Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.Br[CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39]>>[F:37][C:35]1[CH:34]=[CH:33][C:32]([C:38]([F:39])([F:40])[F:41])=[C:31]([CH:36]=1)[CH2:30][O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(O)c4c3)cn2)CC1
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Product: Fc1ccc(C(F)(F)F)c(COn2ccc3ncc(-c4cnn(C5CCNCC5)c4)cc32)c1

Procedure:
The entitled compound is prepared from tert-butyl 4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate and 2-(bromomethyl)-4-fluoro-1-(trifluoromethyl)benzene as described in the last 2 steps of Example 18.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Cl:38])[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Cl:38])[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.1 g) and triethylamine (1.0 ml), and 3,4-dichlorobenzoyl chloride (1.0 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [F:1][CH:2]([F:47])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:22]([N:24]([CH:41]([CH3:43])[CH3:42])[C@H:25]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:28]([CH2:38][CH2:39][OH:40])[CH2:27][CH2:26]3)=[O:23])[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]=2[O:11][C:10]([CH3:45])([CH3:44])[C:9]1=[O:46])=[O:4].C[N+]1([O-])CCOCC1>C(Cl)Cl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:47][CH:2]([F:1])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:22]([N:24]([CH:41]([CH3:42])[CH3:43])[C@H:25]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[C@@H:28]([CH2:38][CH:39]=[O:40])[CH2:27][CH2:26]3)=[O:23])[C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=2[O:11][C:10]([CH3:45])([CH3:44])[C:9]1=[O:46])=[O:4]
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)C(F)F)[C@@H]1CC[C@H](CCO)N(C(=O)OC(C)(C)C)C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)C(F)F)[C@@H]1CC[C@H](CC=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 69 %

Procedure:
Under the nitrogen atmosphere, to a solution of tert-butyl (2R,5R)-5-[{[4-{2-[(difluoroacetyl)-amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]-2-(2-hydroxyethyl)piperidine-1-carboxylate (1.1 g) in methylene chloride -acetonitrile (5 ml, 5 ml) were added N-methylmorpholine oxide (283 mg) and molecular sieve 4 Å (750 mg), and the mixture was stirred at room temperature for a while. Then, tetrapropylammonium perruthenate (56 mg) was added thereto, and the mixture was stirred at room temperature for 3 hours. Then, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone=2/1) to give the title compound (757 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[CH:19]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2F)=[O:23])[CH2:21][CH2:20]1.C(O[K])(C)(C)C.O>CN(C)C(=O)C>[CH:19]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[O:23])[CH2:20][CH2:21]1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: O=C(c1cccc(F)c1F)C1CC1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1ccc(Nc2ncnc3ccc(Oc4c(F)cccc4C(=O)C4CC4)cc23)n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (70 mg; 0.290 mmol) and 63 mg (0.346 mmol) of cyclopropyl(2,3-difluorophenyl)methanone were added to a solution of 81 mg (0.723 mmol) of tert-butoxy potassium in 6 ml of N,N-dimethylacetamide and the mixture was stirred at 110° C. for 1 hour. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel chromatography (chloroform:methanol=10:1) to give 36 mg (yield: 31%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:9]=[CH:10][N:11](C)C)=[N:5][CH:6]=[CH:7][N:8]=1)#[N:2].N[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(O)(=O)C>C(O)C>[N:9]1[C:4]2[C:3](=[N:8][CH:7]=[CH:6][N:5]=2)[C:1]([NH:2][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:11][CH:10]=1
Reactant: CN(C)C=Nc1nccnc1C#N
Reactant: NCCc1ccc(O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc(CCNc2ncnc3nccnc23)cc1

