Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[N:4][C:5]([F:18])=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.Cl[S:21]([OH:24])(=[O:23])=[O:22]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:19])=[N:4][C:5]([F:18])=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:21]([OH:24])(=[O:23])=[O:22])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)c(F)nc(F)c2Cl)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(Oc2c(Cl)c(F)nc(F)c2Cl)cc1S(=O)(=O)O
Yield: 70 %

Procedure:
3,5-Dichloro-2,6-difluoro-4-(4-methoxyphenoxy)pyridine (1.5 g, 4.9 mmol) and chlorosulfonic acid (0.39 ml, 5.8 mmol) were stirred in 5 ml of methylene chloride overnight. The resulting solid-was filtered and washed with cold CH2Cl2. Compound 43a was obtained as solid in 70% yield.
Reaction SMILES: [CH:1](=O)[CH3:2].C(O)(=O)C.[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:39])[C@@H:16]([N:18]2[CH2:22][CH2:21][C@H:20]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([Cl:37])[CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:19]2=[O:38])[CH3:17])[CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C([N+](CC)(CC)CC)C>C(Cl)Cl>[Cl:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:24]([NH:23][C@H:20]1[CH2:21][CH2:22][N:18]([C@@H:16]([CH3:17])[C:15]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][CH2:1][CH3:2])[CH2:10]3)=[O:39])[C:19]1=[O:38])(=[O:26])=[O:25])[CH:36]=[CH:35]2
Reactant: CC=O
Reactant: C[C@@H](C(=O)N1CCCC(N)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[N+](CC)(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNC1CCCN(C(=O)[C@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of acetaldehyde (0.041 ml from a stock solution made up from 0.01271 acetaldehyde dissolved in 1 ml DCM)) in dry DCM (0.4 ml) treated with acetic acid (0.1 ml from a stock solution made up from 0.0054 ml acetic acid dissolved in 1 ml DCM) was added N-{(3S)-1-[(1S)-2-(3-aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide [Example 365] (0.045 g) followed by tetraethylammonium triacetoxyborohydride (0.0059 ). The mixture was stirred at room temperature, under nitrogen, for 60 h. DCM (1 ml) was added and the resultant solution washed with saturated sodium bicarbonate (1 ml) in a hydrophobic frit. The solvent was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.8 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CN)c1ccc(F)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 4-fluorophenylacetonitrile (50 g, 370 mmol, 1.0 equiv) and iodomethane (70 mL, 1.11 mol, 3 equiv) in THF (370 mL) was added KOt-Bu (124 g, 1.1 mol, 3 equiv) as a solid in portions such that the reaction mixture did not exceed 50° C. The reaction mixture was stirred overnight and then quenched by the addition of brine. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-(4-fluorophenyl)-2-methylpropanenitrile as a yellow oil (57 g, 94%), which was used without further purification in the next step. To a solution of the nitrile in dry THF (800 mL) was added a solution of LAH (210 mL, 2 M in ether, 420 mmol, 1.2 equiv). After mixture was heated to reflux overnight, the reaction was allowed to cool to room temperature followed by a Fieser and Fieser work-up. Filtration of the resulting solids provided the title compound as an orange oil (57 g, 92%). m/z=168.1 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:21])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.[Cl-].[Na+].O>[CH2:22]([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
An aqueous sodium hydroxide solution prepared by dissolving 3.99 g (100 mmol) NaOH in 4 ml water was added slowly to non-polydispersed hexaethylene glycol (28.175 g, 25 ml, 100 mmol). Benzyl chloride (3.9 g, 30.8 mmol, 3.54 ml) was added and the reaction mixture was heated with stirring to 100° C. for 18 hours. The reaction mixture was then cooled, diluted with brine (250 ml) and extracted with methylene chloride (200 ml×2). The combined organic layers were washed with brine once, dried over Na2SO4, filtered and concentrated in vacuo to a dark brown oil. The crude product mixture was purified via flash chromatography (silica gel, gradient elution: ethyl acetate to 9/1 ethyl acetate/methanol) to yield 8.099 g (70%) of non-polydispersed 16 as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]#[N:15])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].[H-].[Na+]>CN(C=O)C>[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[C:8]([CH2:13][C:14]#[N:15])=[CH:9]1)=[O:19]
Reactant: N#CCc1c[nH]c2cc([N+](=O)[O-])ccc12
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)n1cc(CC#N)c2ccc([N+](=O)[O-])cc21

