Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4]2[O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH2:24][NH:23][C:22](=[O:25])[NH:21][CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].Cl[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1>CN(C)C=O.O>[CH:3]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4]2[O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH2:24][N:23]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)[C:22](=[O:25])[N:21]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)[CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C2CNC(=O)NC2)cc1OC1CC2CCC1C2
Reactant: ClCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2CN(Cc3ccc4ccccc4n3)C(=O)N(Cc3ccc4ccccc4n3)C2)cc1OC1CC2CCC1C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.6 %

Procedure:
NaH (63 mg, 1.58 mmol, 1.0 eq, 60% oil dispersion) was added to a mixture of (0.500 g, 1.58 mmol, 1.0 eq) 5-[3-(bicyclo[2.2.1]hept-2-yloxy)4-methoxyphenyl]tetra-hydro-2(1H)-pyrimidinone and (0.279 g, 1.58 mmol, 1.0 eq) 2-chloromethylquinoline in 12 ml of anhydrous dimethylformamide. After stirring for 18 hours at room temperature, the reaction mixture was diluted with 250 ml of H2O and extracted with ethyl acetate. The ethyl acetate extract was washed once with H2O, once with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on a silica gel column, eluting with 21/2% CH3OH-CH2Cl2 to yield 50 mg of a solid, which was recrystallized from ethyl acetate-hexane to afford 45 mg, 5%, of a white crystalline solid. M.P.: 135°-136° C.
Reaction SMILES: [NH2:1][C@:2]1([CH2:24][OH:25])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][CH:8]=2)[CH2:3]1.[OH-].[K+].[C:28](Cl)(Cl)=[O:29].CCOC(C)=O>C1(C)C=CC=CC=1.O>[CH2:17]([O:16][CH2:15][C:14]#[C:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:4]2[CH2:5][CH2:6][C@@:2]3([NH:1][C:28](=[O:29])[O:25][CH2:24]3)[CH2:3]2)=[CH:8][CH:9]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)Cl
Reactant: N[C@]1(CO)CC[C@@H](c2ccc(C#CCOCc3ccccc3)cc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1N[C@@]2(CC[C@@H](c3ccc(C#CCOCc4ccccc4)cc3)C2)CO1
Yield: 79 %

Procedure:
To a solution of ((1R,3R)-1-amino-3-(4-(3-(benzyloxy)prop-1-ynyl)phenyl)cyclopentyl)methanol (25 g, 55.9 mmol) in toluene (200 mL) was added a solution of potassium hydroxide (12.54 g, 224 mmol) in water (40 mL) followed by a solution of 20% phosgene in toluene (41.5 g, 84 mmol). After about 4 hours EtOAc was added and the organic layer was separated and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/DCM) to provide (5R,7R)-7-(4-(3-(benzyloxy)prop-1-ynyl)phenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (20 g, 44.3 mmol, 79% yield) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19]>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1NC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)O)c(C(F)(F)F)cc1NC(C)=O
Yield: 90.8 %

Procedure:
A solution of 5-acetyl-2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (4 g, 13.2 mmol) in THF (40 mL) was hydrogenated at r.t. for 2 h over Pd—C (10%, 250 mg). The reaction mixture was filtered on a sintered funnel. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 2:1 hexanes/EtOAc) to give the title product (3.66 g, 91% yield) as colorless crystals. m.p.: 120-123° C., ESI-MS: m/z 306 [M+H]+.
Reaction SMILES: O[C:2]1([O:22][CH3:23])[C:15]2[C@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([OH:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)[CH2:7][C:6]=2[CH:5]=[CH:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cl-].C1([N+](C)(C)C)C=CC=CC=1>[OH:21][C@:9]12[C@@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]1([C:15]1[C:2]([O:22][CH3:23])=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:7]3)[CH2:13][C:12](=[O:20])[CH2:11][CH2:10]2
Reactant: COC1(O)CC=CC2=C1[C@]13CCN(C)[C@H](C2)[C@]1(O)CCC(=O)C3
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1cccc2c1[C@]13CCN(C)[C@H](C2)[C@]1(O)CCC(=O)C3
Temperature: 90 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To a solution of 2.2 g (7.66 mmol) 4,14-dihydroxy-4-methoxy-N-methylmorphinan-6-one in 50 ml dry DMF were added 2.12 g (15.34 mmol) anhydrous K2CO3 and 3.96 g (23.07 mmol) phenyltrimethylammonium chloride and this mixture was stirred at 90° C. (bath temperature) for 4 h. After cooling to room temperature, the mixture was filtered, washed with CHCl3 and evaporated (90° C. bath temperature). The residue was partitioned between ethyl acetate and water, the organic layer separated and washed with water, dried and evaporated to give 2.1 g of a crystalline residue. After recrystallization with ethanol 1.78 g (77%) of 14-hydroxy-4-methoxy-N-methylmorphinan-6-one, m.p. 191°-193°, [α]D26 --83.9° (C 0.88, CHCl3) were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O>CN(C=O)C>[N:15]1([CH:21]2[CH2:26][CH2:25][N:24]([CH2:13][C@:11]([CH3:14])([OH:12])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCC(N2CCCCC2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.500 g, 2.29 mmol) and 4-piperidinopiperidine (0.425 g, 2.53 mmol) were dissolved in DMF (5 ml), and the solution was stirred at 70° C. for 5 hours. The reaction mixture was added water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/2) using basic silica gel to afford (S)-1-(4-piperidinopiperidin-1-yl)-3-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-propan-2-ol (0.656 g, yield 74%) as a brown oil.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](OC)=[O:4].[H][H]>O1CCCC1>[CH3:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4]
Reactant: [H][H]
Reactant: COC(=O)[C@@H](C)Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@H](CO)Cc1ccccc1