Procedure:
To a solution of N′-(3-cyanopyrazin-2-yl)-N,N-dimethylformamidine (prepared as in Albert and Ohta, J. Chem. Soc. C 1971, 3727-3730, which is expressly incorporated by reference herein; 2.0 g, 11.4 mmol) in ethyl alcohol (EtOH; 50 mL) was added 4-(2-aminoethyl)-phenol (4.7 g, 34 mmol) and acetic acid (3.9 mL, 4.1 g, 68 mmol). The solution was heated to reflux for 19 h, concentrated in vacuo, and the residue was slurried with H2O and suction filtered. The filter cake was washed with H2O and dried in a vacuum oven (80° C., 0.5 torr) to yield 4-[2-(pteridin-4-ylamino)-ethyl]-phenol (2.7 g) as a white solid: mp>210° C.; 1H NMR (DMSO-d6) δ 9.20 (s, 1H), 9.08 (s, 1H), 8.94 (s, 1H), 8.95 (t, J=6.0 Hz, 1H), 8.82 (s, 1H), 8.64 (s, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.69 (d, J=8.2 Hz, 2H), 3.75 (t, J=6.2 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H); ESIMS m/z 268 (M+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=1.CCN(CC)CC.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:24]([O:14][C:9]1[C:8]([O:15][CH3:16])=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:11][C:10]=1[O:12][CH3:13])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc(-c2ccco2)cc(OC)c1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2ccco2)cc(OC)c1OC(=O)c1ccccc1
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of 4-(furan-2-yl)-2,6-dimethoxyphenol (1.3 g, 5.9 mmol) in anhydr CH2Cl2 (20 mL) under argon was added Et3N (1.6 mL, 11.5 mmol) then the mixture was cooled over an ice bath. Benzoyl chloride (0.75 mL, 6.4 mmol) was added dropwise and the reaction was stirred for 3 hrs. 10% aqueous NaHCO3 and CH2Cl2 were added, stirred, and the layers were separated. The organics were washed with H2O and saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. Purification by chromatography (0-25% EtOAc-hexanes) gave 4-(furan-2-yl)-2,6-dimethoxyphenyl benzoate as a light yellow solid (0.54 g isolated from chromatography of approximately half of the crude product; 57% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[F-:12].[Cs+]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][F:12])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1
Reactant: COc1cc(CCl)nc(N)n1
Reactant: [F-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(CF)nc(N)n1

Procedure:
A mixture of 17.0 parts of 2-amino-4-chloromethyl-6-methoxypyrimidine, 59.5 parts of caesium fluoride and 130 parts of dry dimethylformamide was stirred under reflux for 2 hours. The mixture was cooled and evaporated in vacuo. The residue was taken up in ethyl acetate and the solution was washed four times with water. The organic phase was dried with anhydrous magnesium sulphate, stirred with decolourising charcoal, filtered and evaporated. The crude product was purified by chromatography on silica, eluted with ethyl acetate to give 2-amino-4-fluoromethyl-6-methoxypyrimidine m.p. 119°-121° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C@H:19]1[CH2:21][O:20]1>CO>[O:20]1[CH2:21][C@H:19]1[CH2:18][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: ClC[C@H]1CO1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc2c(c1)CCN(C[C@@H]1CO1)C2
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 1,2,3,4-tetrahydroisoquinoline (1 g, 7.52 mmol) in MeOH (40 mL) was added K2CO3 (5.19 g, 37.6 mmol) under 0° C. After stirring for 30 minutes, (R)-2-(chloromethyl) oxirane (0.692 g, 7.52 mmol) was added the reaction. The mixture was then stirred at 0° C. overnight before filtration and washing of the solid by with MeOH. The solution was concentrated and the residue purified by column separation to give the title compound as a colorless oil (70% purity). This crude was used directly in the next step. LCMS (m/z): 190.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([NH:8][OH:9])=[O:7].[CH2:17]([C:19]([CH2:26][CH3:27])([C:23](Cl)=[O:24])[C:20](Cl)=[O:21])[CH3:18]>>[CH3:16][O:15][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH3:14])[C:6]([N:8]1[C:20](=[O:21])[C:19]([CH2:26][CH3:27])([CH2:17][CH3:18])[C:23](=[O:24])[O:9]1)=[O:7]
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Reactant: COc1cc(C(=O)NO)cc(OC)c1OC
Product: CCC1(CC)C(=O)ON(C(=O)c2cc(OC)c(OC)c(OC)c2)C1=O
Yield: 81.4 %

Procedure:
A mixture consisting of 2.27 g (0.0100 mol) of 3,4,5-trimethoxybenzohydroxamic acid (recrystallized from absolute ethanol prior to the reaction), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round-bottom flask. The mixture was cooled in an ice bath, and 2.00 g (0.0101 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period. The reaction mixture was stirred for one hour at room temperature after which time all of the hydroxamic acid had dissolved. The solution was extracted three times with 50 ml portions of water, four times 50 ml portions of 5% hydrochloric acid, and two times with 50 ml portions of 5% sodium carbonate. The methylene chloride solution was dried (MgSO4) and evaporated to dryness under reduced pressure to give 2.86g (81.5%) of crude 2-(3,4,5-trimethoxybenzoyl)-4,4-diethylisoxazolidine-3,5-dione; as a solid residue: mp 103-106° C. Recrystallization of 2.72 g of the crude product from 20 ml of absolute ethanol gave 2.14 g of 2-(3,4,5-trimethoxybenzoyl)-4,4-diethylisoxazolidine-3,5mp 107- 109.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6]([CH3:14])=[N:5]2.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C.S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6]([CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:5]2
Reactant: Cc1nc2cc(F)c(F)cc2[nH]c1=O
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(F)c(F)cc2nc1C=Cc1ccccc1
Temperature: 85 °C
Yield: 86.2 %

