Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28]C(C)(C)C)=O)[C:18]([C:36]([F:39])([F:38])[F:37])=[CH:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.O[N:48]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C(Cl)Cl.C1COCC1.CN(C=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([NH2:48])=[O:28])[C:18]([C:36]([F:39])([F:37])[F:38])=[CH:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)OC(C)(C)C)c4)n3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)cc2)CC1
Temperature: 35 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
tert-Butyl 3-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzoate (I21) (0.025 g, 0.046 mmol) was dissolved in dry DCM (3 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.177 mL, 2.31 mmol) was added to the solution and the reaction was stirred at 35° C. for 2 hours. The mixture was concentrated to dryness, toluene (˜2 mL) was added to the residue and the solvent was removed in vacuo to give a yellow solid. This material was dissolved in dry THF (3 mL) and dry DMF (0.2 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.009 g, 0.064 mmol) and EDCI (0.012 g, 0.064 mmol) and N,N-diisopropylethylamine (0.048 mL, 0.276 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (0.018 g, 0.18 mmol) was added in one portion, and the reaction was stirred room temperature for 20 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (20 mL) and saturated aq. NaHCO3 (10 mL). The layers were separated and the organic layer was washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give a pale yellow solid. The product was dissolved in DCM (˜4 mL) and MeOH (˜1 mL) and the solvents were removed in vacuo. The process was repeated 3 times with DCM only and to give the title compound (2) (0.017 g, 76% yield over 2 steps) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.95 (br s, 1H), 7.79 (s, 1H), 7.75-7.66 (m, 1H), 7.57-7.47 (m, 2H), 7.40-7.30 (m, 3H), 6.94-6.86 (m, 2H), 3.14-3.01 (m, 8H), 2.47-2.42 (m, 4H), 2.21 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Br[C:62]1[C:67]([F:68])=[CH:66][CH:65]=[CH:64][C:63]=1[Cl:69].Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:69][C:63]1[CH:64]=[CH:65][CH:66]=[C:67]([F:68])[C:62]=1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Fc1cccc(Cl)c1Br
Reactant: Cc1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 146.1 g (1.36 mol) of p-toluidine, 12.6 g (0.02 mol) of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 261.9 g (2.73 mol) of sodium t-butoxide, 314.1 g (1.50 mol) of 2-bromo-3-fluoro-chlorobenzene and 6.3 g (0.0069 mol) of tris(dibenzylideneacetone)dipalladium(0) in 3000 ml of toluene is heated to 110° over 30 minutes and stirred an additional 4 hours at this temperature. The mixture is cooled to room temperature and a solution of 680 ml 37% hydrochloric acid and 680 ml of water is added over 15 minutes. The mixture is stirred for 20 minutes and filtered through a pad of Celite. The layers are separated and the organic phase is washed twice with 680 ml of water and once with a solution of 225 g of sodium chloride in 680 ml of water. The solvents are evaporated under reduced pressure to give N-(2′-chloro-6′-fluorophenyl)-4-methylaniline as an oil, b.p. 129-131°/0.5 mm Hg.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br)#[N:2].[C:14]1([CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[CH:16]=1)[OH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOCC>[OH:15][C:14]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[O:18][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:5]=1[O:4][CH2:3][C:1]#[N:2]
Reactant: Cc1cccc(CBr)c1OCC#N
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cccc(COc2cccc(O)c2)c1OCC#N
Temperature: 60 °C

Procedure:
Heated (60° C.) a mixture of 2-cyanomethoxy-3-methylbenzyl bromide (10.2 g, 42.7 mmoles, example 24), resorcinol (18.8 g, 171 mmoles), and potassium carbonate (47.2 g, 342 mmoles) in acetonitrile (140 mL) for two hours. The reaction is diluted with ether and washed three times with distilled water, once with brine, and dried over MgSO4. The organic layer is isolated and concentrated, and the resulting residue is purified by column chromatography (silica, 5% EtOAc/CH2Cl2) to yield the title compound as a white crystalline solid. MS(EI) 269 (M)+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>CN(C=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([Br:13])=[CH:15][CH:16]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)Nc1ccc(Br)cc1
Temperature: 115 °C
Reaction time: 60 h

