Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:12]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: C1CCNC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: O=C(O)Cc1ccccc1N1CCCC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 10.7 g of 2-(2-bromophenyl)acetic acid, 20 cm3 of pyrrolidine and 1.66 g of copper acetate is heated at 90° C. with stirring for 2 hours; after return to room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 5 cm, height 55 cm), eluting with 1000 cm3 of 1,2-dichloroethane then with mixtures of 1,2-dichloroethane and methanol (proportions by volume): 1000 cm3 (98:2), 2000 cm3 (97:3), 1000 cm3 (96:4) and 1000 cm3 (95:5) and collecting fractions of 250 cm3. Fractions 21 to 29 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2 g of 2-[2-(1-pyrrolidinyl)phenyl]acetic acid are obtained in the form of an orange-coloured oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](Cl)(Cl)Cl)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].Cl.Cl.[CH:20]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)([CH3:22])[CH3:21].C([O-])(O)=[O:31].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:31])[NH:29][CH:26]3[CH2:27][CH2:28][N:23]([CH:20]([CH3:22])[CH3:21])[CH2:24][CH2:25]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(C(Cl)(Cl)Cl)nc12
Reactant: O=C([O-])O
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.99 g (13.6 mmol) 2-trichloromethyl-1H-benzoimidazole-4-carboxylic acid methyl ester in 40 mL THF was added slowly to a mixture of 2.9 g (13.6 mmol) 1-isopropyl-piperidin-4-ylamine-dihydrochloride and 13.7 g (0.163 mol, 12 equivalents) NaHCO3 in 200 mL THF and 120 mL water. The reaction mixture was stirred for 2 h at RT. The THF was distilled off. The resulting aqueous suspension was diluted with 200 mL CH2Cl2 and extracted twice with 150 mL water. The organic layer was concentrated under reduced pressure and the resulting residue was purified by flash-chromatography on silica gel using an ethyl acetate/methanol-(4:1)-mixture as eluent. The title compound was obtained as a light brown crystalline material.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=[O:16])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH:29]=1>>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[O:16])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCCCOc2ccccc2C(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCOc2ccccc2C(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O
Yield: 65 %

Procedure:
The reaction of 0.79 g of 2-[3-(4-acetyl-3hydroxy- 2-propylphenoxy)propoxy]benzoic acid with 0.35 g of 3-pyridine butanamine according to Example 40 gave 0.70 g, mp 104°-107°, (65% yield) of 2-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy]-N-[4-(3-pyridinyl)butyl]benzamide, the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:21])[CH:16](Cl)[C:17](=O)[CH3:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[S:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:9][C:17]=1[CH3:18])=[O:21])[CH3:13]
Reactant: COc1ccc(C(N)=S)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C
Yield: 69.7 %

Procedure:
A mixture of 4-methoxy-thiobenzamide (5 g, 30 mmol) and 2-chloro-3-oxo-butyric acid ethyl ester (4.6 mL, 33 mmol) in ethanol is stirred under reflux overnight. The reaction mixture is concentrated and the residue is triturated with ether to give the title compound as a yellow solid (5.8 g, 70%). LC-ES/MS m/e 278 (M+1)
Reaction SMILES: C([OH:3])C.ClCCl.[CH3:7][C:8]1[S:12][C:11]([S:13][CH2:14][C:15]2[CH2:32][S:31][C@@H:18]3[C@H:19]([NH:22][C:23]([CH2:25][N:26]4[N:30]=[N:29][N:28]=[CH:27]4)=[O:24])[C:20](=[O:21])[N:17]3[C:16]=2[C:33]([OH:35])=[O:34])=[N:10][N:9]=1.C([O-])(=[O:38])C.[Na+:40]>O>[CH3:7][C:8]1[S:12][C:11]([S:13][CH2:14][C:15]2[CH2:32][S:31][C@@H:18]3[C@H:19]([NH:22][C:23]([CH2:25][N:26]4[N:30]=[N:29][N:28]=[CH:27]4)=[O:24])[C:20](=[O:21])[N:17]3[C:16]=2[C:33]([O-:35])=[O:34])=[N:10][N:9]=1.[OH2:3].[OH2:38].[OH2:3].[OH2:3].[OH2:3].[Na+:40]
Reactant: CC(=O)[O-]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)Cn4cnnn4)[C@H]3SC2)s1
Reactant: CCO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1nnc(SCC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)Cn4cnnn4)[C@H]3SC2)s1
Reaction time: 4 h

