Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:9]2([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=O)=[CH:12][CH:11]=3)[CH:5]1[CH2:6][N:7]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2.S(C)C.CO>C1COCC1>[CH3:1][O:2][CH2:3][CH:4]1[C:9]2([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:14][CH:15]=3)[CH:5]1[CH2:6][N:7]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2
Reactant: COCC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(N2CCCC2=O)cc1
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: COCC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(N2CCCC2)cc1
Yield: 83.2 %

Procedure:
To a solution of tert-butyl 6-(methoxymethyl)-1-(4-(2-oxopyrrolidin-1-yl)phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.29 mmol) obtained in Step 2 of Example XXXIII, in dry THF (10 mL), was added BH3.Me2S complex (3.23 mL, 6.47 mmol, 2M in THF) at 0° C. under nitrogen atmosphere. The reaction mixture was refluxed for 4 h. After completion of the reaction as confirmed by TLC, methanol (20 mL) was added and the reaction mixture was heated to reflux for 1 h. The solvents were removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 3:7 EtOAc:Pet. ether) to afford the title compound (400 mg, 86%) as a viscous oil.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([N:65]1[CH2:70][CH2:69][CH:68]([NH2:71])[CH2:67][CH2:66]1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:71][CH:68]5[CH2:69][CH2:70][NH:65][CH2:66][CH2:67]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-N—Boc 4-amino piperidine. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml). The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.27 (m, 1H) 1.30-1.51 (m, 4H) 1.52-1.69 (m, 3H) 1.69-1.90 (m, 6H) 2.41-2.59 (m, 2H) 2.97 (d, J=12.38 Hz, 2H) 3.31 (s, 3H) 3.73-3.89 (m, 1H) 3.94 (s, 3H) 4.06 (t, J=13.52 Hz, 2H) 4.38-4.52 (m, 1H) 7.48 (dd, J=8.34, 1.77 Hz, 1H) 7.51 (d, J=1.77 Hz, 1H) 7.90 (s, 1H) 8.14 (d, J=7.83 Hz, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H). [M+H] calc'd for C27H35F2N7O3 544. found 544.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13])[CH3:10]>CN(C=O)C.CCOC(C)=O.[F-].[K+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:9]([O:11][CH2:12][CH3:13])=[CH2:10])=[CH:7][N:6]=1
Reactant: Brc1cnc(Br)cn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc(Br)cn1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
To a solution of 2,5-dibromopyrazine (1 g, 4.20 mmol) in DMF was added 1-ethoxyvinyltri-n-butyltin (1.420 mL, 4.20 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.148 g, 0.210 mmol). The reaction mixture was heated at 100° C. for 4 hrs. The reaction mixture was diluted with EtOAc and aq. KF. The two phase mixture was stirred for 20 min at rt before being filtered through diatomaceous earth (Celite®). The filtrate was washed with sat. NaHCO3, sat. NaCl, dried over anhydrous Na2SO4, concentrated. The crude product was purified by silica gel chromatography (0-100% EtOAc in hexane) to yield 2-bromo-5-(1-ethoxyvinyl)pyrazine (0.65 g). LC/MS (Cond. N-1): [M+H]+ 229.05, RT=3.799 min.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8](Cl)[CH:7]=[CH:6]1)(=[O:3])[CH3:2].[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C.[Cl-].[Na+].O.C(OCC)C.O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:12]=[N+:13]=[N-:14])[CH:7]=[CH:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C=C[C@H](Cl)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(=O)O[C@@H]1C=C[C@@H](N=[N+]=[N-])CC1
Yield: 85.9 %

Procedure:
To a stirred solution of cis-1-acetoxy-4-chloro-2-cyclohexene (6.87 g, 39.4 mmol) in DMF (160 mL) was added sodium azide (5.29 g, 81.1 mmol) and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into brine (160 mL) and diluted with diethyl ether (300 mL) and water (80 mL). The phases were separated and the organic phase was washed with brine (5×50 mL). The organic phase was dried (MgSO4), and concentrated to provide 6.13 g (85%) of trans-1-acetoxy-4-azido-2-cyclohexene as a pale red oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:15][Mg]Br.CCOCC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:14])[CH3:15])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cnc(-c2ccc(F)cc2)s1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cnc(-c2ccc(F)cc2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 2-(4-fluorophenyl)thiazole-5-carbaldehyde (500 mg, 2.41 mmol) in THF (25 mL) was added 3M methyl magnesium bromide in ether (1.61 mL, 4.83 mmol) slowly at 0° C. The reaction mixture stirred for 1 hour at 0° C. and then at room temperature for about 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (25 mL), extracted with ethyl acetate (3×150 mL), the organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. The crude product was purified by flash chromatography (100-200μ; 30% ethyl acetate in hexane) to afford 1-(2-(4-fluorophenyl)thiazol-5-yl)ethanol as light yellow solid (420 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.93 (t, 2H), 7.67 (s, 1H), 7.30 (t, 2H), 5.71 (d, 1H), 5.01 (t, 1H), 1.45 (d, 3H); LC-MS m/z calculated for [M+H]+224.05. found 224.