Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[C:28]([C:30]3[O:34][N:33]=[C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:31]=3[C:41]([F:44])([F:43])[F:42])[O:27][N:26]=2)=[CH:21][CH:20]=1)[C:3]([NH:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O)=[O:4].[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>>[OH:1][CH:2]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:29]=[C:28]([C:30]3[O:34][N:33]=[C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:31]=3[C:41]([F:42])([F:43])[F:44])[O:27][N:26]=2)=[CH:23][CH:24]=1)[C:3]([NH:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)=[O:4].[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]
Reactant: CC(C)(C)OC(=O)N1CCCC1CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CCCN1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.5 h

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), 2-(aminomethyl)-1N-Boc-pyrrolidine (20.9 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 25 mL/min, 220 nM, product retention=32.9 min) to provide (R/S)-tert-butyl 2-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)pyrrolidine-1-carboxylate (28 mg, 0.046 mmol, 65.6% yield): LCMS=614.3 [M+H]+. The (R/S)-tert-butyl 2-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)pyrrolidine-1-carboxylate (28 mg, 0.046 mmol) was added to TFA (1 mL, 12.98 mmol) and stirred for 30 min. The reaction mixture was concentrated to provide (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(pyrrolidin-2-ylmethyl)acetamide, TFA (24 mg, 0.037 mmol, 80% yield): LCMS=514.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=7.92 Hz), 7.54-7.79 (7 H, m), 5.21 (1 H, s), 3.66-3.81 (1 H, m), 3.48-3.62 (2 H, m), 3.16-3.30 (2 H, m), 1.91-2.18 (3 H, m), 1.70-1.82 (1 H, m); HPLC peak RT=8.3 min (Condition A).
Reaction SMILES: [CH2:1]([NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2C(=O)C3=CC=CC=C3C2=O)[N:8]=1)[CH2:2][CH3:3].[NH3:30]>CN(C=O)C>[CH2:1]([N:4]=[C:5]([NH2:30])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[N:8]=1)[CH2:2][CH3:3]
Reactant: N
Reactant: CCCNC(=S)Nc1ccnc(CCCCCN2C(=O)c3ccccc3C2=O)n1
Solvent: CN(C)C=O
Product: CCCN=C(N)Nc1ccnc(CCCCCN)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(3-propylthioureido)-2-(5-phthalimidopentyl)pyrimidine (1.7 g.), DMF (25 ml.) saturated ethanolic ammonia (10 ml.) and yellow mercuric oxide (1.1 g.) was stirred at room temperature for 2 hours. The mixture was evaporated to dryness and the residue was redissolved in ethanol, filtered and the filtrate evaporated to dryness. A solution of this residue in EtOH (20 ml.) was treated with hydrazine (5 ml.) and stirred at room temperature for 16 hours. The mixture was evaporated to dryness and the residue was dissolved in water, acidified with 2N aqueous HCl and filtered. The filtrate was basified with 10N aqueous NaOH and the mixture was extracted twice with EtOAc. The extract was dried (MgSO4) and evaporated to give 4-[2-propylguanidino]-2-(5-aminopentyl)pyrimidine as a gum (0.4 g.) which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([CH3:8])=[CH:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1.[C-:15]#[N:16].[K+].O>CS(C)=O>[CH3:8][C:7]1[C:3]([CH2:2][C:15]#[N:16])=[N:4][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1
Reactant: [C-]#N
Reactant: Cc1cn(-c2ccccc2)nc1CBr
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn(-c2ccccc2)nc1CC#N
Temperature: 60 °C
Yield: 113.2 %