Procedure:
To a reactor equipped with a jacket were added 10 ml ethanol, 50 ml dichloromethane, 20 ml water, 5 g cefazolin acid and 0.9 g sodium acetate, stirred until the solution was clear, the finishing point pH was adjusted to be 7.4, the mixture was directly filtered into a glass crystallizer, agitated for 60 minutes, added dropwise about 20 ml of isopropanol and methanol mixed liquid (the amount of methanol is 3%) and methionine, turbidness occurred in the solution, hold for 4.0 hours, added isopropanol and methanol in a volume 10 times as much as the mixture at 1.5 MPa. The resultant was filtered, the filter cake was washed with acetic acid, dried at 80° C. for 0.5 hours to give cefazolin sodium pentahydrate.
Reaction SMILES: [Mg].II.[CH2:4]([O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[B:18](OC)([O:21]C)[O:19]C.S(=O)(=O)(O)O>C(OC1C=CC(Br)=CC=1)CCCCC.C1COCC1>[CH2:4]([O:10][C:11]1[CH:16]=[CH:15][C:14]([B:18]([OH:21])[OH:19])=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCOc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
In a baked-out apparatus filled with argon, magnesium turnings (1.89 g; 78 mmol) were treated with a crystal of iodine and covered with dried THF. Subsequently, a few drops of 4-hexyloxybromobenzene were added to the static solution. The Grignard reaction commenced very quickly and the 4-hexyloxybromobenzene (total amount: 20 g; 78 mmol) was subsequently added dropwise while stirring at such a rate that the mixture boiled gently; during this addition, the mixture was diluted with THF (total of about 100 ml). The mixture was refluxed for 3 hours (only a few flakes of magnesium remaining in the solution) and was subsequently allowed to cool. The Grignard soltuion was transferred in a countercurrent of protective gas to a 250 ml dropping funnel and added dropwise at −70° C. to a solution of trimethyl borate (8.9 g; 9.6 ml; 86 mmol) in 50 ml of dry THF while stirring, with a precipitate being formed. The mixture was allowed to warm to RT overnight and the reaction mixture was poured into a mixture of 100 g of ice and 3 ml of concentrated sulfuric acid while stirring. The organic phase was separated off and the aqueous phase was extracted with 3×100 ml of chloroform, the combined organic phases were evaporated. The crude product was subsequently recrystallized from hexane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][C:15]=2[F:27])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:29](F)(F)[C:30]([OH:32])=O>C(Cl)Cl>[CH:22]1([C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([CH:29]([C:19]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:30]([N:8]([CH2:13][CH3:12])[CH2:9][CH3:10])=[O:32])[CH2:9][CH2:10]3)=[C:15]([F:27])[CH:16]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)C3CCCC3)cc2F)CC1
Solvent: ClCCl
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(C(=O)C3CCCC3)cc2F)CC1