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[Si](C)(C)CC[Si]2(C)C)[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.[S:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][C:7]=1[C:24]1([OH:27])[CH2:25][CH2:26][S:22][CH2:23]1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Reactant: O=C1CCSC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Nc1ccc(C2(O)CCSC2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (EXAMPLE 20, Step 1, 1.00 g) in dry tetrahydrofuran (16 mL) at -78° C. under N2 is treated with sec-butyllithium (1.3 M in cyclohexane, 3.30 mL) dropwise over 2 mins, and the resulting mixture is stirred at -78° C. for 2 hrs. The mixture is then treated with a solution of tetrahydrothiophen-3-one (423 mg) in dry tetrahydrofuran (4.1 mL) dropwise over 2 mins and is stirred at -78° C., allowing the cooling bath to expire over 4 hrs. The mixture is then quenched with saturated aqueous ammonium chloride (25 mL), diluted with water (25 mL), the layers are separated, and the combined organic phase is washed with saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (16 mL) and treated with anhydrous potassium carbonate (1.09 g), and the mixture is stirred at ambient temperature for 30 mins, concentrated under reduced pressure, diluted with water (20 mL) and extracted with diethyl ether (2×20 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude 3-fluoro-4-[3-(hydroxy)tetrahydrothiophen-3-yl]benzenamine intermediate (Rf =0.37 by TLC, ethyl acetate/hexane (50/50)). A solution of this intermediate in tetrahydrofuran (16 mL) and water (8 mL) is then treated with sodium bicarbonate (662 mg) and benzyl chloroformate (0.56 mL), and the resulting mixture is stirred at ambient temperature for 4 hrs, diluted with water (8 mL), the layers are separated, and the organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with ethyl acetate/hexane (25/75), and those fractions with an Rf =0.19 by TLC (ethyl acetate/hexane, 25/75) are pooled and concentrated to give the title compound, mp 134-135° C.
Reaction SMILES: [O:1]=O.[CH2:3]([N:5]1[C:11]2[N:12]=[CH:13][C:14]([CH2:16][CH:17]=C)=[CH:15][C:10]=2[C:9](=[O:19])[N:8]([CH3:20])[C:7]2[CH:21]=[CH:22][CH:23]=[N:24][C:6]1=2)[CH3:4].[BH4-].[Na+].[NH4+].[Cl-]>C(Cl)Cl.CO>[CH2:3]([N:5]1[C:11]2[N:12]=[CH:13][C:14]([CH2:16][CH2:17][OH:1])=[CH:15][C:10]=2[C:9](=[O:19])[N:8]([CH3:20])[C:7]2[CH:21]=[CH:22][CH:23]=[N:24][C:6]1=2)[CH3:4]
Reactant: O=O
Reactant: C=CCc1cnc2c(c1)C(=O)N(C)c1cccnc1N2CC
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A stream of ozonized oxygen was bubbled through a cold (−78° C.) solution of 5,11-dihydro-11-ethyl-5-methyl-8-(2-propenyl)-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one 1g (22.19 g, 75.4 mmol) in CH2Cl2 (150 mL) and MeOH (150 mL) for 2.5 h. A stream of N2 was next bubbled through the solution for 15 min and then solid NaBH4 (4.99 g, 132 mmol) was added to the solution. The reaction mixture was allowed to warm to room temperature. After 1 h, aqueous saturated NH4Cl (200 mL) was added and the mixture was stirred at room temperature for 2 h. The organic solvents were removed under reduced pressure. Water (300 mL) and CHCl3 (300 mL) were added to the residue. The phases were separated and the aqueous layer was extracted with CHCl3 (3×300 mL). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc/CHCl3, 4/1) to give compound 1 h (16.1 g, 72% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([OH:14])[CH:13]=1)[NH:10][C:9](=[O:15])[CH2:8][CH2:7]2)([O-:3])=[O:2].[C:16](=O)([O-])[O-].[K+].[K+].CC(C)=O.S(OC)(OC)(=O)=O>O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:14][CH3:16])[CH:13]=1)[NH:10][C:9](=[O:15])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: O=C1CCc2cc([N+](=O)[O-])cc(O)c2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CC(C)=O
Product: COc1cc([N+](=O)[O-])cc2c1NC(=O)CC2
Reaction time: 4 h
Yield: 77 %

