Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>C(N(CC)CC)C.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>[CH3:14][C:6]1([CH3:15])[C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:10]=2[C:9](=[O:13])[CH2:8][CH2:7]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8.8 g (47.8 mmol) of 6-ethynyl-1,2,3,4-tetrahydro-4,4-dimethylnaphthalen-1-one (Compound K) flushed for 15 minutes with a stream of argon, and 13.2 g (47.8 mmol) of ethyl 4-iodobenzoate in 200 ml of triethylamine was added 1.1 g (1.6 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.30 g (1.6 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then stirred at ambient temperature for 18 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: B(F)(F)F.CCOCC.[Cl:10][C:11]1[C:16]2[C:17]3([CH2:29][O:28]3)[C:18]3[C:23]([C:24]4([CH2:26][O:25]4)[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[C:22]([Cl:27])[CH:21]=[CH:20][CH:19]=3>C1(C)C=CC=CC=1>[Cl:10][C:11]1[C:16]2[CH:17]([CH:29]=[O:28])[C:18]3[C:23](=[C:22]([Cl:27])[CH:21]=[CH:20][CH:19]=3)[CH:24]([CH:26]=[O:25])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc2c1C1(CO1)c1cccc(Cl)c1C21CO1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=CC1c2cccc(Cl)c2C(C=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 0.1 ml. of boron fluoride etherate in 100 ml. of anhydrous toluene is added 500 mg. of 1',5'-dichloro-dispiro[oxirane-2,9'(10'H)-anthracene-10',2"oxirane]. The mixture is stirred at room temperature for 6 hours and filtered. The filtrate is washed twice with 10 ml. portions of a mixture of 10 ml. of saturated sodium bicarbonate and 10 ml. of ice water, dried over anhydrous sodium sulfate and filtered. The toluene is removed by water pump evacuation at 30° C. to give 0.5 g. of the desired product as a pale yellow solid, mp. 160°-172° C.
Reaction SMILES: CSCS(C)=O.[OH-].[Na+].C([O:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][CH3:27])=[C:21]([CH:24]=1)[CH:22]=O)C1C=CC=CC=1.[C:28]([O:31][CH2:32]C)(=[O:30])C>>[CH2:26]([O:25][C:20]1[CH:19]=[CH:18][C:17]([OH:16])=[CH:24][C:21]=1[CH2:22][C:28]([O:31][CH3:32])=[O:30])[CH3:27]
Reactant: CCOc1ccc(OCc2ccccc2)cc1C=O
Reactant: CCOC(C)=O
Agent: CSCS(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc(O)cc1CC(=O)OC
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
A mixture of methyl methylthiomethyl sulfoxide. (0.30 g) and finely triturated sodium hydroxide (0.015 g) was stirred at 70° C. for 30 min. To the reaction mixture was added 5-benzyloxy-2-ethoxybenzaldehyde (0.30 g), and the mixture was further stirred at 70° C. for 1.5 hrs. To the reaction mixture was added ethyl acetate, and the organic layer was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. A mixture of the obtained residue and 10% hydrogen chloride-methanol (15 mL) was heated under reflux for 15 hrs. To the reaction mixture was added ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-(2-ethoxy-5-hydroxyphenyl)acetate as a colorless oil (0.11 g, 44%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:18]([O:20][CH2:21]C)=[O:19])[CH:10]=[C:11]([CH:17]=1)[C:12]([O:14]CC)=[O:13])(=[O:4])=[O:3].[OH-].[Na+]>C1COCC1.CO.O>[CH3:21][O:20][C:18]([C:9]1[CH:10]=[C:11]([CH:17]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1)[C:12]([OH:14])=[O:13])=[O:19]
Reactant: CCOC(=O)c1cc(CNS(C)(=O)=O)cc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(CNS(C)(=O)=O)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To a solution of 901 mg (2.73 mmol) of diethyl 5-(methylsulfonamidomethyl)isophthalate in 10 mL of THF and 10 mL of MeOH was added 115 mg of NaOH in 2.7 mL of H2O. After the solution was stirred at r.t. for 50 h, the solution was concentrated, and H2O and CHCl3 were added. The aqueous layer was acidified to pH=1-2 with 1N HCl and extracted with the extract of (40 mL of CHCl3: 5 mL of MeOH, and 5 mL of H2O) several times. The combined extracts were dried over Na2SO4, filtered, and concentrated to give crude 3-(methoxycarbonyl)-5-(methylsulfonamidomethyl)benzoic acid which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[CH2:23](Br)[CH:24]=[CH2:25].[H-].[Na+]>CN(C)C=O>[CH2:25]([O:8][C:7]1[C:2]([Br:1])=[CH:3][C:4]([F:22])=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])[CH:6]=1)[CH:24]=[CH2:23]
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Br)cc1F
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Br