Procedure:
A solution of 4-(4-cyclopentanecarbonyl-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.11 g, 0.29 mmol) in DCM (5 mL) was treated with trifluoroacetic acid (1.5 mL). After 3 h the solvent was removed and water (5 mL) and 1 M NaOH were added (˜pH 10). The mixture was extracted with DCM and the solvent removed. The residue was then taken up in DMF (2 mL) and K2CO3 was added (0.13 g, 0.91 mmol). This mixture was then treated with 2-bromo-N,N-diethyl-2-phenyl-acetamide (0.11 g) as described in previous examples to provide 0.072 g of the title compound. MS: 466.6. 1H NMR (CDCl3): 7.69-7.66 (m, 1H), 7.63-7.59 (m, 1H), 7.47-7.43 (m, 2H), 7.38-7.30 (m, 3H), 6.90-6.86 (m, 1H), 4.26 (s, 1H), 3.63-3.56 (m, 1H), 3.51-3.35 (m, 2H), 3.31-3.14 (m, 6H), 2.76-2.67 (m, 4H), 1.92-1.85 (m, 4H), 1.75-1.57 (m, 4H), 1.09 (t, J=7.1, 3H) 1.04 (t, J=7.1, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]=[C:12]1[CH2:18][CH:17]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:16]2[CH:28]=[C:29]([C:32](=[O:34])[CH3:33])[CH:30]=[CH:31][C:15]=2[O:14][CH2:13]1.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl>O1CCCC1.ClCCl.O>[CH2:35]([C:17]1([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:16]2[CH:28]=[C:29]([C:32](=[O:34])[CH3:33])[CH:30]=[CH:31][C:15]=2[O:14][CH2:13][C:12](=[CH2:11])[CH2:18]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: C=C1COc2ccc(C(C)=O)cc2C(S(=O)(=O)c2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1COc2ccc(C(C)=O)cc2C(Cc2ccccc2)(S(=O)(=O)c2ccccc2)C1
Reaction time: 0.25 h
Yield: 97 %

Procedure:
0.152 ml (2.2 equivalents) of 1,3-dimethylpropyleneurea and then 1.286 ml (2.2 equivalents) of 1.06M lithium bis(trimethylsilyl)amide in tetrahydrofuran are added at ambient temperature to 200 mg (0.58 mmol) of 1-[3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-yl]ethanone, prepared according to example 13, in solution in 5.8 ml of tetrahydrofuran. The reaction medium then assumes a dark yellow color. After 15 minutes, 0.0698 ml (1 equivalent) of benzyl bromide is added. Water is immediately added, and 1N hydrochloric acid and dichloromethane. After separating the organic and aqueous phases, the aqueous phase is extracted 3 times with dichloromethane. The combined organic phases are washed with brine, are dried and are finally concentrated under vacuum. The crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 30/70) to provide 245 mg (97%) of 1-[5-benzyl-3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-yl]ethanone in the form of a white solid; M.p.=131–132° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[C:6]([OH:8])=O.[NH:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:19].C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([NH:19][NH:18][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:8])[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1
Reactant: COc1cc(C(=O)O)ccc1-n1cnc(C)c1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCP(=O)(C#N)CC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a mixture of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoic acid (12.1 g) and tert-butyl hydrazinecarboxylate (7.61 g) in DMF (100 mL) was added diethyl phosphoryl cyanide (8.55 mL) at room temperature. After stirring at room temperature for 30 min, triethylamine (21.6 mL) was added, and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.00 g).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:24])=[CH:21][C:20]=1[Cl:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO>[Cl:35][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:19]=1[NH:18][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])[C:23]([NH:25][CH:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)=[O:24]
Reactant: CN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CC(C)CC(C)O
Product: CC(C)N1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3Cl)nc21
Temperature: 140 °C
Yield: 30.6 %

