Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[CH:8][C:7]=2[C:15]([F:16])([F:17])[F:18])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(OCC2CC2)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccc(OCC2CC2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzoic acid in THF (7 mL) at 0° C. was slowly added BH3DMS (2.0 M in THF) (1.592 mL, 3.18 mmol). After stirring for 0.5 h at 0° C., the reaction was allowed to return to room temperature and stirred overnight. The reaction mixture was slowly added to a saturated solution of NaHCO3 at 0° C. and extracted with EtOAc (thrice). The combined extracts were dried over MgSO4 and purified by silica gel column chromatography to give the title compound as a solid (0.358 g). 1H NMR (400 MHz, CDCl3) δ ppm 0.34-0.43 (m, 2H), 0.57-0.67 (m, 2H), 1.22-1.32 (m, 1H), 3.94 (d, J=6.57 Hz, 2H), 4.66 (s, 2H), 6.96 (d, J=8.46 Hz, 1H), 7.46 (dd, J=8.46, 2.02 Hz, 1H), 7.57 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH3:27])[C:4](=[O:28])[C:3]=1[CH:29]([CH3:31])[CH3:30].[H-].[Na+].I[CH3:35]>C1COCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[N:7][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:5]([CH3:27])[C:4](=[O:28])[C:3]([CH:29]([CH3:31])[CH3:30])=[C:2]3[NH:1][CH3:35])=[CH:17][CH:16]=1
Reactant: CI
Reactant: CC(C)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1c(C(C)C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reaction time: 0.17 h

Procedure:
The product of EXAMPLE 54 (30 mg) in THF (2.5 mL) was combined with sodium hydride (5 mg, 60% in mineral oil). The suspension was stirred for 10 min were upon iodomethane (37 uL) was added. The reaction was stirred for about 6.5 hours at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and diluted with EtOAc. The EtOAc solution was dried (Na2SO4). The concentrated residue was purified by preparative TLC on silica gel eluted with 35% EtOAc in hexane affording the title compound. HPLC/MS: 486.2 (M+1), 488.2 (M+3); Rt=4.72 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:30])[C:3]=1[Cl:10]
Reactant: OCc1cncc(Br)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1c(Br)cncc1CBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
(5-Bromo-4-chloro-pyridin-3-yl)-methanol (400 mg, 1.80 mmol) and triphenylphosphine (566 mg, 2.16 mmol) are dissolved in DCM (20 mL) and N-bromosuccinimide (384 mg, 2.16 mmol) is added. The mixture is stirred for 4 hrs at room temperature. Then the reaction mixture is purified by flash column chromatography directly (without work-up) to give 300 mg of 3-bromo-5-bromomethyl-4-chloro-pyridine.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: c1ccc(NC2CCCCC2)cc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1ncc(Br)c(N(c2ccccc2)C2CCCCC2)n1
Temperature: 120 °C
Yield: 20.4 %

Procedure:
5-Bromo-2,4-dichloro-pyrimidine (2.17 ml, 17.14 mmol) and cyclohexyl-phenyl-amine (2.0 g, 11.43 mmol) were dissolved in N-methylpyrrolidone (NMP) (25 ml), and this reaction was heated to 120° C. for 24 hours. The reaction was cooled to room temperature and diluted with ethyl acetate, washed with water and brine. The organic phase was dried using sodium sulfate and concentrated. Purification by flash chromatography (ethyl acetate/hexane) gave compound 37 as a yellow solid (855 mg, 24%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.27 (1 H, s), 7.41 (3 H, m), 7.21 (2 H, m), 4.62 (1 H, m), 1.93 (2 H, d, J=10 Hz), 1.75 (2 H, d, J=10 Hz), 1.58 (1 H, d, J=10 Hz), 1.34 (2 H, m), 1.15 (2 H, m), 0.91 (1 H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[C:18](Cl)(=O)[CH3:19]>C1(C)C=CC=CC=1>[CH3:18][C:19]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(C(=O)O)ccc1Nc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc2cc(C(=O)O)ccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.7 %

