Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([OH:14])=O)[CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH2:40][CH:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl.O>[CH2:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:51][CH2:52][N:43]1[CH2:42][CH:41]([OH:53])[CH2:40][NH:39][C:12](=[O:14])[CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)Cc1cccc2cccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1cccc2cccnc12)NCC(O)CN1CCc2ccccc2C1
Reaction time: 3 h
Yield: 13.3 %

Procedure:
A solution of 2-(quinolin-8-yl)acetic acid (187 mg, 1 mmol), HATU (387.6 mg, 1.02 mmol) and TEA (196.1 mg, 1.94 mmol) in DCM (10 mL) was stirred at room temperature for 10 min. 1-Amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (210 mg, 1.0 mmol) was then added, and the solution stirred at for another 3 h, at which point LCMS indicated completion of the reaction. The reaction mixture was diluted with water and extracted with DCM (10 mL×3). The organic layers combined and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give the desired compound (50 mg, Yield 13%). 1H NMR (400 MHz, MeOD): 8.92 (d, J=2.8 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.73 (d, J=6.8 Hz, 1H), 7.55-7.50 (m, 2H), 7.10-6.97 (m, 4H), 4.25 (dd, J1=10.8 Hz, J2=14.0 Hz, 2H), 3.90 (m, 1H), 3.54-3.51 (m 2H), 3.32-3.25 (m, 2H), 2.82-2.80 (m, 2H), 2.67-2.66 (m, 2H), 2.40-2.39 (m, 2H). LCMS (m/z): 376.1 (M+1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42]/[CH:43]=[CH:44]/[C:45]([CH3:55])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH3:46]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:42]/[CH:43]=[CH:44]/[C:45]([CH3:55])([O:47][Si:48]([CH2:51][CH3:52])([CH2:53][CH3:54])[CH2:49][CH3:50])[CH3:46])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C/CBr
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C/CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 88.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and (E)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (116 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) to give the title compound as a colorless oil (73.4 mg, 89%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]([NH:33][C@H:34]1[CH2:39][CH2:38][N:37]([C:40]2[S:44][C:43]([C:45]([O:47][CH3:48])=[O:46])=[C:42]([CH:49]([OH:51])[CH3:50])[CH:41]=2)[CH2:36][C@H:35]1[O:52][CH3:53])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:49]([C:42]1[CH:41]=[C:40]([N:37]2[CH2:38][CH2:39][C@H:34]([NH:33][C:31]([O:30][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:32])[C@H:35]([O:52][CH3:53])[CH2:36]2)[S:44][C:43]=1[C:45]([O:47][CH3:48])=[O:46])(=[O:51])[CH3:50]
Reactant: COC(=O)c1sc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)cc1C(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1sc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)cc1C(C)=O
Reaction time: 1 h
Yield: 49.5 %

Procedure:
The Dess-Martin reagent (305 mg, 0.72 mmol) was added to a solution of methyl 5-((3R*,4S*)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-3-(1-hydroxyethyl)thiophene-2-carboxylate obtained in Example (246d) (215 mg, 0.48 mmol) in dichloromethane (5 mL) at room temperature, followed by stirring for one hour. Aqueous sodium thiosulfate solution was added to the reaction solution, followed by stirring at room temperature. Then, the mixture was extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/1) to obtain 106 mg of the title compound as a yellow oily substance (50%).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[S:13](=O)(=[O:16])([OH:15])[OH:14]>O>[S:13]([OH:16])([O:12][CH2:11][CH2:10][N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: CCN(CCO)c1ccccc1
Solvent: O
Product: CCN(CCOS(=O)(=O)O)c1ccccc1
Reaction time: 2 h

Procedure:
In 1.1, 16.5 grams (g) (0.10 mol) of 2-(N-ethylanilino)ethanol were added to 25.0 milliliters (ml) of concentrated sulfuric acid at a temperature of 35 to 40 degrees Celsius (° C.). The reaction proceeded slightly exothermically and was held within the specified temperature range by cooling with iced water. The mixture was stirred for an additional 2 hours. On completion of the reaction, the mixture was poured onto ice and made up to 250 ml by adding water. The result was a transparent yellow solution, which was used in the next stage with no further processing.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[CH2:17]([N:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]1[O:6][CH2:5][C:4]([OH:24])=[O:3])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)COC1c2ccccc2C(=O)N1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)COC1c2ccccc2C(=O)N1Cc1ccccc1
Yield: 93 %