Procedure:
10-chloro-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 76, 100 mg, 0.39 mmol) and 4-amino-3-chloro-N-(1-methyl-4-piperidyl)benzamide (Intermediate 79; 127 mg, 0.47 mmol) were suspended in 4-methyl-2-pentanol (3 mL) and p-toluenesulphonic acid monohydrate (74 mg, 0.97 mmol) added. The mixture was heated at 140° C. for 4 hours The mixture was cooled causing a white solid to formed. The whole mixture was diluted with MeOH to give a solution which was absorbed on to an SCX-3 column, washed with methanol and eluted with ammonia/methanol. Concentration and column chromatography (1-2-3-5% NH3 in MeOH/DCM) of the product containing fractions gave the title compound as a white solid (58 mg, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:19](O)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]([O:12][CH2:19][CH3:20])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)CNc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)CNc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 21.3 g of 3-bromophenylglycine in 160 cm3 of 6.5N hydrochloric ethanol is heated with stirring for 24 hours at a temperature in the region of 80° C. The reaction medium is filtered and the filter cake is then washed with twice 30 cm3 of ethanol. The filtrate is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. An oil is obtained, which is basified by addition of aqueous sodium carbonate solution. The mixture is extracted with 3 times 100 cm3 of ethyl acetate. The extracts are combined, washed with twice 100 cm3 of aqueous sodium chloride solution, dried over sodium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 4.7 g of ethyl 3-bromophenylglycinate are obtained in the form of a yellow oil. (Rf=0.38 in a 90/5 by volume dichloromethane/methanol mixture, on a Merck 60F254R silica plate).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]3[CH2:14][O:15][CH2:16][CH:9]2[CH2:10][O:11][CH2:12]3)[N:5]=[C:4]([N:17]2[CH:22]3[CH2:23][O:24][CH2:25][CH:18]2[CH2:19][O:20][CH2:21]3)[N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[CH:22]12[N:17]([C:4]3[N:5]=[C:6]([N:8]4[CH:13]5[CH2:14][O:15][CH2:16][CH:9]4[CH2:10][O:11][CH2:12]5)[N:7]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][CH:29]=4)[N:3]=3)[CH:18]([CH2:25][O:24][CH2:23]1)[CH2:19][O:20][CH2:21]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Clc1nc(N2C3COCC2COC3)nc(N2C3COCC2COC3)n1
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: Nc1ccc(-c2nc(N3C4COCC3COC4)nc(N3C4COCC3COC4)n2)cc1
Temperature: 120 °C
Yield: 69.3 %

Procedure:
To a 10 mL vial were added 9,9′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(3,7-dioxa-9-azabicyclo[3.3.1]nonane) (150 mg, 0.406 mmol), 4-aminophenylboronic acid pinacol ester (133 mg, 0.61 mmol), Pd(PPh3)4 (10 mg), toluene (1 mL), EtOH (1 mL) and 2M Na2CO3 aqueous solution (0.305 mL). The resulting mixture was heated at 120° C. for 20 minutes in microwave oven. The reaction mixture was cooled to room temperature. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over (MgSO4). The solvent was removed under reduced pressure and the residue was subjected to HPLC separation to give 4-(4,6-di(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl)aniline as a white solid (120 mg).
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[CH3:16][O:17][C:18](=[O:28])[C:19]1[C:24]([Br:25])=[CH:23][C:22]([Br:26])=[CH:21][C:20]=1[NH2:27].CCCCCC>CCOC(C)=O>[CH3:16][O:17][C:18](=[O:28])[C:19]1[C:24]([Br:25])=[CH:23][C:22]([Br:26])=[CH:21][C:20]=1[NH:27][C:8](=[O:10])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:11]
Reactant: CC(C(=O)O)c1ccccc1
Reactant: COC(=O)c1c(N)cc(Br)cc1Br
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1c(Br)cc(Br)cc1NC(=O)C(C)c1ccccc1
Yield: 91.9 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-phenyl-propionic acid (2.00 g, 13.3 mmol), SOCl2 (3.47 mL, 40.0 mmol), and 2-amino-4,6-dibromo-benzoic acid methyl ester (2.74 g, 8.88 mmol). After normal workup, the pure objective compound (3.60 g, 92%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=20:1): 1H NMR (200 MHz, CDCl3) δ 1.60 (d, J=7.3 Hz, 3H, CH3), 3.65-3.75 (m, 4H, CO2CH3 & CH) 7.24-7.44 (m, 5H, ArH), 7.48 (d, J=2.0 Hz, 1H, ArH), 8.55 (d, J=2.0 Hz, 1H, ArH), 8.68 (br s, 1H, NH).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([NH:7][CH3:8])=[O:6].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>C(C(C)=O)C(C)C>[ClH:1].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][C:4]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:5]([NH:7][CH3:8])=[O:6])[CH2:32][CH2:33]2)=[CH:24][CH:23]=1
Reactant: CNC(=O)C(CCCl)(c1ccccc1)c1ccccc1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CC(=O)CC(C)C
Product: CNC(=O)C(CCN1CCC(O)(c2ccc(Cl)cc2)CC1)(c1ccccc1)c1ccccc1
Product: Cl
Yield: 32 %