Procedure:
A 2-neck flask was charged with 3-amino-4-phenylaminobenzoic acid (see Synthesis Example 1-2) (1.40 g, 6.35 mmol) and anhydrous toluene (15 mL) and this was refluxed. To this was added dropwise over approx. 15 minutes acetyl chloride (1.00 g, 12.70 mmol) in toluene solution (approx. 2.5 mL), and this was stirred under these conditions for 2.5 hours. This was allowed to cool to room temperature, and was extracted with dilute aqueous sodium hydroxide solution (10%, 200 mL). After separating the dark orange aqueous layer, it was cooled in ice (5 to 10° C.), and concentrated hydrochloric acid (12 M) was added to the liquid to give approx. pH 4. The precipitated crystals were filtered off, washed with distilled water, and dried under reduced pressure with heating to yield the title compound (1.34 g, 83.5% yield) as a light purple solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([CH2:14][C:15]1[C:16]([NH2:22])=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=1)[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[H-].[Na+]>CS(C)=O.O>[Br:21][C:19]1[CH:18]=[N:17][C:16]2[NH:22][C:3](=[O:2])[CH2:4][N:5]([CH2:6][CH2:7][N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH2:14][C:15]=2[CH:20]=1
Reactant: COC(=O)CN(CCN1CCOCC1)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CN(CCN2CCOCC2)Cc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
A solution of [(2-amino-5-bromo-pyridin-3-ylmethyl)-(2-morpholin-4-yl-ethyl)amino]acetic acid methyl ester (0.34 g, 0.88 mmol) in DMSO (10 mL) was treated with NaH (60% dispersion in mineral oil, 35 mg, 0.88 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (20 mL), and then extracted with EtOAc (4×50 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. The resulting pale yellow oil was purified by flash column chromatography (silica gel, CH2Cl2,/MeOH, 97:3 to 90:10) to give the title compound (0.24 g, 57%) as an off-white solid: MS (ESI) m/e 355 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:28])[C@@H:4]([NH:10][C:11](=[O:27])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]#[C:21][C@@H:22]2[CH2:24][C@H:23]2[CH2:25][OH:26])=[CH:14][CH:13]=1)[C:5]([CH3:9])([S:7][CH3:8])[CH3:6].[OH:29]O>C(#N)C.O>[OH:1][NH:2][C:3](=[O:28])[C@@H:4]([NH:10][C:11](=[O:27])[C:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]#[C:21][C@@H:22]2[CH2:24][C@H:23]2[CH2:25][OH:26])=[CH:16][CH:17]=1)[C:5]([CH3:9])([S:7]([CH3:8])=[O:29])[CH3:6]
Reactant: OO
Reactant: CSC(C)(C)[C@H](NC(=O)c1ccc(C#CC#C[C@@H]2C[C@H]2CO)cc1)C(=O)NO
Solvent: CC#N
Solvent: O
Product: CS(=O)C(C)(C)[C@H](NC(=O)c1ccc(C#CC#C[C@@H]2C[C@H]2CO)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 18 h
Yield: 89800 %

Procedure:
To a stirring solution of N—((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide (3, 0.2 g, 0.50 mmol) in acetonitrile/water (20 mL) was added 30% aqueous hydrogen peroxide (0.015 mL, 0.50 mmol) and the reaction mixture was stirred at room temperature for 18 hr. The reaction mixture was lyophylized to afford N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide (4, 200 mg, 449 mmol, 90%). MS: m/z calcd for C21H24N2O5S 416.14. found [M+H]+ 417.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:31])([F:30])[C:10]1[C:11]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1>C(Cl)Cl>[F:30][C:9]([F:8])([F:31])[C:10]1[C:11]([N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2ncccc2C(F)(F)F)CC1
Reaction time: 1 h
Yield: 58.1 %

