Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:7]1([CH2:11][CH2:10][NH:9][CH2:8]1)[CH2:6][CH:5]2[OH:15].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:23][CH2:24][CH2:25][C:26]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)OCC[O:27]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:7]1([CH2:11][CH2:10][N:9]([CH2:23][CH2:24][CH2:25][C:26]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[O:27])[CH2:8]1)[CH2:6][CH:5]2[OH:15]
Reactant: OC1CC2(CCNC2)c2ccc(Cl)cc21
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCCN1CCC2(CC(O)c3cc(Cl)ccc32)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15 g of 5-chlorospiro[indane-1,3'-pyrrolidin]-3-ol (mixture of diastereoismers of 50 % of the 1RS,3SR and 50 % of the 1RS,3RS isomer) are dissolved in 200 cc of dimethyl formamide and heated to 100° for 6 hours together with 18 g of sodium carbonate and 23 g of 2-(3-chloropropyl)-2-(p-fluorophenyl)-1,3-dioxolane. Filtration is subsequently effected, the filter residue is washed with chloroform and the organic phase is concentrated. The resulting yellow oil is taken up in 300 cc of chloroform and stirred at room temperature for 1 hour with 250 cc of 2 N hydrochloric acid. The reaction mixture is subsequently made alkaline with caustic soda solution while cooling, is extracted with chloroform and the chloroform phase is concentrated. The crude title compound is obtained together with the 1RS,3SR isomer as brown oil. After adding a solution of hydrogen chloride in ethanol, the 1RS,3RS form crystallizes alone. The hydrochloride form of the pure title compound has a M.P. of 203°-206° after recrystallization from ethanol/ether.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:19]([CH:20]=[O:21])=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=[C:16]2[C:8]=1[C:9](=[O:25])[CH2:10][C:11]1([O:15]2)[CH2:14][CH2:13][CH2:12]1)(=O)=O.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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:28][C:29]1[CH:34]=[CH:33][C:32]([C:7]2[C:19]([CH:20]=[O:21])=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=[C:16]3[C:8]=2[C:9](=[O:25])[CH2:10][C:11]2([O:15]3)[CH2:14][CH2:13][CH2:12]2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)c1cc2c(c(OS(=O)(=O)C(F)(F)F)c1C=O)C(=O)CC1(CCC1)O2
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+]
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC1(CCC1)O2
Reaction time: 8 h