Procedure:
A mixture of 3-(bromomethyl)-4-methyl-1-phenyl-1H-pyrazole (112 mg, 446 μmol) and potassium cyanide (33.3 mg, 491 μmol) in DMSO (2 mL) was heated to 60° C. for 2 h. The reaction mixture was cooled to RT, poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The organic phases were washed with water (3×25 mL) and brine 1×25 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 99.6 mg crude material. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow oil (58 mg, 294 μmol, 65.9%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[N:6][CH:7]=[N:8][C:9]=1Cl.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C@@H:12]1([NH:11][C:5]2[C:4]3[CH2:3][CH2:2][NH:1][C:9]=3[N:8]=[CH:7][N:6]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: NCCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: c1ccc2c(c1)CC[C@@H]2Nc1ncnc2c1CCN2
Temperature: 160 °C
Yield: 92.8 %

Procedure:
5-(2-aminoethyl)-6-chloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]pyrimidin-4-amine (1.00 g, 3.46 mmol) and N,N-diisopropylethylamine (1.21 mL, 6.92 mmol) were dissolved in 1,4-dioxane (19 mL) and the solution was heated in a pressure tube at 160° C. for 48 hours. At that time, LCMS indicated complete conversion. Solvent was removed in vacuo and the residue was purified using chromatography on silica gel using gradient 0 to 20% MeOH in methylene chloride to afford the title compound (0.81 g, 93%). LC/MS: Rt=1.55 min, ES+ 253 (AA standard).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[CH:11]=2)[CH:6]=1)=[O:4]>[Cr].[Co]>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Co]
Agent: [Cr]
Product: O=C(O)c1ccc2cc(C(=O)O)ccc2c1

Procedure:
Dimethyl-2,6-naphthalenedicarboxylate was hydrolyzed at elevated temperatures and elevated pressures in the batch-mode in a stirred, 300 ml Hastelloy C autoclave reactor. 37.5 Grams of dimethyl-2,6-naphthalenedicarboxylate were charged to the reactor. No catalyst was used. The 2,6-NDA product was separated from the mother liquor by filtration at room temperature followed by washing with about 150 grams of water. The reaction time, temperature, pressure and analysis of the resulting 2,6-naphthalenedicarboxylic acid are provided in Table 2. During each of the runs reported in Table 2, approximately one-half of the solvent was unintentionally lost. This loss of solvent likely caused the removal of methanol from the reaction mixture thereby shifting the equilibrium towards 2,6-naphthalenedicarboxylic acid. Runs 1, 2 and 3 reported in Table 2 were run consecutively in the same autoclave reactor.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH:47]1[C:51]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3([NH2:61])[CH2:60][CH2:59]3)=[CH:54][CH:53]=2)=[N:50][N:49]=[N:48]1.C(N(CC)CC)C>CN(C)C=O>[NH:50]1[C:51]([C:52]2[CH:53]=[CH:54][C:55]([C:58]3([NH:61][C:7](=[O:9])[C:6]4[CH:10]=[C:2]([Cl:1])[CH:3]=[N:4][C:5]=4[N:11]4[CH2:14][CH:13]([O:15][C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=5)[CH2:12]4)[CH2:59][CH2:60]3)=[CH:56][CH:57]=2)=[N:47][N:48]=[N:49]1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Reactant: NC1(c2ccc(-c3nnn[nH]3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1(c2ccc(-c3nnn[nH]3)cc2)CC1)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To mixture of 5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinic acid (D77) (60 mg, 0.186 mmol) in dry dimethylformamide (1 ml), 1-Hydroxybenzotriazole hydrate (28.5 mg, 0.189 mmol), 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide Hydrochloride (53.5 mg, 0.279 mmol) were added followed by the addition of a solution of 1-(4-(1H-tetrazol-5-yl)phenyl)cyclopropanamine hydrochloride (D17) (44.2 mg, 0.186 mmol) and triethylamine (26 μl, 0.189 mmol) in dry dimethylformamide. The mixture was stirred for 1 h at room temperature. The solvent was evaporated in vacuo and the resulting residue was taken in NH4Cl sat. sol (10 ml) and extracted with ethylacetate (2×10 ml). Collected organics after solvent evaporation afforded a residue that was washed with methanol (2 ml) to afford the title compound (E82) (30.8 mg)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]2[N:8]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2cccc(Cl)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCn1c([C@@H]2CCCNC2)nc2cccc(Cl)c21

