Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[CH:10]([Cl:13])([Cl:12])[Cl:11]>>[C:10]([C:4]([CH:3]([C:2]([F:9])([F:8])[F:1])[F:7])([F:6])[F:5])([Cl:13])([Cl:12])[Cl:11]
Reactant: ClC(Cl)Cl
Reactant: FC(F)=C(F)C(F)(F)F
Product: FC(C(F)(F)F)C(F)(F)C(Cl)(Cl)Cl
Temperature: 290 °C

Procedure:
A 0.5 inch (12.7 mm) by 40 inch (101.6 cm) plug flow reactor that is packed with Helipack Monel support is heated to 290° C. A 50/50 (molar %) mixture of hexafluoropropene and chloroform is fed into the reactor at about 1.5 g/min. The reactor pressure is maintained at 100 psig. The effluent from the reactor is fed into a distillation column and the unreacted reagents removed by distillation and recycled. The product CCl3CF2CHFCF3 is used in the next reaction.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]1[CH:15]=[N:16][N:17]([CH2:19][CH:20]([OH:24])[CH2:21][O:22][CH3:23])[CH:18]=1)=[CH:9][CH:8]=2.I[CH3:26]>C1COCC1>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]1[CH:15]=[N:16][N:17]([CH2:19][CH:20]([O:24][CH3:26])[CH2:21][O:22][CH3:23])[CH:18]=1)=[CH:9][CH:8]=2
Reactant: COCC(O)Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1)OC
Reaction time: 0.25 h

Procedure:
NaH (60%, 3.5 mg) was added to a solution of racemic 1-(4-(3-chloroisoquinolin-6-yl)-1H-pyrazol-1-yl)-3-methoxypropan-2-ol (Preparation 36, 20 mg, 0.063 mmol) in THF (4 mL). After stirring for 15 minutes, iodomethane (20 uL, 0.32 mmol) was added. The resulting solution was stirred at 60° C. under microwave irradiation for 60 minutes. The reaction mixture was extracted with EtOAc, dried over sodium sulphate and concentrated in vacuo. The residue was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[N-:8]([C:11]#[N:12])[C:9]#[N:10].[Na+]>CC(O)C>[CH2:1]([NH:6][C:11]([NH:8][C:9]#[N:10])=[NH:12])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCCNC(=N)NC#N
Yield: 67.9 %

Procedure:
Pentylamine (17.43 g, 0.20 mol) in 2-propanol (175 ml) was acidified with conc. HCl (17 ml, 0.204 mol) and then treated with sodium dicyanamide (23.15 g, 0.26 mol). The mixture was refluxed for 20 hours, allowed to cool and filtered through diatomaceous earth. The filtrate was concentrated in vacuo and the residue dissolved in chloroform. This solution was washed with water and dried over magnesium sulfate. Filtration and evaporation in vacuo gave 20.93 g (67.9%) of off-white solid; mass spec.: M+ at 154.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:39]=[C:38]([O:40][CH3:41])[C:37]([F:42])=[CH:36][C:11]=1[C:12]([CH:14](C(OCC)=O)[C:15]([O:17][CH:18](C1C=CC=CC=1)[C:19]1C=CC=CC=1)=[O:16])=[O:13].FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:39]=[C:38]([O:40][CH3:41])[C:37]([F:42])=[CH:36][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13]
Reactant: CCOC(=O)C(C(=O)OC(c1ccccc1)c1ccccc1)C(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)CC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Yield: 94.2 %

Procedure:
In 2 ml of anisole was dissolved 200 mg of diphenylmethyl ethyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoylmalonate, and 2 ml of trifluoroacetic acid was added thereto with ice-cooling, after which the resulting mixture was subjected to reaction at the same temperature for 10 minutes. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 120 mg (yield 94.3%) of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([C:15]3[N:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]=[CH:18][N:19]=3)(O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-:28].[Cl-].[Cl-].[OH-].[Na+]>>[ClH:28].[ClH:28].[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH2:20][N:16]4[CH:17]=[CH:18][N:19]=[C:15]34)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1(c2nccn2Cc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [Cl-]
Agent: [Al+3]
Agent: [Na+]
Agent: [OH-]
Product: Cl
Product: c1ccc(CN2CCC3(CC2)c2ccccc2Cn2ccnc23)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 1.8 %