Procedure:
Under argon, 4.00 g (9.84 mmol) of 6-formyl-7-isopropyl-4-oxo-3,4-dihydrospiro[chromen-2,1′-cyclobutan]-5-yl trifluoromethanesulfonate (Example 50A), 1.79 g (12.8 mmol) of 4-fluorophenyl-boronic acid, 3.55 g (16.73 mmol) of tripotassium phosphate and 1.25 g (1.08 mmol) of tetrakis(triphenylphosphine)palladium(0) are initially charged and the apparatus is flushed by repeated evacuation and venting with argon. 100 ml of abs. dioxane are then added, the apparatus is closed and the mixture is heated under reflux. After stirring overnight, the mixture is cooled and filtered through a layer of silica gel, the filter cake is washed thoroughly with ethyl acetate and the filtrate is concentrated. The residue is adsorbed on silica gel and chromatographed on a silica gel column (mobile phase: cyclohexane→cyclohexane/ethyl acetate 25:1). The crude product obtained is triturated with hot petroleum ether and cooled slowly, and the precipitate is filtered off with suction. This gives 3.2 g of the target compound in a purity of about 90%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:24]4[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:25]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2cccc(C(F)(F)F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (78 mg, 88%), MS (ISP) m/z=356.5 [(M+H)+], mp 279.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][C:44]([F:47])([F:46])[F:45]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]=2[N:3]1[CH2:43][C:44]([F:47])([F:46])[F:45]
Reactant: FC(F)(F)CBr
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC(F)(F)F)C(=O)CO4)cc2)CCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.106 mmol), potassium carbonate (44 mg, 0.318 mmol) and 2-bromo-1,1,1-trifluoroethane (0.193 mL, 2.121 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give an orange suspension. The reaction mixture was stirred at 80° C. for one hour. The reaction mixture was allowed to cool to room temperature, diluted with saturated sodium bicarbonate solution (5 mL) and extracted into dichloromethane (3×3 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as an off-white solid (31 mg, 53% yield). 1H-NMR (500 MHz, CDCl3) δ 7.38 (1H, s), 7.25-7.37 (7H, m), 7.17-7.23 (2H, m), 5.05 (1H, br s), 4.97 (2H, s), 4.63 (2H, q), 2.20-2.58 (4H, m), 2.00-2.15 (1H, m), 1.75-1.88 (1H, m), 1.10-1.50 (9H, br m). LCMS (Method A) RT=7.65 min, M+H+=554.05.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][NH:21][CH2:22]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][N:21]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCNC4)n2)cc1Cl
Reactant: CC(C)(C)OC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCN(CCC(=O)OC(C)(C)C)C4)n2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1,2,4-oxadiazole (0.1088 g, 0.294 mmol) in DMF (2.94 ml) (briefly heated to 40° C. for complete dissolution). K2CO3 (0.081 g, 0.588 mmol) and tert-butyl 3-bromopropanoate (0.046 ml, 0.276 mmol) was added and the mixture stirred at ambient temperature for 2 hrs. Additional tert-butyl 3-bromopropanoate (0.053 ml, 0.315 mmol) was added and the reaction was stirred at 60° C. over the weekend. Additional tert-butyl 3-bromopropanoate (0.053 ml, 0.315 mmol) was added and the reaction continued heated at 60° C. overnight. Additional K2CO3 (0.041 g, 0.294 mmol) was added, followed by tert-butyl 3-bromopropanoate (0.053 ml, 0.315 mmol). The reaction was heated at 60° C. overnight. The reaction mixture was filtered and the filtrate concentrated in vacuo to give ˜179 mg of crude yellow oil. The crude residue was purified via Analogix system using RediSep RS 12 g column, with a gradient of 0-45% EtOAc/Heptane over 35 min. at 15 mL/min. Fractions 23-28 were combined and concentrated to yield tert-butyl 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (91 mg, 0.183 mmol) as light yellow oil. LCMS (Table 1, Method c) Rt=3.39 min, m/z 500.72 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][C:12]([CH3:17])([C:14]#[C:15][CH3:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([C:14]1[NH:4][C:3]2[C:2]([C:15]=1[CH3:16])=[CH:8][CH:7]=[C:6]([O:9][CH3:10])[CH:5]=2)([CH3:17])([CH3:13])[CH3:11]
Reactant: COc1ccc(Br)c(N)c1
Reactant: CC#CC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc2c(C)c(C(C)(C)C)[nH]c2c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
2-Bromo-5-methoxyaniline (1.01 g; synthesized according to the process reported by J. H. Tidwell et al., J. Am. Chem. Soc., vol. 116, pp. 11797-11810 (1994)), 2,2-dimethyl-3-pentyne (480 mg; mfd. by Chemsampco), palladium acetate (28.1 mg), tetra-n-butylammonium chloride (1.39 g; mfd. by TOKYO KASEI), potassium carbonate (3.45 g) and triphenylphosphine (65.6 mg) were dissolved in N,N-dimethylacetamide (50 mL). After stirring at 100° C. for 20 hours, the reaction mixture was diluted with water and extracted with ether. The organic layer was washed with a saturated aqueous ammonium chloride solution and water, and then dried. The solvent was distilled off under reduced pressure. The residue was purified twice by silica gel column chromatography (5:1 hexane/ethyl acetate) to yield the title compound (202 mg).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]2[C:3]=1[C:4]([CH2:14][CH2:15][NH2:16])=[CH:5][NH:6]2.[F:17][C:18]([F:30])([F:29])[CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)C>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]2[C:3]=1[C:4]([CH2:14][CH2:15][NH:16][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH2:19][C:18]([F:17])([F:29])[F:30])[CH:22]=1)=[CH:5][NH:6]2
Reactant: NCCc1c[nH]c2c(F)c(F)c(F)c(F)c12
Reactant: O=Cc1cccc(OCC(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Fc1c(F)c(F)c2c(CCNCc3cccc(OCC(F)(F)F)c3)c[nH]c2c1F

Procedure:
By a method similar to Example 763, using 2-(4,5,6,7-tetrafluoro-1H-indol-3-yl)ethylamine (484 mg, 2.08 mmol), ethanol (45 mL), 3-(2,2,2-trifluoroethoxy)benzaldehyde (425 mg, 2.08 mmol), anhydrous sodium sulfate (3.5 g) sodium borohydride (236 mg, 6.24 mmol) to give the free base of the title compound as a straw colored solid. Recrystallize from methylene chloride to obtain the title compound: mp 107.2-108.2° C. 1H NMR (400 MHz, dmso-d6): 11.92 (br s, 1H), 7.32 (s, 2H), 6.95-6.99 (m, 2H), 6.87 (dd, 1H, J=2.4, 8.0 Hz) 4.68 (q, 2H, J=8.8 Hz), 3.70 (s, 2H), 2.88 (t, 2H, J=7.2 Hz) 2.75 (t, 2H, J=7.2 Hz). MS (ES+): m/e 421.1 (M+1). CHN (for C19H15F7N2O.1HCl.0.20H2O) calcd: C, 53.83; H, 3.66; N, 6.61. found: C, 53.75; H, 3.33; N, 6.
Reaction SMILES: CC(S([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[CH:12][CH:11]=1)[CH3:9])=O)(C)C.Cl.O1CCOCC1>>[N:19]1[CH:18]=[C:17]([O:16][C:13]2[CH:12]=[CH:11][C:10]([C@@H:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=2)[CH:22]=[N:21][CH:20]=1
Reactant: C[C@H](NS(=O)C(C)(C)C)c1ccc(Oc2cncnc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc(Oc2cncnc2)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 118.8 %