Procedure:
(R)-tert-Butyl 3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (0.222 mmol, 0.090 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir under nitrogen for 4 hr. The reaction was then concentrated and dried in-vacuo affording (R)-7-Chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (30E) a brown oil and used without further purification. ESI-MS: m/z 308.2 (M+H)+.
Reaction SMILES: CO[C:3](=[O:39])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]3=[N:14][CH:15]=2)[CH:7]=[C:6]([F:37])[C:5]=1[OH:38].[CH3:40][NH:41][CH3:42]>C1COCC1>[F:37][C:6]1[C:5]([OH:38])=[C:4]([CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:7]=1)[C:3]([N:41]([CH3:42])[CH3:40])=[O:39]
Reactant: CNC
Reactant: COC(=O)c1cc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)cc(F)c1O
Solvent: C1CCOC1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(F)c(O)c(C(=O)N(C)C)c3)cc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
22 mg (40 μmol) of 3-fluoro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid methyl ester was dissolved in 2 ml of a 2 M solution of dimethylamine in THF. The solution was heated to 100° C. in a closed vial for 24 h and then concentrated. The residue was dissolved in 2 ml of methanol and 350 μl of 50% w/v aqueous potassium hydroxide added. The mixture was left at ambient temperature for 1 h and then neutralized by addition of glacial acetic acid. The crude was directly purified by mass triggered reverse phase HPLC purification to afford 6.0 mg (14 μmol; 37% yield) of 3-fluoro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as an ivory solid. 1H-NMR (d6-DMSO): δ 11.91 (s, 1H), 8.51 (d, 1H), 8.14 (d, 1H), 7.73 (d, 1H). 7.64 (d, 1H) 7.62 (dd, 1H), 7.32-7.25 (m, 2H), 7.14 (d, 1H), 7.05 (m, 1H), 3.82 (s, 3H), 2.99 (s, 3H), 2.87 (s, 3H). MS: m/z 406 [MH+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:20](=O)[NH2:21])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([CH2:20][NH2:21])[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCCC(NC(=O)OC(C)(C)C)C(N)=O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CCCC(CN)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of [1-carbamoyl-4-(4-methoxy-phenyl)-butyl]-carbamic acid tert-butyl ester (0.5 g, 1.48 mmol) in THF (15 mL) is treated dropwise with 1M borane-THF complex (4.47 mL, 4.47 mmol) and then heated at reflux for 2 h. After cooling to RT, MeOH (20 mL) is added and the mixture is heated again at reflux for 2 h. The solvent is removed in vacuo and the resulting oil is dissolved in DCM (10 mL) and filtered through Celite® (filter material). The filtrate is concentrated in vacuo to afford the title compound as a colourless oil. [M+H]+ 308.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.O>[Br:20][C:18]1[CH:17]=[CH:16][C:13]2[C:14]3[N:15]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=3[CH2:9][CH2:10][O:11][C:12]=2[CH:19]=1
Reactant: CCOC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 2 h