Procedure:
6,7-Difluoro-3-methyl-1H-quinoxalin-2-one (2 g, 10.2 mmol) was dissolved in a mixture of glacial acetic acid (40 ml) and 98% sulfuric acid (4 ml). Benzaldehyde (1.08 g, 10.2 mmol) was added and the resulting mixture was stirred at reflux temperature for 3.5 hours. The mixture was allowed to cool to 85° C. and then poured onto ice (400 ml). The solid was filtered, washed with water and ethyl acetate and dried in vacuo at 30° C. overnight to afford 2.5 g (88%) of 6,7-difluoro-3-styryl-1H-quinoxalin-2-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.Br[C:11]1[C:19]2[S:18][CH:17]=[CH:16][C:15]=2[C:14]([F:20])=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCOCC1.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>[F:20][C:14]1[C:15]2[CH:16]=[CH:17][S:18][C:19]=2[C:11]([B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:9])([CH3:1])[O:3]2)=[CH:12][CH:13]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Fc1ccc(Br)c2sccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1(C)OB(c2ccc(F)c3ccsc23)OC1(C)C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (768 mg, 6 mmole) was added drop wise to a solution of 7-bromo-4-fluoro-1-benzothiophene BL (462 mg, 2.0 mmole) and triethylamine (607 mg, 6 mmole) in 12 mL dioxane. The solution was bubbling with argon with stirring for 10 min. PdCl2(PPh3)2 (70 mg, 0.01 mmole) was added to the reaction and continued to bubbling argon for another 10 min. The reaction was heated to 80° C. for 4 hr and cooled down to 25° C. Dioxane was removed in vacuo the residue dissolved in 60 mL Et2O washed with water (60 mL), brine (20 mL), dried (Na2SO4), filtered, concentrated in vacuo, and purified by CombiFlash silica gel column chromatography (eluted with Hexane/EtOAc stepping gradient 100:0 to 80:20) to yield 295 mg (53%) of product.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:22](=[O:24])[NH2:23])[CH2:17][CH2:18][CH2:19][C:20]=3[CH:21]=2)[CH:11]=1)C.[OH-].[Li+]>CCO.O>[C:22]([N:16]1[C:15]2[N:14]=[CH:13][C:12]([C:10]3[CH:11]=[C:6]([CH2:5][C:4]([OH:25])=[O:3])[CH:7]=[N:8][CH:9]=3)=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)(=[O:24])[NH2:23]
Reactant: CCOC(=O)Cc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCCc2cc(-c3cncc(CC(=O)O)c3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
A mixture of [5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-acetic acid ethyl ester (1.0 g, 2.9 mmol) and lithium hydroxide (123 mg, 5.1 mmol) in EtOH (10 mL) and H2O (10 mL) are stirred at room temperature for 16 h. The reaction is concentrated to remove the EtOH and the remaining aqueous mixture is treated with 1N HCl and diluted with EtOAc. The solid formed is filtered, rinsed and dried to give 500 mg of the titled product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1.CC(C)([O-])C.[K+].CN1CCCC1=O>O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][O:14][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][CH:10]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Fc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Brc1ccc(COc2ccccn2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-fluoropyridine (1.6 g), 4-bromobenzyl alcohol (3.08 g), potassium tert-butoxide (2.03 g) and N-methylpyrrolidone (12.8 ml) was heated at 100° C. by microwave irradiation for one minute. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. 2-(4-Bromobenzyloxy)pyridine was obtained in this way.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)(Cl)Cl)=[CH:4][CH:3]=1.Cl.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:21][C:15]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=3[N:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1
Agent: Cl
Product: Clc1ccc(-c2nc3cc(Cl)ccc3o2)cc1