Procedure:
A suspension of 4-chloro-N-methyl-2,2-diphenylbutyramide (1.4 g, 0.005 mol), 4-p-chlorophenyl-4-piperidinol (2.12 g, 0.01 mol), and trace Kl in i-BuCOMe (50 ml) was refluxed for 12 hrs. The reaction mixture was worked-up as described in Example 16 to provide 4-(p-chlorophenyl)-4-hydroxy-N-methyl-α,α-diphenyl-1-piperidinebutyramide hydrochloride (0.8 g, 35%), mp 236-238° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[C:17]([CH3:19])([CH3:18])[O:16][C:15]([CH3:21])([CH3:20])[C:13]=2[N:14]=1)=[O:8].CC(C)([O-])C.[K+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[F:40]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]2[C:17]([CH3:18])([CH3:19])[O:16][C:15]([CH3:20])([CH3:21])[C:13]=2[N:14]\1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[F:40])=[O:8]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nc2c(s1)C(C)(C)OC2(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc2c(n1Cc1ccc(F)cc1F)C(C)(C)OC2(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 5.1 %

Procedure:
To a solution of Example 2A (0.3 g, 0.8 mmol) in N,N-dimethylformamide/tetrahydrofuran (1:4, 10 mL) were added potassium t-butoxide (0.11 g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluorobenzene (Aldrich) (0.21 g, 1.0 mmol). The reaction was stirred at 80° C. overnight and then diluted with ethyl acetate (10 mL). The mixture was washed with 1M NaHCO3 and this aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® IT280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 20 mg (5%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.47 (s, 6H) 1.52 (s, 6H) 3.72 (s, 3H) 5.35 (s, 2H) 7.07 (d, 3H) 7.32 (d, 1H) 7.37 (d, J=2.71 Hz, 1H) 7.40-7.50 (m, J=8.81 Hz, 1H); MS (ESI+) m/z 493 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.[C:15]([O-])([O-:17])=[O:16].[K+].[K+].O>CN(C=O)C>[F:9][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:3]=1)[C:15]([OH:17])=[O:16]
Reactant: c1c[nH]cn1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc(F)cc(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(F)cc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Bromo-3,5-difluorobenzene (1.00 g, 5.18 mmol) was dissolved in anhydrous DMF (10 mL). The solution was chilled in an ice bath. Imidazole (0.36 g, 5.18 mmol) and K2CO3 (0.72 g, 5.18 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours, and at 80° C. for 0.24 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. The intermediate 3-Fluoro-5-Bromo-(1H-imidazol-1-yl)-benzene was used directly in the next step. Using the standard cyanation procedure, 3-Fluoro-5-cyano-(1H-imidazol-1-yl)-benzene was prepared as a colourless solid. The crude product was used directly in the next step. Using the standard saponification procedure, the title compound was prepared as a colourless solid. The crude product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.[N:16]1([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([CH:22]3[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25]3)[CH2:17][CH2:18]2)=[O:13])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Reactant: COc1cc(Cl)c(I)cc1NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(I)cc1NCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of 2-(4-chloro-5-iodo-2-methoxyphenylamino)acetic acid (2.0 g, 5.88 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (1.84 g, 7.64 mmol), EDCI.HCl (2.26 g, 11.76 mmol), and HOBt (1.59 g, 11.76 mmol) in DMF (3 mL) at 0° C., Et3N (3.28 mL, 23.52 mmol) was added. The resulting mixture was stirred at RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was washed by a mixture of ethyl acetate/petroleum ether=1:5 to afford the desired product (2.24 g, 67% yield) as a white solid. ESI-MS m/z: 565.4[M+H]+.