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester from Example 21 (518 mg) in tetrahydrofuran (10 ml) was added a solution of sodium hydroxide (117 mg) in water (2 mL) Methanol (5 mL) was also added to aid dissolution. After 2 hours, the reaction mixture was acidified with HCl (2M) and the reaction mixture was then extracted with dichloromethane, dried (MgSO4) and the solvent removed in vacuo to yield 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]([NH2:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.C(Cl)(=O)OCC.[OH-].[Na+].[C:30](=S)=[S:31]>O1CCCC1.O.C(Cl)Cl>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[C:10]([N:14]=[C:30]=[S:31])[C:11]([CH3:13])=[CH:12][C:3]=1[O:2][CH3:1])=[O:6]
Reactant: COC(=O)c1cc(N)c(C)cc1OC
Reactant: S=C=S
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cc(N=C=S)c(C)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
To a solution of methyl 2-methoxy-4-methyl-5-aminobenzoate (975 mg) in tetrahydrofuran (5 ml) are added triethylamine (1.52 g) and carbon disulfide (1.14 g), and the resultant mixture is stirred at room temperature for 2.5 hours. Ethyl chlorocarbonate (1.63 g) is added to the mixture, which is stirred for additional 20 minutes at room temperature. A solution of sodium hydroxide (1.2 g) in water (32 ml) is added to the mixture, which is stirred for 15 minutes. The reaction mixture is mixed with an excess amount of water and shaken with methylene chloride. The organic layer is dried over Glauber's salt and the solvent is evaporated. The residue is dissolved in methylene chloride and chromatographed on a column of silica gel. Evaporating the solvent from the elution, the residue is dissolved in isopropyl ether and n-hexane is added thereto. The precipitated crystals are filtered to give 3-methoxycarbonyl-4-methoxy-6-methylphenyl isothiocyanate (952 mg) as crystals melting at 86°-87.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[Br:30][CH2:31]/[CH:32]=[CH:33]/[C:34](Cl)=[O:35]>O1CCCC1>[Br:30][CH2:31]/[CH:32]=[CH:33]/[C:34]([NH:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:21][CH3:22])[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)=[O:35]
Reactant: O=C(Cl)/C=C/CBr
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of N4-(3-chloro-4-fluorophenyl)-7-methoxy-4,6-quinazolinediamine (8) (4.0 g, 12.5 mmol) in dry tetrahydrofuran (150 mL) under nitrogen was added triethylamine (19 mmol), followed by freshly prepared (2E)-4-bromo-2-butenoyl chloride (15 mmol) in dry tetrahydrofuran (50 mL). The resulting solution was then stirred at room temperature for 2 hours and concentrated under reduced pressure. Trituration from dichloromethane gave crude (2E)-4-bromo-N-[4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinyl]-2-butenamide (4.6 g) that was used directly.
Reaction SMILES: [CH:1]1([C:6](=O)[CH2:7][N+:8]([O-:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(O)(O)(=O)=O.[NH2:17][OH:18]>C1(C)C=CC=CC=1.C(O)C>[CH:1]1([C:6](=[N:17][OH:18])[CH2:7][N+:8]([O-:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(C[N+](=O)[O-])C1CCCC1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])CC(=NO)C1CCCC1
Yield: 88.7 %