Procedure:
Compound XIV was prepared as in Example 12 at 180° C from p-chlorobenzotrichloride and 2-amino-4-chlorophenol hydrochloride, and purified through a preheated aluminum trioxide column: 16 g of raw product, M.P. 178°-183° C (61% of the theory). Upon recrystallization from benzene: M.P. 190°-192° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([C:19]#[N:20])=[C:8]2[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.[H-].[Na+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].O>CN(C)C=O>[C:19]([C:9]1[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:11][C:12]2[C:7]([C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[CH:6][C:5]([O:4][CH2:3][CH2:2][O:1][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:14][CH:13]=2)#[N:20]
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(OCCO)cc23)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(OCCOCC(=O)OC(C)(C)C)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of 6-(2-hydroxyethoxy)-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (1.0 g, 2.8 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 0.14 g, 3.4 mmol), and the mixture was stirred at room temperature for 1 hr. tert-Butyl bromoacetate (1 ml, 6.8 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 17 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2-{[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}ethoxy)acetate (0.9 g, yield 69%) as an oil.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]([CH3:29])[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[O:19]
Reactant: CN(NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)C(=O)OC(C)(C)C
Yield: 97.6 %

Procedure:
To a solution of tert-butyl 2-{[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate 177 (0.29 g, 0.72 mml) in methanol (15 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate 178 (0.22 g, 98%) as a colorless foam.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1)[C:2]([CH3:4])=O.[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:21][NH2:22]>>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([CH:20]([OH:19])[CH2:21][NH:22][CH:2]([CH3:4])[CH2:1][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:8][CH:7]=2)=[CH:28][CH:27]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Reactant: NCC(O)c1ccc(OCc2ccccc2)cc1
Product: CC(COc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)c1ccc(OCc2ccccc2)cc1

Procedure:
6-[4-[2-[(4-Benzyloxy-β-hydroxyphenethyl)amino]-propyloxy]phenyl]-4,5-dihydro-3(2H)pyridazinone was prepared from 4,5-dihydro-6-(4-acetonyloxyphenyl)-3(2H)-pyridazinone and 2-hydroxy-2-(4-benzyloxyphenyl)ethanamine in an analogous manner to the compound described in Example 38. 1H NMR (DMSO-d6) ppm:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:15]
Reactant: NCCNCc1ncccn1
Reactant: CN=C=O
Product: CNC(=O)NCCNCc1ncccn1

Procedure:
By the procedure of Example 24, N-(2-pyrimidylmethyl)ethylenediamine is reacted with methyl isocyanate to give, after concentrating and separating the residue by column chromatography, the title compound.
Reaction SMILES: [I-].[Na+].I.[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17](Cl)=[N:16][C:15]([S:22][CH3:23])=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1>O1CCOCC1>[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=3)=[N:16][C:15]([S:22][CH3:23])=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CSc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
Sodium iodide (3.9 g, 26 mmol) and hydriodic acid (10 mL, 47% aqueous solution) were added to the solution of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidine (8.0 g, 26 mmol) and 4-aminobenzotrifluoride (5.06 g, 0.031 mol) in dioxane (100 mL) and the reaction solution was stirred at 100° C. overnight. Solid thus formed was filtered out, washed by ethyl acetate and diethyl ether and dried in vacuo. Product was obtained as white needle solid (8.2 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[N:16][CH:17]=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>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:17][N:16]=1
Reactant: Fc1ccc(Br)cn1
Reactant: OB(O)c1ccc(F)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+]
Product: Fc1ccc(-c2ccc(F)nc2)cc1
Yield: 84.2 %

Procedure:
The procedure described in Example 4, step 4.2 is followed. Starting from 2.0 g (14.29 mmol) of 4-fluorobenzeneboronic acid, 5.21 g (14.29 mmol) of 5-bromo-2-fluoropyridine, 0.82 g (0.71 mmol) of Pd(PPh3)4 and 50 ml of a 1M aqueous solution of sodium carbonate, 2.30 g of product is obtained in the form of a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]([OH:16])[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[S:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[S:3])[CH3:2]
Reactant: CC(=S)OCCCC[C@@H](O)c1cccnc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=S)OCCCC[C@@H](OS(C)(=O)=O)c1cccnc1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of (R)-5-hydroxy-5-(3-pyridyl)pentyl thioacetate (2.8 g) in dry dichloro- methane (15 ml) under a nitrogen atmosphere is cooled to -15° C. and treated with triethylamine (1.4 g) using a syringe. It is then treated with methanesulphonyl chloride (1.5 g) by syringe during 5 minutes. The temperature rises spontaneously to -8° C. during this addition. When the addition is complete the reaction mixture is allowed to warm to room temperature. After 2 hours it is washed with water (4×15 ml) until its pH is 7. The organic phase is then dried with magnesium sulphate, filtered and evaporated under reduced pressure, to give (R)-5-methanesulphonyloxy-5-(3-pyridyl)pentyl thioacetate (3.66 g), in the form of a yellow oil. This material is used in the next step without further purification.