Procedure:
To 2-methyl-N—((S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethyl)propane-2-sulfinamide (55 mg, 0.172 mmol) was added 4M HCl in dioxane (800 μL, 3.20 mmol) to give a white suspension. This resulting mixture was stirred at room temperature for ˜35 min and concentrated under reduced pressure to provide crude (S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethanamine (44 mg) as its HCl salt, which was used without further purification. LCMS m/z 217.1 (M+H)+, Rt 0.37 min.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O[C@@:11]([C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[CH:45]=[C:44]([C:49]([NH:51][CH3:52])=[O:50])[CH:43]=[CH:42]2)([C:15]1[N:16]=[CH:17][N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:19]=1)[CH2:12][CH2:13]O.CS(Cl)(=O)=[O:55].Cl>O.C(OCC)(=O)C.C(#N)C.CO.C1COCC1>[OH:55][C:19]1[N:18]=[CH:17][N:16]2[CH2:13][CH2:12][C@@H:11]([C:39]3[CH:40]=[C:41]4[C:46](=[CH:47][CH:48]=3)[CH:45]=[C:44]([C:49]([NH:51][CH3:52])=[O:50])[CH:43]=[CH:42]4)[C:15]=12
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2cc([C@@H]3CCn4cnc(O)c43)ccc2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 456.6 %

Procedure:
7 mL of THF and 0.42 mL (2.47 mmol, 4 eq) of diisopropylethylamine were added to 0.35 g (0.62 mmol) of 6-[(1S)-1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide. 0.072 mL (0.93 mmol, 1.5 eq) of methylsulfonyl chloride was added dropwise at 0˜5° C., and the mixture was stirred at 0˜5° C. for 40 minutes. 1.8 mL of methanol and 3.5 mL of acetonitrile were added, and the mixture was stirred at 60˜65° C. for 4 hours. After cooled to 25° C., 7 mL of ethyl acetate was added, 3.5 mL of 0.5N hydrochloric acid-aqueous saturated ammonium chloride solution was added dropwise at 0˜5° C., and 1 mL of water was added. The aqueous layer was taken, and the organic layer was back extracted with 2 mL of 0.5N hydrochloric acid-aqueous saturated ammonium chloride solution two times. The aqueous layers were combined, and a pH was adjusted to 8 with a 1N aqueous sodium hydroxide solution. The material was stirred at 25° C. for 2 hours, and at 0˜5° C. for 2 hours. Crystals were filtered, and washed with water. Vacuum drying (50° C.) to a constant weight afforded 0.87 g of 6-[(7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]-N-methyl-2-naphthamide (yield 62%, enantiomer excess 98.2% ee).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>>[C:1]1([C:7]2[N:12]=[C:11]([CH2:13][Cl:17])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccnc(-c2ccccc2)n1
Reactant: O=S(Cl)Cl
Product: ClCc1ccnc(-c2ccccc2)n1

Procedure:
A solution of 55 mg 2-phenyl-4-hydroxymethylpyrimidine in 1 mL of thionyl chloride was heated at reflux temperature for 1 hr and the excess thionyl chloride removed by evaporation under reduced pressure to yield 50 mg of 2-phenyl-4-chloromethylpyrimidine as an oil which was used in the next step without further purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C@@H:6]([C:32]1[CH:33]=[N:34][C:35]([O:38][CH3:39])=[N:36][CH:37]=1)[CH2:7][C:8](=[O:31])[CH:9]=[CH:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:17]=2[N:30]=1)=[O:4]>C(O)(C)C.[Pd]>[CH3:1][O:2][C:3]([CH2:5][C@@H:6]([C:32]1[CH:33]=[N:34][C:35]([O:38][CH3:39])=[N:36][CH:37]=1)[CH2:7][C:8](=[O:31])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[C:17]=2[N:30]=1)=[O:4]
Reactant: COC(=O)C[C@H](CC(=O)C=CCCc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCCC2)c1cnc(OC)nc1
Agent: [Pd]
Solvent: CC(C)O
Product: COC(=O)C[C@H](CC(=O)CCCCc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCCC2)c1cnc(OC)nc1
Reaction time: 2 h