Procedure:
Using the procedure of Example 1, Step A, the N-alkylation reaction of 346.6 mg (1.72 mmol) of 6-nitro-1H-indolyl-3-acetonitrile (13) from Example 2, Step C with 0.3 ml (2.44 mmol) of trimethylacetyl chloride and 70.8 mg (1.77 mmol) of NaH (60% dispersion in oil) as a base in 8 ml of DMF yielded after chromatographic purification, 287.7 mg (43.2%) of [1-(2,2-dimethyl-propionyl)-6-nitro-1H-indol-3-yl]-acetonitrile (18) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C([Mg]Cl)(C)C.[Li]CCCC.CCCCCCC.CN(C)[CH:37]=[O:38].Cl>O.C(O)(C)C.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:5]2[S:10][C:9]([CH:37]=[O:38])=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCCC
Solvent: O
Product: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 52.5 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
4-(2-Chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholine VI (27.0 g, 100 mmol) was charged to a suitably sized reactor and tetrahydrofuran (anhydrous, 270 mL) was added. The reaction mixture was cooled to below −10° C., and a 20 wt % solution of i-PrMgCl in tetrahydrofuran (25.7 g, 50.0 mmol) was slowly added, followed by a slow addition of a 25 wt % solution of n-BuLi in heptane (30.0 g, 117 mmol) while an internal temperature below −10° C. was maintained. The mixture was allowed to stir at below −10° C. for 2 h. Anhydrous N,N-dimethylformamide (14.6 g, 200 mmol) was slowly added while keeping the internal temperature below −10° C. The reaction mixture was stirred for 1-2 h, transferred to a mixture of 80% acetic acid, 37% aqueous hydrochloric acid, isopropanol and water. The resulting slurry was heated to 50-55° C. and stirred for 1-3 h. The suspension was concentrated under reduced pressure to remove tetrahydrofuran. The suspension was then cooled to rt, filtered and rinsed with water. The cake was dried under reduced pressure at 40-60° C. to afford 2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV as a yellow solid (29.2 g, 98% yield). 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 4.03-4.05 (m, 4H), 3.85-3.87 (m, 4H), 2.76 (s, 3H)
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:14]=2[N:15]=1
Reactant: NCc1ccccc1
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccccc3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>O1CCOCC1>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:20]=[CH2:21])[C:3]1=[O:19]
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: C1COCCO1
Product: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2OC)c1=O

Procedure:
100 g (308 mmol) of the compound from Example 19A are dissolved in 1.4 l of anhydrous dioxane, and 8.9 g (7.7 mmol) of tetrakis(triphenylphospine)palladium and 117 g (370 mmol) of tributylvinyltin are added. The mixture is heated at reflux for 16 h. The reaction solution is then allowed to cool and filtered through kieselguhr. The filtrates are concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and concentrated to dryness under reduced pressure. Petroleum ether is added until crystallization sets in. The crystals are filtered off and dried under reduced pressure. This gives 37 g (41% of theory) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.CN([CH:24]=[O:25])C>C(OCC)C>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[CH:24]=[O:25])=[N:13]1
Reactant: CN(C)C=O
Reactant: COc1ccc(C2=NC(C)(C)CO2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C2=NC(C)(C)CO2)c(C=O)c1
Reaction time: 4 h
Yield: 84 %

Procedure:
In dry environment under N2, 2-(4-methoxy-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (20 g, 0.097 mole), prepared as described in example 1, was dissolved in ethyl ether (200 ml) and added at −2° C. with n-butyl lithium (44 ml, 0.11 mole), keeping the temperature below 5° C. The mixture was stirred and after 4 hours added with DMF (15.4 g, 16.3 ml, 0.21 mole). After stirring overnight at room temperature, the mixture was cooled and extracted with water/ice. The aqueous phase was extracted again with ethyl ether. The organic phase was washed with water/NaCl, discoloured with charcoal, anhydrified and concentrated under vacuum to give 19 g of the title compound (yield: 84%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][NH:29][CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:15])[F:14])[C:5]=12.[Si]([O:40][CH2:41][CH:42]=O)(C(C)(C)C)(C)C.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(Cl)Cl>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][N:29]([CH2:42][CH2:41][OH:40])[CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:14])[F:15])[C:5]=12
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(CCO)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.4 %

Procedure:
To a mixture of 5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitrile dihydrochloride (20 mg, 0.04 mmol, Example 129, Step 2), {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (9.1 μL, 0.048 mmol), and triethylamine (19 μL, 0.14 mmol) in methylene chloride (0.3 mL) was added sodium triacetoxyborohydride resin (38 mg, 0.087 mmol). The resulting mixture was stirred at room temperature for 3 h. The mixture was filtered and concentrated. The crude product was dissolved in tetrahydrofuran (1.0 mL) and 1.0 M tetra-n-butylammonium fluoride in THF (0.44 mL, 0.44 mmol) was added and stirred at room temperature. After 1.5 h, the solvents were evaporated. The crude residue was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 4.1 mg (20%) of the desired product. The product was isolated as a racemic mixture. LCMS calculated for C22H26F2N7O2 (M+H)+: m/z=458.2; Found: 458.2.
Reaction SMILES: [C:1](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14](O)[CH3:15].S(=O)(=O)(O)O.C(Cl)(Cl)Cl>O>[C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)/C=C/C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)/C=C/C(=O)c1ccccc1
Yield: 92.9 %