Procedure:
To a solution of compound 21 (2.0 g, 6.15 mmol) in methanol (20 mL) and water (5 mL) was added potassium carbonate (1.3 g, 9.4 mmol) and the resulting reaction mixture was allowed to stir at reflux for 2 hours. The reaction mixture is poured onto 1N HCl and extracted with dichloromethane (3×100 mL) and the combined dichloromethane extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to provide 1.7 g of 22 as a white solid (1.83 g theoretical, 93% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[C:20]([CH:23]=1)[CH:21]=[O:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:19]2[CH:18]=[CH:17][C:16]([Br:15])=[CH:23][C:20]=2[CH:21]=[O:22])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)Cc1ccc(Cl)c(O)c1
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(Br)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 4, using the following starting materials: (4-chloro-3-hydroxy-phenyl)-acetic acid ethyl ester and 5-bromo-2-fluorobenzaldehyde.
Reaction SMILES: [N+:1]([O:4][CH:5]([CH2:33][O:34][N+:35]([O-:37])=[O:36])[CH2:6][O:7][C:8]([O:10][CH2:11]/[C:12](/[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[C:13](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[C:14]([OH:16])=[O:15])=[O:9])([O-:3])=[O:2].[N+](=[CH:40][CH3:41])=[N-]>C1COCC1.C(OCC)C>[N+:1]([O:4][CH:5]([CH2:33][O:34][N+:35]([O-:37])=[O:36])[CH2:6][O:7][C:8]([O:10][CH2:11]/[C:12](/[C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1)=[C:13](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[C:14]([O:16][CH2:40][CH3:41])=[O:15])=[O:9])([O-:3])=[O:2]
Reactant: CC=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)/C(=C(\COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc(S(C)(=O)=O)cc1)c1ccccc1

Procedure:
To a 0° C. solution of 454 mg of (2Z)-4-({[2,3-bis(nitrooxy)propoxy]carbonyl}oxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 20 mL of THF was added excess diazoethane in diethylether until crude NMR revealed complete conversion to ethyl ester. Evaporation of the solvent followed by flash chromatography of the crude residue over silica gel (30-90% EtOAc/hexane) afforded 420 mg of the title compound as a clear colourless oil. 1H NMR (500 MHz, acetone-d6): δ 7.80 (d, 2H), 7.49 (d, 2H), 7.23-7.18 (m, 3H), 7.14-7.08 (m, 2H), 5.79-5.73 (m, 1H), 5.35 (s, 2H), 5.05 (dd, 1H), 4.85 (dd, 1H), 4.64 (dd, 1H), 4.47 (dd, 1H), 4.31 (q, 2H), 3.08 (s, 3H), 1.29 (t, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:12]([CH:28]=[O:29])=[C:11]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:19][CH2:20][CH2:21]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:12]([C@H:28]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=3)[OH:29])=[C:11]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC2(CCC2)Cc2nc(C3CCOCC3)c(C=O)c(C3=CCOCC3)c21
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC2(CCC2)Cc2nc(C3CCOCC3)c([C@@H](O)c3ccc(C(F)(F)F)cn3)c(C3=CCOCC3)c21

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-(3,6-dihydro-2H-pyran-4-yl)-2′-(tetrahydro-2H-pyran-4-yl)-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 2-bromo-5-(trifluoromethyl)pyridine.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CCCCCC>[CH:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: C1CCNCC1
Solvent: CCCCCC
Product: O=C(NC1CCCCC1)N1CCCCC1
Yield: 98.3 %