Procedure:
6-Nitro-8-hydroxy-3,4-dihydrocarbostyril (10 g) and potassium carbonate (13.3 g) were mixed with acetone (70 ml) and water (70 ml) and the mixture was refluxed with adding dropwise 12.1 g of dimethyl sulfate. After refluxing was continued for 4 hours, the reaction mixture was cooled, and crystals which precipitated were collected by filtration and washed with water to give 8.22 g of 6-nitro-8-methoxy-3,4-dihydrocarbostyril.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)(=[O:37])=[O:36]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.48 mmol) in CH2Cl2 (5 mL) was added Et3N (240 mg, 2.4 mmol) and methanesulfonyl chloride (164 mg, 1.4 mmol) at 0° C. The reaction solution was stirred at rt for 1 h. The reaction was quenched with H2O and the mixture was extracted with CH2Cl2. The organic phase was concentrated to give 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl methanesulfonate (234 mg, 98%), which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1)=[O:4].[CH3:11][O:12][C:13]([NH:15][C@@H:16]([CH:20]([CH3:22])[CH3:21])[C:17](O)=[O:18])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:17](=[O:18])[C@@H:16]([NH:15][C:13]([O:12][CH3:11])=[O:14])[CH:20]([CH3:22])[CH3:21])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester in dry DCM (200 mL) was added (S)-2-methoxycarbonylamino-3-methyl-butyric acid (10 g, 55 mmol), HATU (24 g, 63.25 mmol), and triethylamine (16.7 g, 165 mmol. The reaction mixture was stirred at RT overnight. DCM (200 mL) was added and the solution was washed with brine, dried, concentrated and purified by silica gel column chromatography (eluted with petroleum ether:EtOAc 10:1 to 1:4)) to give the title intermediate as a yellow oil (20 g). (m/z): [M+H]+ calcd for C13H22N2O6 303.15. found 303.1.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][O:12][CH3:13])[C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCCCC)CCC.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C1COCC1.CO>[NH2:9][CH:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1([N:2]([CH3:1])[CH2:10][CH2:11][O:12][CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [Li]c1ccccc1
Reactant: COCCN(C)C1(C#N)CCCC1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Solvent: CO
Product: COCCN(C)C1(C(N)c2ccccc2)CCCC1
Yield: 42 %

Procedure:
The title compound (1.22 g; 42%) was prepared from 1-{methyl[2-(methyloxy)ethyl]amino}cyclopentanecarbonitrile D35 (2.0 g; 11 mmol), and phenyllithium in di-n-butylether (6.7 ml of 1.8M solution; 12 mmol) in THF (25 ml), followed by reaction with sodium borohydride (1.25 g; 33 mmol) in methanol (25 ml) in a similar manner to that described in D2. Mass Spectrum (Electrospray LC/MS). Found 263 (MH+). C16H26N2O requires 262. Ret. time 1.57 min.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:13]([NH:25][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
Preparation according to Example 1, from D-galactose and dodecylamine.
Reaction SMILES: [C:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]=1)([O:3][CH3:4])=[O:2].[N+:15]([C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][N+:26]([O-:28])=[O:27])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16].N12CCCN=C1CCCCC2>C(#N)C.C(OCC)(=O)C>[C:1]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[CH:25]([N+:26]([O-:28])=[O:27])[CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=1)([O:3][CH3:4])=[O:2]
Reactant: O=[N+]([O-])CCc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)C1=CCCc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)C1c2ccccc2CCC1C(Cc1cccc([N+](=O)[O-])c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a mixture of 2 g (10.6 mmol) of 1-carbomethoxy-3,4-dihydronaphthalene, from Step 1 of Example 46, and 2.08 g (10.6 mmol) of 2-(3-nitrophenyl)-1-nitroethane, from Step 2, in 1 mL of acetonitrile was added 0.2 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction mixture was stirred at ambient temperature for 0.5 h and then diluted with ethyl acetate. The reaction mixture was washed with 2N aqueous hydrochloric acid solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 3.96 g (97% yield) of the title compound as a mixture of diastereomers which was taken on without purification to the next step; MS DCI-NH3M/Z: 402 (M+NH4)+ ; 1H NMR (CDCl3) δ1.52-1.86 (1H, m), 2.1-2.35 (1H, m), 2.42-2.65 (1H, m), 2.78- 3.15 (2H, m), 3.2-3.33 (1H, m), 3.38-3.55 (1H, m). 3.78-3.81 (3H, s), 3.91-4.18 (1H, m), 4.68-4.88 (1H, m), 7.12-7.42 (4H, m), 7.48-7.58 (2H, m), 8.01-8.18 (2H, m).