Procedure:
A mixture of 7.50 g of trans-β-benzoylacrylic acid, 2.36 g of ethanol, 0.50 g of sulfuric acid and 30 ml of chloroform was refluxed for 5 hours while azeotropically removing water produced from the reaction system. After cooling, the reaction mixture was washed with a saturated solution of NaHCO and then with water. The solvent was distilled away to give 8.08 g of ethyl trans-β-benzoylacrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](OC(C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[N:22]2[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]2=[O:31])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@H](c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC[C@@H]1[C@H](c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of 242 (0.400 g, 0.972 mmol) and DCE (10 mL) at RT was added TEA (0.295 g, 2.91 mmol) and formaldehyde (0.631 g, 7.77 mmol) and the reaction was stirred for 10 min before NaBH(OAc)3 (0.824 g, 3.89 mmol) was added. The reaction was stirred for 2 h at RT. The reaction was poured into satd. aq. Na2CO3 and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a hexane/EtOAc gradient (3:1 to 1:1) to afford 0.3 g (79.3%) of 2-((S)-(3,4-dichlorophenyl)((R)-1-methylpyrrolidin-2-yl)methyl)isoindoline-1,3-dione (244).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CCN(C(C)C)C(C)C.[O:35]1[C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=[N:36]1>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:40]([C:39]2[O:35][N:36]=[CH:37][CH:38]=2)=[O:41])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: O=C(Cl)c1ccno1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)c1ccno1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 39.9 %

Procedure:
To a solution of 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.060 g, 0.162 mmol) in dry THF (5 mL) was added DIPEA (3 mL) and stirred for 20 minutes. The reaction mixture was cooled to 0° C. and isoxazole-5-carbonyl chloride (0.032 g, 0.243 mmol) was added and stirred for 3 h at room temperature. The reaction mass was quenched in water, extracted with DCM: MeOH and concentrated to afford crude product which was purified by column chromatography eluting with MeOH:DCM to afford 0.030 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 4.50-4.52 (d, J=8 Hz, 2H), 7.09-7.10 (d, J=2 Hz, 1H), 7.43-7.45 (d, J=8.4 Hz, 1H), 7.50-7.53 (d, J=10.4 Hz, 1H), 7.59-7.64 (d, J=18 Hz, 1H), 7.82-7.85 (d, J=8.8 Hz, 2H), 8.17-8.19 (d, J=8.4 Hz, 2H), 8.74-8.75 (d, J=2 Hz, 1H), 9.58-9.61 (t, 1H), 12.61-12.74 (br s, 1H); MS (m/z): 464.11 (M+H+).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([CH3:17])([CH2:11][CH2:12][C:13](Cl)([CH3:15])[CH3:14])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:7][C:1]1[CH:6]=[CH:5][C:4]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][C:9]([CH3:17])([CH3:10])[C:3]=2[CH:2]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
In a round bottom flask there are introduced 64 ml (600 mmoles) of toluene and 36.6 g (200 mmoles) of 2,5-dichloro-2,5dimethyl hexane. The reaction mixture is cooled to 0° C. and there are added, by small amounts, 4.1 g (30 mmoles) of aluminum chloride. The reaction mixture is stirred for 1 hour at ambient temperature, poured into water and extracted with CH2Cl2. The organic phase is decanted, dried on magnesium sulfate and evaporated. The resulting oil is purified by distillation. 39.4 g (98%) of 2-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which boils at 68° C. (under 1 mm of mercury) are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH:12]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH:13]1[CH2:20]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:32][S:33](Cl)(=O)=O.C[S-].[Na+]>ClCCl.CN(C=O)C.CCOC(C)=O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH:12]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH:13]1[CH2:20][S:33][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCC(CNC(=O)OCc2ccccc2)C(CO)O1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCC1OC(C)(C)OCC1CNC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of benzyl((4RS,5RS)-4-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methylcarbamate (0.884 g, 2.86 mmol) in dry dichloromethane (30 mL) was added diisopropylethylamine (1.417 ml, 8.57 mmol) and then methanesulfonyl chloride (0.288 ml, 3.71 mmol) and the solution was stirred at RT. After 30 mins the reaction mixture was washed with water, dil HCl and then sat aq NaHCO3. Normal processing afforded a syrup, which was dissolved in DMF (15 mL) and then sodium thiomethoxide (0.601 g, 8.57 mmol) was added with stirring. After 1 h, toluene was added and the mixture was washed with water (×2) and processed normally. Chromatography (EtOAc/Hex 1:2) gave benzyl((4RS,5RS)-2,2-dimethyl-4-(methylthiomethyl)-1,3-dioxan-5-yl)methylcarbamate (0.839 g, 2.472 mmol, 86% yield) as a syrup. 13C NMR (CDCl3) δ 156.9, 136.8, 128.9, 128.6, 128.5, 99.2, 72.3, 67.3, 62.4, 40.4, 39.9, 38.4, 29.0, 20.3, 17.3.
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](O)[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]([CH3:30])[CH2:9]1)=[O:6])[CH3:4].C1(C)C=CC=CC=1.[OH-].[Na+]>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]3[O:26][C:25](=[O:27])[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]([CH3:30])[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](O)C[C@@H](O)CC(=O)O)[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
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]3C[C@@H](O)CC(=O)O3)[C@H]21
Temperature: 90 °C