Procedure:
A solution of TFA (10 mL) and CH2Cl2 (10 mL) was added to a flask containing the tert-butyl carbamate from Step 17A (1.39 g, 4.0 mmol). After 1 h, the mixture was concentrated, diluted with CH2Cl2 (100 mL), washed with 1N NaOH (100 mL), H2O (100 mL) and brine (100 mL), dried (MgSO4), and concentrated to afford the amine (0.57 g, 57%), a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.38-1.70 (m, 2H), 1.75-2.08 (m, 2H), 2.44 (br s, 2H), 2.71-3.21 (m, 3H), 3.59 (d, J=13.4 Hz, 2H), 6.76-7.13 (m, 1H), 7.85 (dd, J=7.7, 1.9 Hz, 1H), 8.41 (dd, J=4.8, 1.3 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[Br:20][CH2:21][CH2:22]Br>CC(N(C)C)=O>[Br:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1
Reactant: Cc1cccc(Nc2ncnc3ccc(O)cc23)c1
Reactant: BrCCBr
Solvent: CC(=O)N(C)C
Product: Cc1cccc(Nc2ncnc3ccc(OCCBr)cc23)c1
Temperature: 80 °C
Yield: 47 %

Procedure:
Using an analogous procedure to that described in Example 39, except that DMA was used in place of DMF and that the reaction mixture was heated to 80° C. for 4 hours, 6-hydroxy-4-(3'-methylanilino)quinazoline was reacted with 1,2-dibromoethane to give 6-(2-bromoethoxy)-4-(3'-methylanilino)quinazoline in 47% yield, m.p. 129°-135° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C-]#N.CO[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1.Cl>CO.C1(C)C=CC=CC=1>[OH:19][C:12]1[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:14][C:9]([CH2:8][C:1]#[N:2])=[CH:10][C:11]=1[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: COCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CC#N)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Sodium cyanide (2.94 g; 50 mmol) was slurried in methanol (20 mLs) in a 100 mL round bottom flask and the slurry was heated to a gentle reflux. To the cyanide slurry, a solution of 4-methoxymethyl-2,6-di-t-butyl phenol (12.5 g; 50 mmol), toluene (20 mLs) and methanol (25 mLs) was added dropwise over a period of time of 55 minutes. The resultant black reaction mixture was refluxed an additional 35 minutes after complete addition of the 4-methoxymethyl-2,6-di-t-butyl phenol. Upon cooling to ambient temperature, 2N hydrochloric acid (40 mLs) was added to the reaction flask. A yellow slurry which resulted was extracted with diethyl ether. The ether extract was dried (MgSO4) and concentrated in vacuo to afford 11.74 grams of 4-hydroxy-3,5-di-t-butylphenylacetonitrile as identified by NMR. Analysis by VPC indicated a 95% yield of 4-hydroxy-2,6-di-t-butylphenylacetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:15]4[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCCC2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCCC2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 91 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[2-(piperidin-1-yl)phenoxy]phenyl}-N-methyl-carbamate (1.19 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.80 g).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([NH2:23])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:27]=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>>[C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([NH:23][CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cc(OCc2ccccc2)c(OCc2ccccc2)cn1)C(=O)OCC
Temperature: 120 °C