Procedure:
using 1-(4-bromo-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and allyl bromide with sodium hydride in dimethylformamide there is obtained 1-(5-allyloxy-4-bromo-2-fluorophenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone. m.p. 107°-110° C.;
Reaction SMILES: Br[C:2]1[N:12]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH3:20])[CH2:16][CH2:15]2)[C:5]2[C:6]([Cl:11])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=2[N:3]=1.[C:21]1([C@@H:27]2[CH2:32][O:31][CH2:30][CH2:29][NH:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[F-].[K+].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:11][C:6]1[C:5]2[N:12]([CH2:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([CH3:20])[CH2:16][CH2:15]3)[C:2]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][C@H:27]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:3][C:4]=2[CH:9]=[C:8]([Cl:10])[N:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(Cl)nc(Cl)c32)CC1
Reactant: c1ccc([C@@H]2COCCN2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(Cl)c32)CC1
Temperature: 100 °C

Procedure:
To a vial were added 2-bromo-4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (3.13 g, 8.30 mmol), (R)-3-phenylmorpholine (purchased from Beyond Pharmatech) (2.71 g, 16.6 mmol), potassium fluoride (2.41 g, 41.5 mmol), DMSO (25.5 mL), and N,N-diisopropylethylamine (7.25 mL, 41.5 mmol). The vial was sealed and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% ethyl acetate/hexanes, linear gradient) to afford 4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine. MS ESI calc'd. for C24H28Cl2N4O [M+H]+ 459. found 459.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Cl)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[Si:22]([O:29][CH2:30][CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].ClC1C=C(NC2C=CN(C(C)C)N=2)C2N(C(C(NC3C=CN=CC=3F)=O)=CN=2)N=1>CO>[Si:22]([O:29][CH2:30][CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:4]2[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=[C:2]([Cl:1])[CH:3]=2)=[N:33]1)([C:25]([CH3:28])([CH3:26])[CH3:27])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Cl)cc(Cl)nn12
Agent: CC(C)n1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1

Procedure:
Compound 50A was prepared from 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-pyrazol-3-amine in a similar way as 48A. HPLC Rt=3.891 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=531.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:30]([NH:39][CH3:40])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@H:30]([N:39]([CH3:40])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:18])[CH3:17])[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2002079134) (0.88 g, 2.76 mmol) in CH2Cl2 (2 ml) was added drop wise to a stirred solution of rac-((3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-yl)-methyl-amine (0.72 g, 2.70 mmol) and ethyl-diisopropyl-amine (0.64 ml, 3.76 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 1 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:4) yielded 1.05 g (74%) of the title product as colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.Br[C:22]1[N:23]=[C:24]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[C:35]([O:42][CH3:43])[CH:34]=2)=[O:32])[N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12>O1CCOCC1.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>[CH3:43][O:42][C:35]1[CH:34]=[C:33]([C:31]([C:24]2[N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]3=[C:22]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:23]=2)=[O:32])[CH:38]=[CH:37][C:36]=1[N+:39]([O-:41])=[O:40]
Reactant: COc1cc(C(=O)c2nc(Br)c3ccccn23)ccc1[N+](=O)[O-]
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nc(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)n3ccccc23)cc1