Procedure:
Methyl (S)-2-methyl-3-phenylpropionate (5 mmol, 78.4% ee), a ruthenium complex 1 (0.01 mmol), and tetrahydrofuran (2 mL) were charged into a 100-mL autoclave equipped with a stirrer. Then, the mixture was subjected to hydrogenation at a hydrogen pressure of 5 MPa at 80° C. for 16 hours. The reaction liquid was analyzed by gas chromatography. As a result, (S)-2-methyl-3-phenylpropanol was obtained at a conversion rate of 99.0% and a selectivity of 98.6%. The obtained alcohol had an optical purity of 77.9% ee.
Reaction SMILES: [CH:1]1([N:4]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=2[Cl:36])[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[CH:1]1([N:4]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=2[Cl:36])[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:2][CH2:3]1
Reactant: Cn1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)cc1=O
Agent: Cl
Solvent: ClCCl
Product: Cn1ccc([C@@H]2CCNC[C@H]2C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)cc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a CH2Cl2 solution (0.05 M) of trans-1,1-dimethylethyl 3-({cyclopropyl[(2,3-dichlorophenyl)methyl]amino}carbonyl)-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridinyl)-1-piperidinecarboxylate (1 eq.) from the previous step was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 94:6 (v/v) CH2Cl2:2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. MS (ESI+, M+H): 434.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]([CH3:11])([CH3:10])[CH3:9].CN(C)C(=O)C.[N+:18]([C:21]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])([O-:20])=[O:19]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C.O>[N+:18]([C:21]1[CH:29]=[C:28]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][C:22]=1[C:23]([O:25][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:24])([O-:20])=[O:19]
Reactant: CC(C)(C)Br
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 18 h

Procedure:
9.9 g of potassium carbonate, 0.82 g of benzyltriethyl-ammonium chloride and 21 mL of 2-bromo-2-methylpropane were added to 14 mL of N,N-dimethylacetamide solution containing 0.93 g of 2-nitro-4-phenoxybenzoic acid at room temperature and stirred at 55° C. for 18 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution, 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure to obtain 0.86 g of tert-butyl 2-nitro-4-phenoxybenzoate as white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[Cl:11][CH2:12][C:13](Cl)=[O:14]>>[Cl:11][CH2:12][C:13]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:14]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(Cl)CCl
Product: NC(=O)CC[C@H](NC(=O)CCl)C(=O)O

Procedure:
To illustrate, creatyl-L-glutamine can be synthesized as follows. First, L-glutamine as the starting material is reacted with 2-chloroacetyl chloride to obtain N-chloroacetyl-L-Glutamine. This intermediate is converted to sarcosyl-L-glutamine in aqueous methylamine solution. Sarcosyl-L-glutamine is further treated to obtain creatyl-L-glutamine. In this way, a dipeptide creatyl-L-glutamine is obtained from glutamine.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: Oc1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(COc2cnc(Br)cn2)CC1
Temperature: 70 °C