Procedure:
A mixture of isatoic anhydride (4.00 g, 24.5 mmol) and 4-bromoaniline (4.20 g, 24.5 mmol) in anhydrous DMF (30 mL) was stirred at 115° C. for 60 hours under nitrogen. DMF was removed under vacuum and the residue was partitioned between ethyl acetate (75 mL) and water (75 mL). The organic phase was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to give crude 2-amino-N-(4-bromophenyl)benzamide. Yield: 1.00 g (14%).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11]Cl)=[CH:5][CH:4]=1.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:11][CH:10]=[CH:9][C:6]3[CH:7]=[N:8][C:3]([CH3:2])=[CH:4][CH:5]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Cc1ccc(C=CCCl)cn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc(C=CCN2CCc3nc(N)sc3CC2)cn1
Yield: 30 %

Procedure:
Prepared from 3-(6-methyl-3-pyridyl)allyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 30% of theory, Melting point: 180°-184° C. (ether).
Reaction SMILES: B(Br)(Br)Br.[C:5]([NH:13][C@@:14]1([C:26]([O:28]C)=[O:27])[CH2:23][CH2:22][C:21]2[C:16](=[C:17]([O:24]C)[CH:18]=[CH:19][CH:20]=2)[CH2:15]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+].C(OCC)(=O)C>ClCCl>[C:5]([NH:13][C@@:14]1([C:26]([OH:28])=[O:27])[CH2:23][CH2:22][C:21]2[C:16](=[C:17]([OH:24])[CH:18]=[CH:19][CH:20]=2)[CH2:15]1)(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@]1(NC(=O)c2ccccc2)CCc2cccc(OC)c2C1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(N[C@@]1(C(=O)O)CCc2cccc(O)c2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
28.7 ml of boron tribromide solution (1M in dichloromethane) were added dropwise under argon and while cooling with ice to a solution of 1.95 g (5.75 mmol) of methyl (S)-2-benzamido-8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylate in 15 ml of dichloromethane. The reaction mixture was stirred at 0° for 30 minutes and at room temperature for 3 hours and then poured into a mixture of ice, saturated ammonium chloride solution and ethyl acetate. The organic phase was separated, extracted with saturated sodium chloride solution, dried over MgSO4 and concentrated. The residue was dried in a high vacuum, suspended in diethyl ether/hexane (1:4) and filtered off. The filter residue was dried, there being obtained 1.75 g (97.8%) of (S)-2-benzamido-8-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid. [α]D =+84.3° (c=0.3, methanol). IR (KBr): 3362m(br.), 3064w, 3022w, 2976w, 2938w, 2620w, 1718s, 1644s, 1588m, 1523s, 1487m, 1467s, 1330m, 1278s, 1082w, 716m.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1cccc(C)c1
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: Cc1cccc(C#Cc2cnc3cc(C(C)(C)C)nn3c2)c1

Procedure:
The title compound, yellow solid, MS: m/e=290.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-3-methylbenzene.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:14]=2)[C:9](F)=[N:10][CH:11]=1.N#N.[CH3:41][O:42][C:43]1[N:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1C=CC=CC=1.C1COCC1.C(Cl)Cl>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:15]2[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]3[C:9]([NH:49][C:46]4[CH:47]=[N:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=4)=[N:10][CH:11]=[C:6]([CH:7]=3)[CH:2]=[O:3])[N:14]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4OCCO4)cnc3F)n2)cc1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#N
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 8 h
Yield: 61 %

Procedure:
A stock solution of 4-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 143, Step 1) (5.85 g, 11.30 mmol) in benzene (50 mL) contained in a 250 mL round-bottomed flask with stir bar was frozen and lyophilized overnight (pale yellow solid obtained). The flask was opened to N2 and THF (50 mL) was added followed by 6-methoxypyridin-3-amine (1.332 mL, 12.43 mmol). The solution was cooled in an ice bath and LiHMDS (44 mL of a 1.0 M solution in THF, 44 mmol) was added. The mixture was stirred for 40 min and then quenched with water (3 mL) and concentrated to dryness. The residue was taken up in a mixture of DCM and 2N aqueous HCl and stirred for 30 min. The product was extracted into DCM from 2N HCl, washed with saturated aqueous NaHCO3, dried (MgSO4) and concentrated to give a brown solid. This was dissolved in DCM and purified by flash chrormatography (30% EtOAc, 10% DCM, 60% hexane) to give 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (3.98 g, 6.89 mmol, 61.0% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.09 (s, 1H); 9.90 (s, 1H); 9.14 (d, J=2.35 Hz, 1H); 8.77 (d, J=2.35 Hz, 1H); 8.31 (d, J=2.74 Hz, 1H); 7.87 (dd, J=8.80, 2.74 Hz, 1H); 7.28 (d, J=8.61 Hz, 2H); 7.21 (d, J=8.80 Hz, 2H); 6.87-6.94 (m, 2H); 6.78-6.87 (m, 3H); 4.83 (d, J=7.24 Hz, 4H); 3.85 (s, 3H); 3.74 (s, 3H); 3.69 (s, 3H); 2.58 (s, 3H). m/z (ESI, +ve ion) 578 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])=[O:4]
Reactant: [H][H]
Reactant: CS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Cc1ccc(N)cc1
Yield: 55.2 %