Procedure:
0.447 g (0.003 mol) of 4-methoxyphenylboronic acid, 2.24 g (0.009 mol) of K3PO4.H2O and then 0.131 g (0.011 mol) of tetrakis(triphenylphosphine)palladium(0) are added to 0.850 g (0.023 mol) of (1-bromoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone obtained in example 20 in 30 ml of dioxane under an argon atmosphere. The mixture is heated at reflux for 1 hour. The reaction medium is poured onto water and extracted with ethyl acetate. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The product is purified by filtration through silica gel, elution being carried out with a dichloromethane/cyclohexane (2/1) mixture and then with dichloromethane. After evaporation, 0.850 g of an orange solid is collected. Melting point: 185° C.; 1H NMR (d6-DMSO): 3.85 (3H, s), 4.06 (3H, s), 7.12 (2H, d), 7.41-7.44 (1H, m), 7.54-7.58 (1H, m), 7.95 (2H, d), 8.08-8.10 (2H, m), 8.34 (1H, d), 8.36 (1H, s), 9.81 (1H, d)
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[S:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[F:15][C:16]1[CH:26]=[C:25]([NH2:27])[CH:24]=[C:23]([F:28])[C:17]=1[C:18]([O:20][CH2:21]C)=[O:19]>>[F:15][C:16]1[CH:26]=[C:25]([NH:27][C:12]([C:6]2[S:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:24]=[C:23]([F:28])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCOC(=O)c1c(F)cc(N)cc1F
Reactant: CC(C)c1cc(C(=O)O)sc1C(C)C
Product: COC(=O)c1c(F)cc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1F
Yield: 61.2 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylthiophene-2-carboxylic acid (80 mg, 0.377 mmol) and ethyl 2,6-difluoro-4-aminobenzoate (137 mg, 0.681 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [n-hexane-ethyl acetate (40:1)] to obtain methyl 2,6-difluoro-4-[(4,5-diisopropylthiophene-2-carbonyl)amino]benzoate (88 mg, 59%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:43])[CH2:32][N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][O:41]C)[CH2:35][CH2:34]4)[CH:25]=3)=[CH:22][C:15]=2[N:14]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:43])[CH2:32][N:33]4[CH2:34][CH2:35][N:36]([CH2:39][CH2:40][OH:41])[CH2:37][CH2:38]4)[CH:25]=3)=[CH:22][C:15]=2[N:14]=1
Reactant: COCCN1CCN(CC(=O)Nc2cc(Oc3ccc4c(c3)nc(Nc3cc(C(F)(F)F)ccc3F)n4C)ccn2)CC1
Solvent: ClCCl
Product: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(NC(=O)CN4CCN(CCO)CC4)c3)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamide (1 eq) in methylene chloride at −78° C. was added 1M borontribromide in methylene chloride (10 eq) and the resulting mixture was stirred at −78° C. for 1 h. It was then brought to ambient temperature and stirred for 2 h. LC/MS showed formation of the product. The reaction was quenched with saturated sodium carbonate solution at 0° C. The mixture was concentrated and then brought to pH=9. It was then extracted with ethyl acetate and the organic layer was dried with sodium sulfate and concentrated and purified on preparative chromatography to yield N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide. MS: MH+=588.6.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:22][CH:23]1[CH2:27][CH2:26][NH:25][CH2:24]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[Na])(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][CH:23]1[CH2:27][CH2:26][N:25]([C:2]2[C:3]([CH:8]3[CH2:11][N:10]([C:12]4[CH:21]=[CH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH2:9]3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:24]1
Reactant: Brc1cccnc1C1CN(c2ccc3ccccc3n2)C1
Reactant: CC1CCNC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1CCN(c2cccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a solution of 2-[3-(3-bromo-pyridin-2-yl)-azetidin-1-yl]-quinoline (339 mg, 1 mmol), 3-methyl-pyrrolidine (93.5 mg, 1.1 mmol), BINAP (31.1 mg, 0.05 mmol), t-BuONa (196 mg, 2 mmol) in dioxane (25 mL) was added Pd2(dba)3 (45.75 mg, 0.05 mmol) then the reaction mixture was stirred at 90° C. under nitrogen atmosphere overnight. The reaction mixture was filtered through CELITE® and washed with EtOAc (50 mL). The filtrate was concentrated and the crude product was purified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether) to give 2-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyridin-2-yl]-azetidin-1-yl}-quinoline (64 mg, 0.19 mmol, yield 19%).
Reaction SMILES: C1[O:17][C:4](OC)([CH2:5][CH2:6][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)OC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[K+].C1C[O:30][CH2:29][CH2:28]1>>[CH2:28]1[O:14][C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([CH2:6][CH2:5][CH2:4][OH:17])[O:30][CH2:29]1
Reactant: C1CCOC1
Reactant: COC1(CCC(=O)c2ccccc2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Product: OCCCC1(c2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 19 h
Yield: 93 %