Procedure:
The lovastatin acid in the extract was converted into the lactone by heating it to 90° C. for 3 hours (yield of conversion was 99.2%). After cooling to room temperature, the toluene was mixed with 80 ml of water, while the pH was adjusted to pH=10 with NaOH. After separation of the layers, the toluene layer was mixed again with 80 ml of fresh water, while the pH was adjusted to pH=4 with sulfuric acid. After separation of the layers, the toluene layer was treated with 0.1 g of active coal, Norit SX ultra. Subsequently the toluene solution was filtrated and further concentrated to 15 ml by evaporation. Cooling to -10° C. resulted in crystallization. The crystals were washed with 5 ml of cold toluene, and dried under vacuum at room temperature. In these crystals no 4-acetyl lovastatin could be detected, neither by TLC nor by proton NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:33][C:10]3([CH2:15][CH2:14][N:13]([C:16]4[S:17][C:18]([N:21]5[CH:25]=[CH:24][N:23]([CH2:26][C:27]([O:29]CC)=[O:28])[C:22]5=[O:32])=[CH:19][N:20]=4)[CH2:12][CH2:11]3)[CH:9]=2)=[CH:4][CH:3]=1.BrC1SC(N2CCC3(C=C(C4C=CC(F)=CC=4)C4C(=CC=CC=4)O3)CC2)=NC=1.O=C1NC=CN1CC(OCC)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N.CNCCNC.[Al]>O1CCOCC1.C(Cl)Cl.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:33][C:10]3([CH2:15][CH2:14][N:13]([C:16]4[S:17][C:18]([N:21]5[CH:25]=[CH:24][N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]5=[O:32])=[CH:19][N:20]=4)[CH2:12][CH2:11]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1ccn(-c2cnc(N3CCC4(C=C(c5ccc(F)cc5)c5ccccc5O4)CC3)s2)c1=O
Agent: [Cu]I
Agent: CCOC(=O)Cn1cc[nH]c1=O
Agent: CNCCNC
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)Cn1ccn(-c2cnc(N3CCC4(C=C(c5ccc(F)cc5)c5ccccc5O4)CC3)s2)c1=O
Reaction time: 0.05 h

Procedure:
Step 4 Ethyl 2-(3-(2-(4-(4-fluorophenyl)spiro[chromene-2,4′-piperidine]-1′-yl)thiazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)acetate A mixture of 1′-(5-bromothiazol-2-yl)-4-(4-fluorophenyl)spiro[chromene-2,4′-piperidine] (93.2 mg, 0.20 mmol), ethyl (2-oxo-2,3-dihydro-1H-imidazol-1-yl)acetate (Example 38, Step 2) (52 mg, 0.31 mmol), copper(I) iodide (39 mg, 0.21 mmol) and K3PO4 (105 mg, 0.49 mmol) was suspended in dry dioxane (2 mL). The reaction mixture was stirred under vacuum for 3 min, then the reaction mixture was backfilled with N2, treated with neat N1,N2-dimethylethane-1,2-diamine (22.9 mg, 0.26 mmol), covered with aluminum foil and stirred in an oil bath preheated at 94° C. for 3.5 h. The reaction mixture was then diluted with DCM (3 mL), washed with saturated NH4Cl (10 mL), 5% KHSO4 (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting oily residue was purified by Combiflash™ chromatography (SiO2 (12 g), eluting with 5-70% EtOAc/hexanes) to afford the title compound as a foam.