Procedure:
The solution of the enone intermediate of Example 9 in isopropanol was charged to a hydrogenation vessel under an atmosphere of nitrogen. A slurry of wet (58 wt % water) palladium on carbon catalyst (1.27 kg) in isopropanol (10 L) was added, washing with further isopropanol (15 L). After degassing the resulting reaction mixture was hydrogenated at 2.8 bar for 2 hours. The catalyst was filtered and washed with isopropanol (4×15 L). The combined filtrates (88.0 kg) were concentrated under reduced pressure to a total volume of ca. 20 L and the solution was directly used in Example 11 without isolation of the product.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[OH:30]C(CCO)CC(O)=O>>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:30])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Reactant: O=C(O)CC(O)CCO
Product: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21

Procedure:
For example, lovastatin (Ia) is prepared by lactonisation of the 3,5-dihydroxy pentanoic acid derivative (II) to (Ia) either by heating in an organic solvent or in the presence of an acid catalyst. The former, viz. mevinolinic acid, is obtained from a fermentation broth containing Asperigillus Terreus.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])(=O)=O)=CC=1.[C:27]([O-])(=[S:29])[CH3:28].[K+].Cl>CN(C)C=O>[C:27]([O:10][CH2:11][CH2:12][C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])(=[S:29])[CH3:28]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=S)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 57.6 %

Procedure:
A mixture of 42.65 g of 3,3,4,4,5,5,6,6,6-nonafluorohexyl p-toluenesulfonate, 100 ml of N,N-dimethylformamide and 11.65 g of potassium thioacetate was heated and stirred at 80° C. for 4 hours under a nitrogen atmosphere. A reaction vessel was cooled in an ice bath. To the reaction mixture was added an aqueous 1N hydrochloric acid solution, and the mixture was extracted with 200 ml of ethylacetate twice. Organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 18.91 g of 3,3,4,4,5,5,6,6,6-nonafluorohexyl thioacetate represented by the formula:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[O:16])[CH:9]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.C(C1CCN(C(OC(C)(C)C)=O)CC1)(=O)N.ClC1C=C(C2C=CC(F)=CC=2OC)C=CN=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=2)=[C:4]([O:30][CH3:31])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccnc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cc(F)ccc1-c1ccnc(NC(=O)C2CCNCC2)c1
Yield: 23.5 %

Procedure:
The Boc-protected precursor of Example 3 tert-butyl 4-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-ylcarbamoyl)piperidine-1-carboxylate was synthesized according to Method B starting from the above obtained compound tert-butyl 4-carbamoylpiperidine-1-carboxylate (100 mg, 0.44 mmol), 2-chloro-4-(4-fluoro-2-methoxy-phenyl)pyridine (94 mg, 0.4 mmol), Cs2CO3 (184 mg, 0.56 mmol), xantphos (13 mg, 23 μmol) and Tetrakis(triphenylphosphine)palladium (0) (9 mg, 8 μmol) in 1,4-dioxane (10 ml) at 125° C. for 3 h, and was purified after usual workup by column chromatography using DCM, petroleum ether, MeOH to afford the product in a yield of 23.5% as colorless oil. 1H-NMR (400 MHz, CDCl3): δ=8.34 (s, 1H), 8.25 (d, 1H), 8.00 (s, 1H), 7.70-7.65 (m, 1H), 7.48-7.42 (m, 1H), 7.35-7.32 (m, 1H), 7.22 (d, 1H), 6.76-6.70 (m, 2H), 4.17 (s, 2H), 3.83 (s, 3H), 2.82 (t, 2H), 2.45-2.40 (m, 1H), 1.93-1.90 (m, 2H), 1.79-1.70 (m, 2H), 1.46 (s, 9H), 0.88-0.86 (m, 4H), MS (m/z): 430.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16](B2OC3C=CC=CC=3O2)[O:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([C:16]2[O:17][CH:18]=[C:14]([CH3:13])[CH:15]=2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: Cc1coc(B2Oc3ccccc3O2)c1
Reactant: CSc1nc(N)nc(Cl)c1C#N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CSc1nc(N)nc(-c2cc(C)co2)c1C#N
Temperature: 90 °C
Yield: 46.9 %

Procedure:
To a stirred suspension of 2.19 g (10.9 mmol) 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile in 40 ml benzene at room temperature were added 2,40 g (12.0 mmol) 2-(4-methyl-furan-2-yl)-benzo[1,3,2]dioxaborole, 252mg (0.22 mmol) tetrakis(triphenylphosphine)palladium(O) and 11 ml (22.0 mmol) 2M aqueous sodium carbonate. The reaction mixture was heated at 90° C. for 16 h, then concentrated in vacuo. Chromatography (1/3 ethyl acetate/hexane then 1/1 ethyl acetate/hexane) afforded 1.26 g (47%) 2-amino-4-(4-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 246 (M+, 61), 245 ([M—H]+, 100).