Procedure:
1-(phenylmethyl)-4-[1-(phenylmethyl)-1H-imidazol-2-yl]-4-piperidinol (0.124 mol) and AlCl3 (0.31 mol) were stirred in a melt at 120° C. for 1 h. The mixture was cooled, AlCl3 (0.31 mol) was added and the mixture was stirred at 120° C. for 1 h. The mixture was poured into ice, alkalized with NaOH 50% and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered off and evaporated. The residue was purified by HPLC (eluent: CH2Cl2/(CH3OH/NH3)99/1). The pure fractions were collected and evaporated. The residue was converted into the hydrochloric acid salt (1:2) in (C2H5)2O, yielding 0.91 g of 1′-(phenylmethyl)spiro[imidazo[1,2-b]isoquinoline-10[5H],4′-piperidine]dihydrochloride.dihydrate (2%) (interm. 3; mp. 161.2° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][N:13]([CH3:14])[C:7]2=[N:6][C:5]=1[CH3:15].[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[N:23]=[C:22]1[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:17].[C:37](=[O:40])([O-:39])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[C:9]([OH:10])(=[O:18])/[CH:4]=[CH:5]/[C:37]([OH:39])=[O:40].[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[N:23]=[C:22]1[CH2:30][N:31]1[CH2:32][CH2:33][N:34]([CH2:2][CH2:3][C:4]2[C:9](=[O:10])[N:8]3[CH:11]=[CH:12][N:13]([CH3:14])[C:7]3=[N:6][C:5]=2[CH3:15])[CH2:35][CH2:36]1)[CH3:17]
Reactant: Cc1nc2n(C)ccn2c(=O)c1CCCl
Reactant: CCOCCn1c(CN2CCNCC2)nc2cccnc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCOCCn1c(CN2CCN(CCc3c(C)nc4n(C)ccn4c3=O)CC2)nc2cccnc21
Product: O=C(O)/C=C/C(=O)O
Reaction time: 44 h
Yield: 47.3 %

Procedure:
A mixture of 2.7 parts of 6-(2-chloroethyl)-1,7-dimethyl-1H,5H-imidazo[1,2-a]pyrimidin-5-one, 2.9 parts of 3-(2-ethoxyethyl)-2-(1-piperazinylmethyl) -3H-imidazo[4,5-b]pyridine, 1.06 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone was stirred first for 44 hours at reflux temperature and then over weekend at room temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the (E)-2-butenedioate salt in 2-propanol. The salt was filtered off and dried, yielding 3.36 parts (47.3%) of 6-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]methyl]1-piperazinyl]ethyl]-1,7-dimethyl-1H, 5H-imidazo[1,2-a]pyrimidin-5-one (E)-2-butenedioate(1:2); mp. 162.5° C. (compound 81).
Reaction SMILES: [CH2:1]([N:8]([C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH3:50])([CH2:44][O:45]S(C)(=O)=O)[C:12]1=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:62]1(O)[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([N:8]([C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH3:50])([CH2:44][O:45][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:12]1=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(COS(C)(=O)=O)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(COc1ccccc1)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 29.3 %

Procedure:
A solution of tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-2-{[(methylsulfonyl)oxy]methyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate (170 mg), phenol (18 mg) and cesium carbonate (186 mg) in N,N-dimethylformamide (2 ml) was stirred at 80° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (49 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([Br:18])=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=[O:6])[CH3:2].[N+:20]([O-])([OH:22])=[O:21]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[C:9]([N+:20]([O-:22])=[O:21])=[CH:10][C:11]([Br:18])=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=[O:6])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc(Br)c2cccnc12
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2cccnc12
Yield: 45 %