Procedure:
A solution of methyl 3-benzoylpropionate ethylene ketal (7.9661 g, 33.7 mmol), prepared in the previous step in 150 ml of anhydrous THF was added under nitrogen dropwise over 1 hour to a suspension of LAH (1.6656 g, 43.9 mmol) in 75 ml of anhydrous THF. After the addition the mixture was stirred at room temperature for 19 hours. Water (1.7 ml) was then added dropwise followed by the addition of 1.7 ml of 15% KOH and then 5.1 ml of water. The resulting mixture was stirred for 15 minutes and then filtered. The filtrate was concentrated under reduced pressure to remove most of the THF. The residue was partitioned between methylene chloride-water. The organic layer was separated and the aqueous layer extracted two times with methylene chloride. The combined organic extracts were dried (MgSO4) and the solvent removed under reduced pressure to give 4-hydroxybutyrophenone ethylene ketal (6.51 g, 93%) as a white solid, mp 39-42° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[CH:15]/[C:16]2[N:17]=[CH:18][S:19][CH:20]=2)=[CH:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][CH2:15][C:16]2[N:17]=[CH:18][S:19][CH:20]=2)=[CH:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=C/c1cn(-c2ccccc2)nc1OCc1ccccc1)\c1cscn1
Agent: [Pd]
Solvent: C1CCOC1
Product: c1ccc(COc2nn(-c3ccccc3)cc2CCc2cscn2)cc1
Yield: 71.2 %

Procedure:
4-[(E)-2-(3-Benzyloxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-1,3-thiazole (0.81 g), 5% palladium on carbon (0.80 g) and tetrahydrofuran (80 mL) were subjected to catalytic reduction under a hydrogen atmosphere and atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:3, v/v) to give 4-[2-(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)ethyl]-1,3-thiazole as a colorless oil (0.58 g, yield 70%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4]O.[Br:13]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:13][CH2:4][C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(F)c(CBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-fluoro-5-nitrobenzyl alcohol (1 g, 5.84 mmol) in 25 mL ether, was added tetrabromomethane (3.87 g, 11.7 mmol), followed by triphenylphosphine (3.39 g, 11.7 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was concentrated and the crude residue purified by column chromatography (silica, 10% EtOAc/hexane) to give pure 2-bromomethyl-1-fluoro-4-nitro-benzene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].Cl>[OH-].[Na+]>[C:15]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
In a 2 N-aqueous solution of sodium hydroxide (500 ml) was dissolved 11-aminoundecanoic acid (30.2 g, 0.15 mol) under mild heating (50° C.). With intense stirring, carbobenzoxy chloride (30.7 g, 0.18 mol) was added in 4 installments over a period of 30 minutes, after which the mixture was stirred for 2 hours. The reaction mixture was cooled with ice, adjusted to pH 2 with 6 N-hydrochloric acid and extracted with ethyl acetate (600 ml). The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and petroleum ether was added to the crystalline residue. After cooling, the crystals were recovered by filtration. By the above procedure there was obtained 36.0 g of N-carbobenzoxy-11-aminoundecanoic acid. m.p. 96°-97° C.; Rf1 =0.67.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1.CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O>C1CCCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:27])=[O:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:16]=1
Reactant: OCc1cc(F)c(-c2ccc(OCc3ccccc3)cc2)c(F)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(F)c(-c2ccc(OCc3ccccc3)cc2)c(F)c1

Procedure:
An oxidation was carried out with 107 mg of the product of Stage B, with Jones' reagent under the conditions as described in Example 2, Stage C to obtain 86 mg of the expected product with a Rf=0.06 cyclohexane/ethyl acetate 7/3).
Reaction SMILES: [CH:1]1([N:4]2[CH:9]3[CH2:10][CH2:11][CH:5]2[CH2:6][C:7](=O)[CH2:8]3)[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl.[NH2:20][OH:21]>C(O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH:1]1([N:4]2[CH:9]3[CH2:10][CH2:11][CH:5]2[CH2:6][C:7](=[N:20][OH:21])[CH2:8]3)[CH2:3][CH2:2]1
Reactant: O=C1CC2CCC(C1)N2C1CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1CC2CCC(C1)N2C1CC1
Temperature: 23 °C
Yield: 84 %

Procedure:
A mixture of 8-cyclopropyl-8-aza-bicyclo[3.2.1]octan-3-one (CAS no: 60206-33-9) (17.86 g, 108.08 mmol) in ethanol (500 mL) with pyridine (13.05 mL, 162.1 mmol) and hydroxylamine hydrochloride (9.764 g, 140.51 mmol) was refluxed overnight. Cooled to 23° C., filtered off, washed with ethanol and ether and dried in vacuum to give a white solid, which was suspended in 200 mL sat. Na2CO3 solution and extracted 3 times with dichloromethane, the combined organic layers were dried over Na2SO4, filtered off and evaporated totally, dried in high vacuum to give the title compound as white crystals (16.3 g, 84%); MS: m/e=181.2 (M+H+).