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]([Cl:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[Na+].[H][H]>C(O)C.[Pt]>[Cl:12][C:9]([F:10])([F:11])[CH2:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)CC(F)(F)Cl
Reactant: [H][H]
Agent: [Pt]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC(F)(F)Cl
Yield: 75 %

Procedure:
22.1 g of ethyl 2,4-dichloro-4,4-difluorobutyrate are dissolved in 200 ml of absolute ethanol. 8.2 g of anhydrous sodium acetate and 2.0 g of 5% platinum/carbon catalyst are added and then gaseous hydrogen is passed in under atmospheric pressure until the hydrogen uptake is 100% of theory. The catalyst is removed by filtration and the ethanol is removed by distillation and then the remaining oil is poured onto water, and the organic phase is separated off, dried with sodium sulfate, filtered and distilled under atmospheric pressure. 14.0 g of ethyl 4-chloro-4,4-difluorobutyrate are obtained in the form of a colourless oil of boiling point 154°-156° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH2:34][NH:35][C:36]2[CH:44]=[CH:43][C:39]([C:40]([OH:42])=O)=[CH:38][CH:37]=2)=[CH:26][CH:25]=1.C(N(CC)CC)C.[NH2:52][CH:53]1[CH2:58][CH2:57][N:56]([CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:55][CH2:54]1>CN(C)C=O>[C:60]1([CH2:59][N:56]2[CH2:57][CH2:58][CH:53]([NH:52][C:40](=[O:42])[C:39]3[CH:38]=[CH:37][C:36]([NH:35][CH2:34][C:27]4[C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:24]=[CH:25][CH:26]=4)=[CH:44][CH:43]=3)[CH2:54][CH2:55]2)[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: O=C(O)c1ccc(NCc2ccnc3ccccc23)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(NCc2ccnc3ccccc23)cc1
Temperature: 100 °C
Yield: 50.6 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.62 g, 18.9 mmol), 1-hydroxybenzotriazole hydrate (2.43 g, 18.0 mmol), and 4-[(4-quinolinylmethyl)amino]benzoic acid (5.00 g, 18.0 mmol) were placed in a flask under nitrogen. N,N-Dimethylformamide (83 mL) was then added followed by triethylamine (4.5 g, 45 mmol, 6.3 mL) and finally 4-amino-1-benzylpiperidine (3.1 g, 3.3 mL, 16 mmol). The mixture was heated at 100° C. for 45 minutes and the N,N-dimethylformamide was then removed under reduced pressure. The resulting viscous orange oil was triturated overnight with a mixture of 75 mL of water and 50 mL of ethyl acetate with vigorous overhead stirring. The resulting solid was filtered, washed with water and dried under reduced pressure at 60° C. for 25 hours. Flash chromatography on silica gel (65 mm column, 5% ammonia saturated methanol in methylene chloride eluent) afforded fractions containing the product which were concentrated to the point where a white powder formed. The powder was filtered and washed with a small amount of methanol and then ether. Drying under reduced pressure at 60° C. for 19.5 hours afforded 3.65 g (8.1 mmol, 50% yield) of the title compound, m.p. 184°-188° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1ccccc1CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2ccccc2)cc1CC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.2 %

Procedure:
To a stirred ice bath cooled solution of diethylbenzene (1.7 mL, 10 mmol) in methylene chloride (30 mL) under nitrogen was added aluminum chloride (2.93 g, 22 mmol). A slight exotherm resulted. To the resulting reaction mixture was added benzoyl chloride (1.2 mL, 10 mmol). The reaction mixture was allowed to warm to room temperature and was then stirred at room temperature for 1.5 hours. The reaction mixture was poured into 60 mL of iced water and stirred for 20 minutes. The resulting mixture was extracted with methylene chloride (2×40 mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to afford the crude product as an orange oil. The crude product was purified by flash column chromatography (silica gel, 2.5% ethyl acetate/hexane) to afford 1.22 g (51%) of the product as a yellow oil: 1H NMR (CDCl3) δ7.85-7.41 (m, 7 H), 7.30-7.20 (m, 1 H) 2.83-2.61(m, 4 H), 1.35-1.17 (m, 6 H); 13C NMR (CDCl3) δ196.8, 147.0, 141.9, 138.1, 135.3, 132.1, 132.1, 130.1, 130.0, 128.1, 128.1, 25.6, 25.4, 15.1, 15.0; Anal. Calcd for C17H18O. Theoretical: C, 85.67; H, 7.61. Found: C, 85.38; H, 7.42.