Procedure:
A solution of the product from Example 82 (23.5 g, 58 mmol) in 30 mL fuming nitric acid and 150 mL trifluoroacetic acid was heated at 80° C. for 18 hours. The solvent was removed and the residue was treated with water to give a solid. The solid was collected by filtration and washed with ether and dried to give the title compound (9.5 g, 45% yield).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[Na].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[CH3:12][C:13]([C:16]1[CH:21]=[C:20]([SH:22])[CH:19]=[C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[OH:27])([CH3:15])[CH3:14]>C(O)C.O>[CH3:26][C:23]([C:18]1[CH:19]=[C:20]([S:22][CH2:7][CH:9]([OH:11])[CH2:10][S:1][CH2:2][C:3]([OH:5])=[O:4])[CH:21]=[C:16]([C:13]([CH3:15])([CH3:14])[CH3:12])[C:17]=1[OH:27])([CH3:24])[CH3:25]
Reactant: O=C(O)CS
Reactant: ClCC1CO1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(SCC(O)CSCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
Mercaptoacetic acid (1.32 g, 0.0144 mole) was added to a solution of ethyl alcohol (100 ml) containing sodium (0.66 g, 0.029 mole). The solution was stirred for 30 minutes and epichlorohydrin (1.33 g, 0.0144 mole) was added by syringe. A solution of the sodium salt of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol prepared from 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (3.43 g, 0.0144 mole) and sodium (0.33 g, 0.0144 mole) in ethyl alcohol (50 ml) was added dropwise and the reaction stirred for 72 hours at room temperature. Water (50 ml) was added and the ethyl alcohol removed using a rotary evaporator. The product was extracted into ethyl acetate, dried over sodium sulfate, filtered and concentrated. The product was isolated as an oil by chromatography on silica. The structure was confirmed by its NMR and IR spectra.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12](B(O)O)=[CH:13][CH:14]=[CH:15][CH:16]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Brc1cccc2[nH]ccc12
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2-c2cccc3[nH]ccc23)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a mixture of 4-bromoindole (1 g, 5 mmol), and 2-biphenylboronic acid (1 g, 5 mmol) in THF (17 mL) were added Palladium catalyst Pd(PPh3)4 (0.2 g, 0. 17 mmol) and the freshly prepared sodium hydroxide solution (0.6 g, 15 mmol in 7 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified on a silica gel column to give 1.26 g (93%) of 4-biphenyl-2-yl-1H-indole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[C:33]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=1)#[CH:34]>C(N(CC)CC)C.CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:34]#[C:33][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=3)[CH:17]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:19]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: C#Cc1ccc(CO)cc1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C

Procedure:
(4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester (270 mg; 0.46 mmol), (4-ethynyl-phenyl)-methanol (296 mg; 2.2 mmol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg; 0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 110° C. for 1.5 h. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were dried and evaporated to dryness and purified by preparative HPLC (method B). Yield: 270 mg (83%). HPLC-MS: m/z: 587.1 (M+H)+; Rt: 2.96 min.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[S:5][CH:6]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:23][C:9]1[N:8]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([C:28]3[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=3)[N:3]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(Br)cs2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3cnc(N)nc3)cs2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-thiazol-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.80) (0.20 g, 0.50 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.133 g, 0.60 mmol) according to the general procedure VI. Obtained as a white solid (0.100 g, 48%/o). MS (ISP) 414.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.CCOCC>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-:21])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc2c(Br)cncc2c1
Solvent: ClCCl
Solvent: CCOCC
Product: [O-][n+]1cc(Br)c2ccc(Cl)cc2c1
Temperature: 25 °C

