br)c(F)c1
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-fluoro-4-bromobenzaldehyde (20.0 g, 98.5 mmol) in dry EtOH (120 mL) was added acetyl chloride (2.04 mL, 29.6 mmol) followed by the addition of triethyl orthoformate (6.55 mL, 39.4 mmol) and the contents were heated to 70° C. for 3 h. The contents were cooled to room temperature and shifted to a rotary evaporator and subjected to reduced pressure (280 mm Hg) with bath temperature 65° C. for 45 min. The pressure was further lowered to remove all the solvent. To this mixture, fresh Ethanol (60 mL), acetyl chloride (1.5 mL), triethyl orthoformate (5.0 mL) and heated to 70° C. for 2 h. The solvent was removed under the reduced pressure and diluted with EtOAc (200 mL), washed with saturated sodium bicarbonate (3×100 mL), brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue purified by silica gel column (basified with 5% Et3N, eluent: EtOAc/hexanes, 1/20) to afford 1-bromo-4-(diethoxymethyl)-2-fluorobenzene as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (t, J=8.1 Hz, 1H), 7.36-7.33 (m, 2H), 5.54 (s, 1H), 3.63-3.52 (m, 4H), 1.25 (m, 6H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[OH:41][C@H:42]([C@@H:65]1[CH2:69][C@H:68]([SH:70])[CH2:67][N:66]1[C:71]([O:73][CH2:74][C:75]1[CH:80]=[CH:79][C:78]([N+:81]([O-:83])=[O:82])=[CH:77][CH:76]=1)=[O:72])[CH2:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=2)=[O:53])[CH2:48][CH2:47]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:70][C@@H:68]3[CH2:67][N:66]([C:71]([O:73][CH2:74][C:75]4[CH:80]=[CH:79][C:78]([N+:81]([O-:83])=[O:82])=[CH:77][CH:76]=4)=[O:72])[C@H:65]([C@@H:42]([OH:41])[CH2:43][C:44]([N:46]4[CH2:47][CH2:48][N:49]([C:52]([O:54][CH2:55][C:56]5[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=5)=[O:53])[CH2:50][CH2:51]4)=[O:45])[CH2:69]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C(C[C@H](O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H]([C@@H](O)CC(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 75.5 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (461.1 mg) and (2S,4S)-2-[(1S)-1-hydroxy-2-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-ylcarbonyl]ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (456.2 mg), reaction and purification were carried out in a similar manner to that described in Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[(1S)-1-hydroxy-2-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-ylcarbonyl]ethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (536.7 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:21]=[CH:20][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]3)=[CH:8][CH:7]=2)[CH2:2]1.[C:22]1([C:28]2[O:32][C:31]([C:33](OCC)=[O:34])=[N:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[C:22]1([C:28]2[O:32][C:31]([C:33]([N:1]3[CH2:2][CH:3]([O:5][C:6]4[CH:21]=[CH:20][C:9]([CH2:10][N:11]5[CH2:12][CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16]5)=[CH:8][CH:7]=4)[CH2:4]3)=[O:34])=[N:30][N:29]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)N1CCN(Cc2ccc(OC3CNC3)cc2)CC1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)cc2)CC1
Temperature: 140 °C
Yield: 10.4 %

Procedure:
23B (0.16 g, 0.53 mmol) and ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.11 g, 0.50 mmol) were mixed together in a microwave vial together with toluene (3 mL). The mixture was heated in a microwave oven at 140° C. for 30 min. The solvent was removed by evaporation. The product was purified by preparative chromatography on a Kromasil C8 column eluting with acetonitrile and 0.1 M NH4OAc. The combined fractions were concentrated and the aqueous solution was pH adjusted to pH 9 with 1M NaOH. The mixture was extracted with EtOAc and the organic layer was dried over Na2SO4. The solvent was removed by evaporation. There was obtained 24 mg (10%) of the product as a foam. 1H NMR (400 MHz, CDCl3): δ 2.08 (s, 3H), 2.32-2.47 (m, 4H), 3.37-3.54 (m, 4H), 3.62 (s, 2H), 4.29-4.40 (m, 1H), 4.59-4.70 (m, 1H), 4.71-4.82 (m, 1H), 5.02-5.19 (m, 2H), 6.74 (d, 2H), 7.26 (d, 2H), 7.49-7.64 (m, 3H), 8.16 (d, 2H), MS (APCI+) m/z 462 [M+H]+, LC purity: 93%.