Procedure:
A solution of 1-[(methylsulphonyl)methyl]-4-nitrobenzene (4 g) in ethyl acetate (300 ml) containing a catalytic amount of palladium on carbon (10%, prehydrogenated, 0.5 g) was hydrogenated at room temperature and pressure until hydrogen uptake ceased (1400 ml, 1 h). The catalyst was filtered off and the filter cake washed with warm ethanol (2×80 ml). The filtrates were combined and concentrated under vacuum to afford the title compound (1.9 g) as a pale yellow crystalline solid, m.p. 167°-168° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12]([NH:14][CH2:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)=[C:5]2[N:4]=[N:3]1.P(Cl)(Cl)(Cl)=O>>[CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12]3[O:23][C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][N:14]=3)=[C:5]2[N:4]=[N:3]1
Reactant: Cn1nnc2c(C(=O)NCC(=O)c3ccccc3)ncn2c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1nnc2c(-c3ncc(-c4ccccc4)o3)ncn2c1=O
Temperature: 110 °C
Reaction time: 3 h
Yield: 32.2 %

Procedure:
3-Methyl-4-oxo-N-(2-oxo-2-phenylethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (0.180 g; 0.58 mmol) was added to phosphorus oxychloride (3.6 mL) and the stirred mixture heated at 110° C. for 1.5 hours. The mixture was cooled and poured onto ice, and allowed to stand for 3 hour. The solid was filtered and extracted with chloroform on Soxhlet apparatus. Concentration under reduced pressure yielded pure title compound as a bright yellow powder (55 mg; 32%). δH (DMSO-d6) 8.94 (1H, s), 7.99 (1H, s), 7.85 (2H, m), 7.55 (2H, m), 7.44 (1H, tt, J=7.8, 1.1), 3.90 (3H, s).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:46][C:47]1[CH:52]=[C:51]([CH3:53])[N:50]=[C:49]([OH:54])[C:48]=1[CH2:55][NH2:56]>ClCCl.O>[NH2:46][C:47]1[CH:52]=[C:51]([CH3:53])[N:50]=[C:49]([OH:54])[C:48]=1[CH2:55][NH:56][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: Cc1cc(N)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(N)c(CNC(=O)c2ccc(Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of 4-phenoxybenzoic acid (196 mg, 0.91 mmol) in dichloromethane (15 mL) were added 1-hydroxybenzotriazole (177 mg, 1.3 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (251 mg, 1.3 mmol) and triethylamine (265 mg, 2.6 mmol). The resulting solution was stirred at room temperature for 30 minutes. Then 4-amino-3-(aminomethyl)-6-methylpyridin-2-ol (200 mg, 1.3 mmol) was added to the solution, and it was stirred at room temperature for 16 hours. Water (20 ml) was added to the mixture. It was extracted with dichloromethane (50 ml). The organic layer was concentrated in vacuo to provide crude product which was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford N-((4-amino-2-hydroxy-6-methylpyridin-3-yl)methyl)-4-phenoxybenzamide (180 mg, 57% yield) as a white solid. LRMS (M+H+) m/z: calcd 350.14. found 350. HPLC Purity (214 nm): 97%. 1H NMR (300 MHz, CDCl3): δ 10.71 (d, J=2.4 Hz, 1H), 7.76-7.79 (d, J=8.7 Hz, 2H), 7.32-7.38 (m, 2H), 7.12-7.17 (m, 1H), 6.94-7.02 (m, 4H), 5.64-5.65 (br, 1H), 5.51 (s, 1H), 4.47-4.49 (d, J=6.6 Hz, 2H), 3.48 (s, 2H), 2.16 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[CH3:22])=[C:6]([CH2:8][C:9](O)=O)[CH:7]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-:37].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:13][C:14]3[C:15]([CH3:22])=[C:16]([O:20][CH3:21])[CH:17]=[CH:18][C:19]=3[C:9](=[O:37])[CH2:8][C:6]=2[CH:7]=1
Reactant: COc1cccc(CCc2ccc(Br)cc2CC(=O)O)c1C
Reactant: [OH-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1C)CCc1ccc(Br)cc1CC2=O
Temperature: 90 °C
Yield: 55 %