Procedure:
4-bromo-7-chloroisoquinoline (3-6)(1 g, 4.12 mmol, 1.0 equiv.) was dissolved in anhydrous CH2Cl2 (8.2 mL) and treated with mCPBA (1.622 g, 9.40 mmol, 2.3 equiv.). The reaction mixture was stirred at room temperature, forming 3-7 as a white precipitate. Following dilution with Et2O, the solid was collected and used without further purification in the next step. LRMS m/z (M+H) 260.1 found, 259.9 required.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:16]1[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[NH3:8].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ncccc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1OC1CCN(Cc2ccccc2)CC1
Product: N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Benzyl-4-hydroxypiperidine (1.5 g, 7.8 mmol) and 3-hydroxy-2-methylpyridine (1.75 g, 16 mmol) were added to mixture of polymer supported triphenylphosphine (1 g, 3 mmol) and di-tert-butyl azodicarboxylate (3.61 g, 16 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 3 hours. Trifluoroacetic acid (16 mL) was then added and the mixture was stirred for a further hour then concentrated in vacuo. The residue was suspended in dichloromethane and basified with 2M sodium hydroxide solution (5 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 90:10:1, to afford the title compound as a liquid in 51% yield, 1.12 g. 1H NMR (CDCl3, 400 MHz) δ: 1.79-1.88 (m, 2H), 1.90-2.01 (m, 2H), 2.25-2.41 (m, 2H), 2.44 (s, 3H), 2.64-2.78 (m, 2H), 3.53 (s, 2H), 4.28-4.39 (m, 1H), 7.00-7.09 (m, 2H), 7.19-7.38 (m, 5H), 8.14 (m, 1H); LRMS APCI m/z 283 [M+H]+
Reaction SMILES: [C:1]1([S:7]([N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[N:20][O:21][CH2:22][CH2:23][OH:24])[CH3:19])=[CH:14][CH:13]=2)[CH3:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:26]1[CH:58]=[CH:57][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[N:33]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]2=[O:56])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([S:7]([N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[N:20][O:21][CH2:22][CH2:23][O:24][C:26]3[CH:58]=[CH:57][C:29]([CH2:30][CH:31]4[S:35][C:34](=[O:36])[N:33]([C:37]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:32]4=[O:56])=[CH:28][CH:27]=3)[CH3:19])=[CH:14][CH:13]=2)[CH3:11])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Yield: 36.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 667 mg of 2-(1-{4-[N-(phenyl-sulfonyl)-N-methylamino]phenyl}ethylideneaminooxy)-ethanol (prepared as described in Preparation 37), 1.02 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 383 mg of diethyl azodicarboxylate, 554 mg of the title compound were obtained as a crystalline powder, melting at 143°-145° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:30])([CH3:29])[CH2:23][CH2:24][N:25]3[CH3:28])=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:28][N:25]1[C:26]2[C:21](=[CH:20][CH:19]=[C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:11]=[CH:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=3)[CH:27]=2)[C:22]([CH3:29])([CH3:30])[CH2:23][CH2:24]1
Reactant: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C)CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(C=Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)N(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 6 h
Yield: 46.8 %

Procedure:
A solution of 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoic acid methyl ester (0.23 g, 0.5 mmole) in 10 mL of a 1:1 THF/methanol mixture was treated with a solution of 0.09 g of lithium hydroxide monohydrate in 2.5 mL of water and stirred at 40° C. for 6 hours. The mixture was diluted with 10 mL of water and the pH adjusted to 2.0 with 2N HCl solution. The mixture was extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by preparative tlc (SiO2, 25% ethyl acetate in hexanes) to yield 0.095 g of 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoic acid as a pale yellow oil. MS (EI): (M+): 405.
Reaction SMILES: CN(C)C=O.[O:6]=[C:7]1[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:9][CH:8]1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[H][H]>[Ru].ClCCl.C1C=CC=CC=1.C1C=CC=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[OH:6][C@H:7]1[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:9][C@@H:8]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Reactant: [H][H]
Agent: Cl[Ru]Cl
Agent: [Ru]
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 99.5 °C
Reaction time: 0.17 h

Procedure:
90 mL of dehydrated N,N-dimethylformamide was added to 2.58 g of benzene ruthenium (II) chloride dimer (5.15 mmol) and 6.73 g of (S)-(−)-2,2,′-bis(diphenylphosphino)-1,1-binaphthyl (S-BINAP) (10.8 mmol). The mixture was stirred for 10 minutes in an oil bath at an external temperature of 97 to 102° C. in an argon atmosphere. Subsequently, the mixture was stood to be cooled at room temperature. Volatile materials were evaporated under reduced pressure in an oil bath at an external temperature of 50 to 60° C. to give a catalyst. 300 g of 1-benzyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (1.03 mol) and 500 mL of dehydrated dichloromethane were placed in an autoclave and the ruthenium catalyst dissolved in 850 mL of dehydrated dichloromethane was added. The mixture was stirred for 6 hours under a hydrogen pressure of 5 MPa at an external temperature of 50 to 62° C. Hydrogen was released and the reaction mixture was concentrated under reduced pressure. This gave 320 g of the title compound as a green oil. This product was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Reactant: ICC1CCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CC3CCCC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and iodomethylcyclopentane.