Procedure:
A mixture of 5-bromo-2-pyrazinol (and tautomers thereof) (0.2 g, 1.14 mmol), 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 131, Step 4, 0.51 g, 1.71 mmol) and K2CO3 (0.32 g, 2.29 mmol) in DMF (12 mL) was stirred at ambient temperature for 30 min, then heated at 70° C. overnight. The mixture was cooled to ambient temperature and poured into water, and then extracted with EtOAc (60 mL×2). The combined organic extract was washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give crude 1-methylethyl 4-{[(5-bromo-2-pyrazinyl)oxy]methyl}-1-piperidinecarboxylate a brown oil, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](N(OC)C)=[O:13])[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.F[C:26](F)(F)S(OC1C(C(N(OC)C)=O)=CC(Cl)=C2C=1N=CC=C2)(=O)=O.C[Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:13])[CH3:26])[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1-c1cccc(F)c1
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a mixture of 5-chloro-8-(3-fluorophenyl)-N-methoxy-N-methylquinoline-7-carboxamide (154 mg, 0.447 mmol) and 5-chloro-7-{[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (154 mg, 0.386 mmol) in tetrahydrofuran (1 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (3.8 mL, 5.3 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resultant residue was purified on silica gel, eluting with 0 to 50% of EtOAc in hexane, to give the desired product (38 mg, 32%). LCMS calculated for C17H12ClFNO(M+H)+: m/z=300.1; found: 300.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1.[NH4+].[Cl-]>C1COCC1>[CH3:13][C:11]1([CH3:14])[CH2:10][O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]3([OH:24])[CH2:22][CH2:23][C:18]4([O:25][CH2:15][CH2:16][O:17]4)[CH2:19][CH2:20]3)=[CH:3][CH:4]=2)=[N:12]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(C3(O)CCC4(CC3)OCCO4)cc2)=N1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 8 g of 2-(4-bromophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (31.5 mmol) in 15 ml of anhydrous THF is poured dropwise onto 956 mg of Mg (39.3 mmol) in such a way as to maintain the mixture at the reflux temperature and the mixture is refluxed for 2.5 hours. The mixture is cooled to room temperature and a solution of 5.41 g of 1,4-cyclohexandione monoethyleneacetal (34.65 mmol) in 20 ml of anhydrous THF is added to it dropwise. The mixture is stirred at room temperature for 1.5 hours and then at reflux temperature for 1 hour. The mixture is poured into 500 ml of a 10% NH4Cl solution and extracted with ethyl acetate. The organic phase is dried and, after filtration, the solvent is evaporated off under reduced pressure. The residue is crystallized in ethyl acetate. The product of the title is obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: COC(=O)c1cc(F)cnc1Cl
Yield: 83.4 %

Procedure:
The title compound (D69) (0022/105/1) (1.8 g) was prepared according to the experimental procedure described in Description 66 starting from 2-Chloro-5-fluoronicotinic acid (2 g, 11.39 mmol) and trimethylsilyldiazomethane (2M solution in diethyl ether) (17 ml, 34.18 mmol)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=[C:17](Br)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=[C:17]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCn1cc(Br)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: OB(O)c1ccc(Cl)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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)CCn1cc(-c2ccc(Cl)cc2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 77 %

Procedure:
Add 4-[4-bromo-1-(2-dimethylamino-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g; 0.0024 mol; 1.0 equiv), 4-chloro phenyl boronic acid (0.58 g; 0.0037 mol; 1.5 equiv), 3M Na2CO3 solution (0.79 g; 0.0074 mol; 3.0 equiv) to ethanol (5 mL) and toluene (5 mL) and degas the reaction with argon. Add Pd(PPh3)4 (0.29 g; 0.00024 mol; 0.1 equiv) and microwave at 110° C. for 20 min. Add EA and filter through a Celite® bed. Add saturated NaHCO3 aqueous and extract with EA. Evaporate the organic layer, and purify the residue over a silica gel column with methanol in DCM to give the title compound (0.8 g; crude).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-])=O)=[N:9][CH:10]=1>C(O)C.ClCCl.[Pd]>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(C(F)(F)F)ccc2Cl)cn1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(Oc2cc(C(F)(F)F)ccc2Cl)cn1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
10% Pd/C (38 mg, 35 μmol, 10 mol % Pd) was added to chloride 3 (113 mg, 353 μmol) in ethanol:dichloromethane (3:1, 4.0 mL). The mixture was degassed and placed under H2 (1 atm) and stirred for 1 h. The mixture, filtered through a 0.45 μm syringe filter and concentrated under reduced pressure provided 4 (98.1 mg, 96%) as a solid: LRESIMS m/z 289.4 [M+H]+, calcd. for C12H9Cl1F3N2O1 289.0.
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:5])[CH:3]=[O:4].[C:17]([S:20][CH:21]1[NH:24][C:23](=[O:25])[CH2:22]1)(=[O:19])[CH3:18]>C1C=CC=CC=1>[C:17]([S:20][CH:21]1[N:24]([CH:3]([OH:4])[C:2]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:5])[C:23](=[O:25])[CH2:22]1)(=[O:19])[CH3:18]
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)SC1CC(=O)N1
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 115.1 %