Procedure:
To a stirred suspension of 5-bromo-2-[2-(3-methoxy-2-methyl-phenyl)-ethyl]-phenylacetic acid (11) (4.38 g; 12.06 mmol) in toluene (20 mL), was added phosphorous pentoxide (6.0 g; 42.2 mmol). The mixture was heated at 90° C. for 16 hours. The mixture was cooled, treated with 1.0 N solution of sodium hydroxide and extracted with chloroform. The extracts were combined, dried over Na2SO4, and evaporated. The resultant residue was chromatograped on silica gel using hexane and ethyl acetate (4:1) to give compound 12 as colorless crystals, 2.40 g; 55% yield.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@@H:16]([CH3:17])[CH2:15][N:14]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([O:29]CC)=[O:28])[CH:22]=3)=[O:19])[C@H:13]([CH3:32])[CH2:12]2)=[CH:7][C:6]=1[C:33]([F:36])([F:35])[F:34])#[N:4].Cl>C1COCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@@H:16]([CH3:17])[CH2:15][N:14]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=[O:28])[CH:22]=3)=[O:19])[C@H:13]([CH3:32])[CH2:12]2)=[CH:7][C:6]=1[C:33]([F:35])([F:36])[F:34])#[N:4]
Reactant: CCOC(=O)c1cc(NC(=O)N2C[C@H](C)N(c3ccc(C#N)c(C(F)(F)F)c3)C[C@H]2C)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1C(=O)Nc1ccnc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A 40 ml portion of 1 N sodium hydroxide aqueous solution was added dropwise to 40 ml of THF solution containing 3.36 g of ethyl (2R,5S)-4-{[4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethylpiperazine-1-carbonyl]amino}pyridine-2-carboxylate synthesized in Example 18-3, and the mixture was stirred at room temperature for 1 hour. This was adjusted to pH 2 to 3 by adding 4 N hydrochloric acid under ice-cooling, and the thus formed precipitate was collected by filtration, washed with purified water and then dried at 70° C. under reduced pressure to obtain 2.80 g of the title compound.
Reaction SMILES: [CH:1]1([C:12]([O:14]C)=[O:13])[CH:3]([C:4]([O:6]C)=[O:5])[CH:2]1[C:8]([O:10]C)=[O:9].[OH-].[Na+].Cl>CO>[CH:2]1([C:8]([OH:10])=[O:9])[CH:3]([C:4]([OH:6])=[O:5])[CH:1]1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)C1C(C(=O)OC)C1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1C(C(=O)O)C1C(=O)O
Yield: 96.5 %

Procedure:
Trimethyl cyclopropane-1,2,3-tricarboxylate (20.6 g, 95.2 mmols) was dissolved in methanol (200 ml), followed by dropwise adding sodium hydroxide (23.7 g, 593 mmol) (dissolved in water (100 ml)) at room temperature, thereafter heating and reacting the mixture under reflux for one hour, cooling the reaction product, adding conc. hydrochloric acid (40 g, 1.1 mol), concentrating the reaction solution, adding acetone (200 ml) to the concentrated residue, heating the mixture under reflux for 2 hours, filtering off the precipitate, and concentrating the filtrate under reduced pressure, to obtain cyclopropane-1,2,3-tricarboxylic acid (16.0 g, 91.9 mmol, 97%).
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:6]([O:8][C@@H:9]1[C@@H:14]2[C@@H:15]([CH2:20][CH2:21][C@@H:22](O)[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([O-:28])=[O:27])[C@@H:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[CH:12][C@H:11]([CH3:31])[CH2:10]1)=O)([CH3:5])[CH3:4].[NH4+].[OH2:33].C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[CH3:1][CH2:2][C:3]([C:6]([O:8][C@@H:9]1[C@@H:14]2[C@@H:15]([CH2:20][CH2:21][C@H:22]3[O:28][C:26](=[O:27])[CH2:25][C@H:24]([OH:29])[CH2:23]3)[C@@H:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[CH:12][C@H:11]([CH3:31])[CH2:10]1)=[O:33])([CH3:4])[CH3:5]
Reactant: O
Reactant: CCC(C)(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: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: CCC(C)(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
Yield: 86.9 %