Procedure:
9.90 g (63 mmol) of 1-cyclopentyl-2-nitro-ethanone (example II) and 20.688 g (126 mmol) of hydroxylamine sulfate are heated under reflux, for 4 hours, in 310 ml of a toluene/ethanol mixture (1:1). The solvent is removed in vacuo and the residue is taken up in ethyl acetate; the organic phase is washed 2 times with water and dried over sodium sulfate and the solvent is removed in vacuo. 9.62 g (74%) of pale yellow solid are obtained.
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]([OH:29])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([O-:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@@H:10]([OH:30])[CH2:9]1)=[O:6])[CH3:4].[Na+].[OH-].[Na+].C(#N)C>C(O)C.O>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:29])[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]([OH:30])[CH2:9]1)=[O:6])[CH3:4]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)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: CC#N
Solvent: O
Solvent: CCO
Product: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Temperature: 50 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Pravastatin sodium (5 g) was dissolved in a 1:1 mixture of ethanol:water (5 ml). The pH was raised to 8.5 by addition of 2M sodium hydroxide in water (1.2 ml) and the solution was heated to 50° C. Acetonitrile (90 ml) was added to the mixture and then the mixture was stirred at elevated temperature for one hour. The mixture was allowed to cool to 20-25° C. (“ambient temperature”), was held at ambient temperature for two hours and then cooled to 5° C. and maintained at 5° C. for 12 hours, whereupon pravastatin sodium crystallized. The crystals were then isolated by filtration and washed with acetonitrile (2×10 ml) and dried under vacuum at 50° C. X-ray diffraction analysis revealed the presence of Form A. Pravastatin Form A was obtained in 92% yield.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.N.CO>O1CCCC1>[N:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]2[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:23][CH:24]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccncc2)cc1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(/C=C/c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a suspension of lithium aluminum hydride (92.8 mg) in tetrahydrofuran (12 ml) was added methyl 4-[(E)-2-(4-pyridyl)vinyl]benzoate (1.17 g), and after stirring for 2 hours at ambient temperature, ammonia solution and methanol were added thereto. The mixture was stirred for 2 hours at ambient temperature. Insoluble material was filtered off, and the filtrate was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized with diisopropyl ether to give 4-[(E)-2-(4-pyridyl)vinyl]benzyl alcohol (762 mg).
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1.[C:14]1([O:22][CH3:23])[C:15](=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:16][CH3:17]>C1(C)C=CC=CC=1>[OH:13][CH:12]([C:9]1[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[C:15]([O:16][CH3:17])[C:14]=1[O:22][CH3:23]
Reactant: COc1ccccc1OC
Reactant: O=Cc1ccncc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COc1cccc(C(O)c2ccncc2)c1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In a 2 L flask, 72 g of veratrole was dissolved in 300 g of toluene and 155.3 g of butyl lithium in toluene were added at temperatures from −10° C. to over 30° C. The mixture was stirred from 1-4 hours at ambient temperature. Then 40 g of 4-pyridinecarboxaldehyde (9) in 180 mL of toluene was added at around ambient temperature. The reaction mixture was stirred from 30 minutes to 5 hours. The solution was then cooled to around 5° C. and quenched with 200 mL of water. The solution was then heated to 40-85° C. and subsequently cooled to −5° C. The product was collected by filtration and washed with 60 g of water and 60 g of toluene. The yield was about 80 g of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].O.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[C:7]([C:8]([N:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27]2)=[O:10])=[CH:6][C:5]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)Oc1ccc(Br)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(OS(C)(=O)=O)ccc2Br)CC1
Reaction time: 0.5 h

Procedure:
To a solution the product from Step A (858 mg, 2.89 mmol), N-tert-butoxycarbonylpiperazine (540 mg, 2.89 mmol), and 1-hydroxybenzotriazole hydrate (546 mg, 4.05 mmol) in 4 mL of dimethylformamide was added 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (718 mg, 3.75 mmol). After 30 minutes, the reaction was poured into EtOAc and washed with water, 3N HCl solution, saturated NaHCO3 solution, and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a white foam which was used without further purification.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([C:22]([NH:10][CH2:9][C:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)=[O:8])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NCC(=O)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)C1CCCCC1)c1ccco1
Yield: 89.3 %

Procedure:
5.0 g of (2-furylcarbonyl)methylamine hydrochloride, 7.6 g of sodium bicarbonate and 4.8 g of cyclohexylcarbonyl chloride are treated in the same manner as described in Preparation 1-(1). 6.5 g of N-cyclohexylcarbonyl-(2-furylcarbonyl)methylamine are thereby obtained. Yield: 91.5%
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CCOC(C)=O.CCCCCC.CCOC(C)=O>O1CCOCC1>[O:12]1[CH2:13][CH2:14][N:9]([C:2]2[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=2)[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: O=Cc1csc(Br)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=Cc1csc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a slurry of 2-bromothiazole-4-carbaldehyde (1.0 g, 5.21 mmol) in p-dioxane (5 mL) was added morpholine (1.36 g, 15.61 mmol) over 1 min. The mixture was heated to 100° C. for 1 h (monitored by TLC, EtOAc/hexane 1:1) and cooled to room temperature. EtOAc (20 mL) was added and the solid residue filtered off and washed with EtOAc (30 mL). The combined organic layer was washed with brine (30 mL) and concentrated. The residue was purified by silica gel flash column chromatography using 20 to 75% EtOAc in hexane to afford the title compound as a light tan solid (780 mg, 75%): 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.49 (s, 1H), 3.82 (t, 41-1, J=4.8 Hz), 3.56 (t, 4H, J=4.8 Hz). MS (ES) m/z 199.1 (M+H+).