Procedure:
A suspension of 4,5-bis(phenylmethoxy)-2-pyridinamine (8.7 g, 28.4 mmol) in diethyl ethoxymethylenemalonate (61.4 g, 284.0 mmol) was heated to 120° C. (bath temperature) for 2 hours. The major part of the diethyl ethoxymethylenemalonate was distilled off in vacuo and 100 ml of ether was added after cooling. The mixture was stored in the refrigerator overnight. The resulting crystals were filtered off with suction, washed with ether and dried in vacuo. Yield: 10.81 g; melting point 117.3° C.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)C(=O)O1.C1(OC2C=CC=CC=2)C=CC=CC=1>CC(OC)(C)C>[S:13]1[C:12]2[C:11](=[N:10][CH:9]=[CH:5][C:6]=2[OH:8])[CH:15]=[CH:14]1
Reactant: CC1(C)OC(=O)C(=CNc2ccsc2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: COC(C)(C)C
Product: Oc1ccnc2ccsc12
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
A 200-mL rb flask was charged with 2,2-dimethyl-5-((thiophen-3-ylamino)methylene)-1,3-dioxane-4,6-dione (6.73 g, 26.6 mmol) and diphenyl ether (25 mL) and heated to about 200 deg C. for about 30-45 min and the mixture was allowed to cool to rt overnight. The mixture was scraped down with a spatula and diluted with MTBE. The mixture was filtered through paper and washed with MTBE. The brown solid was air dried to yield thieno[3,2-b]pyridin-7-ol.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]([CH2:9][CH2:10][C@@H:11]([OH:19])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([OH:17])=O)[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:5]=1[C:33](NC1C=CC=CC=1)=[O:34])[CH3:3].[OH-:42].[Na+].Cl>C1COCC1.O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:7]2[N:8]([CH2:9][CH2:10][C@@H:11]3[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15](=[O:17])[O:19]3)[C:4]([CH:2]([CH3:3])[CH3:1])=[C:5]([C:33]([OH:34])=[O:42])[C:6]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:22]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)O)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@@H](O)CC(=O)O1

Procedure:
A solution of atorvastatin (prepared as described in U.S. Pat. Nos. 5,397,792 and 5,446,054) (1 mmol) and NaOH (10 mmol) in THF (30 mL) and water (10 mL) is maintained at 50° C. The progress of the reaction is monitored by tlc. When the reaction is complete, the solution is acidified with dilute HCl and extracted with CH2Cl2. The extract is then dried and evaporated. The residue is dissolved in toluene (50 mL) and the solution is heated at reflux until tlc monitoring shows that formation of the lactone moiety is complete. The solvent is removed under reduced pressure and compound 18 is purified by chromatography.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH3:23][O:24]/[C:25](=[CH:30]\[C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][CH3:44])[CH:38]=2)=[CH:33][CH:32]=1)/[C:26]([O:28][CH3:29])=[O:27]>>[CH3:23][O:24]/[C:25](=[CH:30]\[C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([N:43]([CH3:44])[C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH:38]=2)=[CH:33][CH:32]=1)/[C:26]([O:28][CH3:29])=[O:27]
Reactant: CNc1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
3.9 g (19.4 mmol) of 4-nitrophenyl chloroformate and then 3.4 mL (19.4 mmol) of diisopropylethylamine are added to a solution of 4.8 g (16.1 mmol) of methyl (Z)-2-methoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate. The reaction medium is stirred at room temperature for 2 hours. The reaction medium is hydrolyzed and then extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. 7.4 g (100%) of methyl (Z)-2-methoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate are obtained in the form of a tacky foam.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](Cl)=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][OH:20])[CH3:16]>C(Cl)(Cl)Cl>[N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([O:20][CH2:19][CH2:18][N:17]([CH2:21][CH3:22])[CH2:15][CH3:16])=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C=CC(=O)Cl)cc1
Reactant: CCN(CC)CCO
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCOC(=O)C=Cc1ccc(N=[N+]=[N-])cc1

Procedure:
In 80 g of chloroform was dissolved 6.2 g (30 millimoles) of the p-azidocinnamic acid chloride obtained in Example 16, and 3.5 g (30 millimoles) of 2-diethylaminoethanol was added dropwise while maintaining the solution temperature at 10° to 20° C., after which the resulting mixture was allowed to react for 1 hour. The chloroform was distilled off under reduced pressure, and 100 ml of water was added to the resulting oily substance, after which a solution of 1.3 g of sodium hydroxyde in 20 ml of water was added thereto on an ice bath. The organic layer separated was extracted with chloroform, and the extract was further washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 7.2 g of an oily substance as the distillation residue. This oily substance decomposed at 130° C. with formation of bubbles and generation of heat. This oily substance was identified as the compound of this invention by analysis using the following spectral means. ##STR117##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([NH2:19])=[CH:13][CH:12]=3)=[O:5])[CH3:2].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(N(C(C)C)C(C)C)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N:19]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)cc12
Reactant: BrCCCCCBr
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N3CCCCC3)cc12
Yield: 45.1 %