Procedure:
23.8 g of cyclohexyl isocyanate (0.190 mol) are added dropwise to a solution of 18.62 g of piperidine (0.219 mol) in 360 ml of hexane, and then the cloudy mixture is refluxed for 2 h and then cooled and filtered, to give 39.3 g of pure N-cyclohexyl-piperidine-1-carboxamide (yield 98.3%). 12 g of POCl3 (78 mmol) are added, over 1 h, to a suspension of 15.05 g of said N-cyclohexylpiperidine-1-carboxamide (71.6 mmol) in 65 ml of dry toluene, and then, after a few hours at 20° C., 18.1 g of N-butyl-N-ethylamine (0.179 mmol) are added over 2 h, and then, after a further 2 h at 20° C., 50 ml of water are added. 49 g of 35% sodium hydroxide are then added while cooling, and the two-phase medium is then extracted with diisopropyl ether. After drying and evaporation to dryness, the oil obtained, 20 g, is distilled at 185° C. under 1 mbar, to give 17 g of the expected guanidine (yield 81%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N+]([O-])=O)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:4][N:3]=1.[ClH:24]>O.[Fe]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:24])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:4][N:3]=1
Reactant: Nc1ncc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c(N)n1
Reactant: Cl
Agent: [Fe]
Solvent: O
Product: Nc1ncc(C2CCN(c3ccc(Cl)cc3)CC2)c(N)n1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
1 g of 2,4-diamino-5-[1-(p-nitrophenyl)-4-piperidinyl]pyrimidine was dissolved in 50 ml of water and 10 ml of conc. hydrochloric acid, treated with 700 mg of iron powder and stirred at 80° C. for 45 minutes. The mixture was filtered over a filter aid, the filtrate was cooled to 0°-5° C., diazotized with 210 mg of sodium nitrite in 2 ml of water and the resulting diazonium solution was added dropwise at 0°-5° C. to a solution of copper (I) chloride (prepared from 250 mg of copper (II) sulfate pentahydrate, 80 mg of sodium chloride and 70 mg of sodium bisulfite) in 0.8 ml of hydrochloric acid. Thereafter, the reaction mixture was heated at 90° C. for 1 hour, treated with active carbon, filtered and concentrated to 50 ml. The residue was neutralized with ammonium hydroxide, filtered off and the product obtained after distilling off the water was chromatographed on silica gel with CHCl3 /EtOH (9:1). Recrystallization from ethanol yielded 2,4-diamino-5-[1-(p-chlorophenyl)-4-piperidinyl]pyrimidine of melting point 254°-255° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:17][CH:18]([CH2:23][CH3:24])[C:19]([CH3:22])([OH:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]2[C:9]=1[CH:10]=[CH:11][N:17]2[CH:18]([CH2:23][CH3:24])[C:19]([OH:21])([CH3:22])[CH3:20]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Reactant: CCC(N)C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(n1ccc2c(Cl)c(C#N)ccc21)C(C)(C)O
Temperature: 60 °C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
A mixture of 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.163 g, 0.647 mmol), 3-amino-2-methylpentan-2-ol (0.091 g, 0.776 mmol), and K2CO3 (0.179 g, 1.294 mmol) in anhyd NMP (3 mL) was stirred in a heating block at 60° C. under N2. After 18 h, the mixture was subjected to microwave heating (140° C.) for 15 min. Upon cooling the mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording 4-chloro-1-(2-hydroxy-2-methylpentan-3-yl)-1H-indole-5-carbonitrile (0.0761 g, 43% yield) as a yellow gum: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=2.2 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.77 (d, J=3.3 Hz, 1H), 4.07 (dd, J=11.6, 3.6 Hz, 1H), 2.09 (m, J=3.6 Hz, 2H), 1.44 (s, 1H), 1.35 (s, 3H), 1.08 (s, 3H), 0.65 (t, J=7.3 Hz, 3H); MS (LCMS ES+) m/z 277 ([M+H]+, 70%), 318 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH:42]2[CH2:47][CH2:46][CH:45]([N:48]([CH2:50][CH3:51])[CH3:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([CH:42]4[CH2:43][CH2:44][CH:45]([N:48]([CH2:50][CH3:51])[CH3:49])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCN(C)C1CCC(c2ccc(N)c3c2CN(C)C3=O)CC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4CCC(N(C)CC)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
This compound was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-{4-[ethyl(methyl)amino]cyclohexyl}-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 236A). 1H NMR (400 MHz, MeOD) δ ppm 1.28 (t, J=7.07 Hz, 6H) 1.39 (t, J=7.33 Hz, 3H) 1.70-1.86 (m, 4H) 2.04 (br. s., 2H) 2.19 (d, J=7.83 Hz, 2H), 2.71 (br. s., 1H) 2.86 (s, 3H) 3.17-3.19 (m, 3H) 3.33 (s, 1H) 3.34-3.37 (m, 2H) 3.39 (s, 1H) 3.43-3.52 (m, 1H) 3.89 (s, 3H) 4.05-4.14 (m, 4H) 4.55 (s, 2H) 7.01 (dt, J=8.02, 2.31 Hz, 1H), 7.15 (t, J=2.02 Hz, 1H) 7.42 (d, J=8.34 Hz, 1H) 7.57 (d, J=8.08 Hz, 1H) 8.36 (br. s., 1H). MS (ES+): m/z 719.25/720.29 (100/20) [MH+]. HPLC: tR=1.17 min (UPLC TOF: polar—3 min).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]([O:27][CH3:28])=[O:26])=[O:14].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:29]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]([O:27][CH3:28])=[O:26])=[O:14])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3Cc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.4 %