Procedure:
p-Nitrobenzyl glyoxylate hydrate (63.4 g., 0.278 mole) was added to a solution of 4-acetylthio-2-azetidinone (36.2 g., 0.250 mole) in 1200 ml. of benzene. The mixture was refluxed for 17 hours in a Dean-Stark apparatus. The solution was concentrated on a rotary evaporator to give the title product as a yellow oil (102 g., 100%). This oil was found to be identical with the product of Example 1A.
Reaction SMILES: [Si]([O:8][C:9]1[C:17]2[N:16]=[N:15][N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=2[CH:12]=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:23][Si:22]([CH3:25])([CH3:24])[CH2:21][CH2:20][O:19][CH2:18][N:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:8])[C:17]=2[N:16]=[N:15]1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2c1nnn2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nnc2c(O)cccc21

Procedure:
A mixture of EXAMPLE 514B (1.32 g) and 1.0 N tetrabutyl ammonium fluoride (10.4 mL) in tetrahydrofuran (15 mL) was stirred for 2 hours. The solvent was removed, and the residue was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using 10% ethyl acetate in hexanes as eluent to give the title compound.
Reaction SMILES: C1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[C:14]([CH3:30])=[N:15][C:16]([CH3:29])=[C:17](C(O)=O)[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[O:12])C=CC=CC=1.S(Cl)(Cl)=O.[CH3:41][N:42]([CH:44]=[O:45])[CH3:43]>>[C:19]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11](=[O:12])[C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[C:17]([C:44]([N:42]3[CH2:43][CH2:11][O:10][CH2:9][CH2:41]3)=[O:45])[C:16]([CH3:29])=[N:15][C:14]=2[CH3:30])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: Cc1nc(C)c(C(=O)OCCC(c2ccccc2)c2ccccc2)c(-c2cccc(Cl)c2)c1C(=O)O
Solvent: O=S(Cl)Cl
Product: Cc1nc(C)c(C(=O)N2CCOCC2)c(-c2cccc(Cl)c2)c1C(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
50.0 mg (0.100 mmol) of 4-(3-chlorophenyl)-2,6-dimethylpyridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester and 5 ml of thionyl chloride were stirred in DMF at room temperature for 1 hour. After concentration under reduced pressure, the residue was dissolved in 3 ml of dichloromethane. 1 ml of morpholine was added and stirred at room temperature for 6 hours. After concentration under reduced pressure, ethyl acetate was added and the residue was washed with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (hexane/ethyl acetate=20/1 to 1/4) to obtain the title compound.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]3[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=3[C:12]=2[NH2:16])[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH2:16][C:12]1[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[CH:9]=[C:8]2[C:13]=1[CH2:14][CH2:15][N:6]([CH3:4])[CH2:7]2
Reactant: CCOC(=O)N1CCc2c(cc3ccccc3c2N)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1CCc2c(cc3ccccc3c2N)C1
Reaction time: 5 h

Procedure:
A solution of 50.0 g of 5-amino-1,2,3,4-tetrahydrobenzo[g]isoquinolin-2-ylcarboxylic acid ethyl ester (see Example 4a-c for production) in 1.2 litres of anhydrous tetrahydrofuran is added dropwise at temperatures of between 15° - 30° to a suspension of 23.0 g of lithium aluminium hydride in 500 ml of anhydrous tetrahydrofuran while cooling. The reaction mixture is stirred for 5 hours at the boiling temperature, is cooled to 0° and is decomposed by the dropwise addition of 90 ml of a saturated sodium sulphate solution at 0° - 5°. The precipitated inorganic product is filtered off, is washed with tetrahydrofuran and concentrated by evaporation. The title compound crystallizes from the evaporation residue with the addition of ethanol and is again recrystallized from ethanol. M.Pt.: 97° - 99°.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:8]=[C:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCCCCC.C(OC(=O)C)C>[Br:25][CH2:17][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([Cl:6])[CH:8]=1
Reactant: Cc1cc(Cl)cc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Clc1cc(CBr)c2ccccc2c1
Yield: 84 %

Procedure:
Carbon tetrachloride(30 ml) was added to 3-Chloro-1-methyl-naphthalene(2.55 g, 14.4 mmol) prepared in Preparation 36-1) and NBS (2.82 g, 15.8 mmol). A small quantity of benzoylperoxide was added as an initiator and the resulting mixture was heated under reflux for 3 hours. The reaction solution was cooled and filtered to remove the insoluble solid. The filtrate was concentrated and subjected to column chromatography(eluent: hexane/ethylacetate=95/5, v/v) to give 3.10 g(12.1 mmol, Yield 84%) of the title compound.