Procedure:
446 mg of 6-amino-beta-carboline-3-carboxylic-acid-ethylester in 17.5 ml of absolute ethanol is heated together with 410 mg of 1.5-dibromopentane and 500 mg of ethyldiisopropylamine under nitrogen for 4 h at the reflux. After adding 74 mg more of 1,5-dibromopentane, boiling proceeds for another 2 h at the reflux. After evaporation, the remainder is introduced in methylene chloride, washed with saturated bicarbonate solution as well as with saturated NaCl solution, filtered and concentrated. After recrystallizing in alcohol, ethyl acetate and a little ether, 255 mg of 6-(1-piperidinyl)-beta-carboline-3-carboxylic-acid-ethylester, m.p. 255°-256° C., is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[ClH:17].O1CCOCC1>C(O)C>[ClH:17].[NH:2]=[C:1]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: C1CCNC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: N=C(c1ccc(C(=O)O)cc1)N1CCCC1
Temperature: 35 °C

Procedure:
4-Cyanobenzoic acid (10.0 g, 68.0 mmol) was dissolved in anhydrous ethanol (10 ml) and 4N hydrochloric acid/1,4-dioxane 90 ml, and the mixture was stirred in a closed system at room temperature for two nights, and further stirred in an open system for at 35° C. 3 hours. The solvent was evaporated under reduced pressure, and the obtained residue was suspended in anhydrous ethanol (100 ml), and pyrrolidine (11.4 ml, 136 mmol) was added thereto, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration, and washed with diethyl ether containing a small amount of 4N hydrochloric acid/1,4-dioxane, and the crystals were collected by filtration to give the title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=CC(C2CN(C(C3C=CC=CC=3)C3C=CC=CC=3)C2)=[CH:5][CH:4]=1.C(C1C=C[C:35]([C:38]2([Cl:55])[CH2:41][N:40]([CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:39]2)=[CH:34]C=1)(C)(C)C>>[Cl:55][C:38]1([C:35]2[CH:34]=[CH:5][CH:4]=[C:3]([C:2]([F:27])([F:26])[F:1])[CH:8]=2)[CH2:41][N:40]([CH:42]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:39]1
Reactant: CC(C)(C)c1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: FC(F)(F)c1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Product: FC(F)(F)c1cccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)c1

Procedure:
This compound was prepared from compound (32) using the procedure described for compound (10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][N:23]([CH3:36])[C:24](=[O:35])[CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](O)=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:26](=[O:27])[CH:25]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:24]([N:23]([CH3:36])[CH3:22])=[O:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NCCc2ccc(OC)c(OC)c2)cc1
Reactant: CN(C)C(=O)C(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(CCc2ccc(OC)c(OC)c2)C(=O)C(C(=O)N(C)C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.7 %

Procedure:
A mixture of 28.7 mg (0.1 mmol) [2-(3,4-Dimethoxy-phenyl)-ethyl]-(4-methoxy-phenyl)-amine (intermediate 2), 20.7 mg (0.1 mmol) N,N-Dimethyl-2-phenyl-malonamic acid (WO2000009481), 38.5 mg (0.12 mmol) TBTU and 38.7 mg (0.3 mmol) DIPEA in 3 mL DMF was stirred at room temperature for 16 h. The mixture was concentrated diluted with methanol and formic acid and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid, the product containing fractions were evaporated to yield 23.2 mg (61%) of the title compound. MS(m/e): 477.2 (MH+).