Procedure:
A mixture of the product of Example 22B (0.72 g, 1.5 mmol), benzyl bromide (0.26 g, 1.5 mmol) and potassium carbonate (3.0 g in 3 mL of H2O) in tetrahydrofuran (6 mL) was stirred at room temperature for 72 hrs, diluted with ethyl acetate, washed with water and partitioned. The isolated organic layer was concentrated and the residue was chromatographed on silica gel, eluting with 60%-100% ethyl acetate/hexanes to afford the title compound (0.58 g, 72%) as an amorphous solid. 1H NMR (300 MHz, d6-DMSO) 9.00 (s, 1H), 8.42 (s, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.48 (m, 1H), 7.28 (m, 5H), 6.95 (d, J=7.5 Hz, 1H), 6.83 (m, 1H), 6.58 (m, J=6.0 Hz, 1H), 6.50 (m, 1H), 6.36 (d, J=7.5 Hz, 1H), 4.64 (m, 2H), 4.01 (s, 3H), 3.57 (m, 1H), 3.41-3.20 (m, 2H), 2.90 (m, 1H), 2.67 (m, 1H), 2.03 (m, 1H), 1.82 (m, 1H); MS (DCI/NH3) m/e 470 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[C:15]([Cl:34])=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.[H-].[Na+].[C:37]([N:41]=[C:42]=[O:43])([CH3:40])([CH3:39])[CH3:38].O>CN(C=O)C>[C:37]([NH:41][C:42](=[O:43])[NH:1][C:2]1[C:3]([C:14]2[C:15]([Cl:34])=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(NC(=O)NC(C)(C)C)nc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N—[3-(7-amino-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-6-yl)-2,4-dichloro-phenyl]-3-trifluoromethyl-benzamide (700 mg, 1.34 mmol) in dry DMF (10 ml) at 0° C. is added NaH (60% oil suspension, 64 mg, 1.6 mmol) slowly. The reaction mixture is stirred at room temperature for 30 minutes and then to this reaction mixture t-butyl-isocyanate (0.19 ml, 1.6 mmol) is added. The reaction is stirred at room temperature for 5 hours. The reaction mixture is diluted into 100 ml water, extracted with 80 ml ethyl acetate three times. The organic phase is combined and washed with brine, dried over Na2SO4. The crude product is purified by flash silica gel column to give the title compound as light yellow solid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].C(OCC)(=O)C>CCO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in EtOH (15 ml). The mixture was stirred at about 70° C. for 4 h (it became clear and turned to a slurry), after which the starting material was not detected by HPLC. Then, 40 ml of ethyl acetate was dripped into the mixture and it was cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with ethyl acetate (10 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain fluvastatin sodium Form XXXVIII (1.78 g, 87.4%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C(#N)C.Br[CH2:21][CH2:22][CH2:23][CH3:24]>O>[CH2:21]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH2:22][CH2:23][CH3:24]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 556.3 %

Procedure:
To a mixture of 15 g (0.015 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 15.93 g (0.115 mol) of K2CO3, and 100 ml of acetonitrile is added drowpwise 11.25 ml (0.105 mol) of 1-bromobutane. The mixture is stirred overnight at room temperature and then at 65° C. for 2 hours. After cooling, the mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to yield 16.63 g (80%) of the title compound as a yellow liquid: IR (neat) 2959 and 1092 cm-1 ; NMR (CDCl3)δ3.97 (s, 4H), 2.56 (s, 4H), 2.38 (m, 2H), 1.77 (t, 4H), 1.49 (m, 2H), 1.34 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][C:20]1=[O:29]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1Cc2ccccc2NC1=O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1Cc2ccccc2NC1=O

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1,2,3,4-tetrahydroquinolin-2-one (Example 5-A), the title compound was prepared as a mixture of diasteromers. The reaction was monitored by tlc on silica gel (Rf=0.38 in 25% ethyl acetate/hexanes) and purification was by flash chromatography using 25% ethyl acetate/hexanes as the eluant.