Procedure:
100 g of simvastatin ammonium salt, 800 ml of chloroform, 43.2 g of p-toluenesulfonic acid monohydrate, and 20 g of anhydrous magnesium sulfate were added to a 1 L reaction flask, and the reaction mixture were allowed to stir at 15˜20° C. until the end of reaction. A TLC monitoring was carried out at the end of the reaction. Subsequently, simvastatin 80.2 g was obtained by the same procedure as described in example 3 with a yield of 86.93%, in which a content of simvastatin was 99.48%, and a content of a dimmer thereof was 0.14%.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:9]([C@H:10]2[O:16][C@@H:15]([CH:17](C(=O)C)[OH:18])[C@:13](C(=O)C)([OH:14])[C@:11]2(C(=O)C)[OH:12])[C:8]2[CH:28]=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:7]=2[N:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[CH:1]([NH:4][C:5]1[N:9]([C@H:10]2[O:16][C@@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@@H:11]2[OH:12])[C:8]2[CH:28]=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)C(O)[C@@H]1O[C@H](n2c(NC(C)C)nc3c(Cl)c(Cl)c(Cl)cc32)[C@](O)(C(C)=O)[C@]1(O)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: CC(C)Nc1nc2c(Cl)c(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 74.6 %

Procedure:
2-(Isopropylamino)-4,5,6-trichloro-1-(2,3,5-triacetyl-beta-L-ribofuranosyl)-1H-benzimidazole (1.00 g, 1.86 mmol), sodium carbonate (0.26 g, 2.45 mmol), water (4 mL), methanol (6 mL) and ethanol (8 mL) were used according to general procedure III. The product was purified by silica gel chromatography using 10:1 dichloromethane/methanol to afford 0.57 g (75%) of a white powder; m.p. 223-224° C. Anal. Calcd. for C15H18Cl3N3O4: C, 43.87; H, 4.42; N, 10.23. Found. C, 43.63; H, 4.55; N, 9.98.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:19])[C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O-:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[N:30][CH:29]=[CH:28]2>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C:10](=[O:12])[C@H:9]([N:8]([CH3:19])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][N:30]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](C(=O)[O-])c1ccccc1
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H](C(=O)Nc1ccc2cnccc2c1)c1ccccc1
Reaction time: 4 h

Procedure:
To (R)-2-(tert-butoxycarbonyl(methyl)amino)-2-phenylacetate (E6) in DMF was added EDC, DMAP and 6-aminoisoquinoline. This mixture was stirred for 4 hours and the reaction was washed with NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, Hexanes/EtOAc) gave pure (R)-tert-butyl 2-(isoquinolin-6-ylamino)-2-oxo-1-phenylethyl(methyl)carbamate (E7).
Reaction SMILES: [CH3:1][O:2][Na].[CH3:4][O:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH2:25]Br)[N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7]>CO.CCOC(C)=O.O>[CH3:4][O:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][O:2][CH3:1])[N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: COC(=O)c1cccc2cc(Oc3ccnc(CBr)n3)ccc12
Reactant: CO[Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COCc1nccc(Oc2ccc3c(C(=O)OC)cccc3c2)n1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
760 μl (4.12 mMol) of a 5.4 M solution of MeONa in MeOH are added to a solution of 1.28 g (3.43 mMol) 6-(2-bromomethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid methyl ester in 70 ml MeOH. After 22 h stirring at rt, the mixture is diluted with EtOAc and water, the aq. layer separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/EtOAc 19: 1→1:3) gives the title compound: MS: [M+1]+=325; 1H NMR (CDCl3): δ ppm 9.06 (d, 1H), 8.66 (d, 1H), 8.24 (d, 1H), 8.03 (d, 1H), 7.70 (s, 1H), 7.59 (t, 1H), 7.46 (d, 1H), 6.82 (d, 1H), 4.58 (s, H2C), 4.06 (s, H3C), 3.53 (s, H3C).