Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[NH:4][CH2:5][CH2:6][N:7]=1)[NH2:2].Br.[OH-].[Na+].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:11]1([CH2:17][C:18]([C:3]2([NH:1][NH2:2])[N:4]=[CH:5][CH:6]=[N:7]2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNC1=NCCN1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: NNC1(C(=O)Cc2ccccc2)N=CC=N1

Procedure:
Phenylacetic acid (PAA), 0.037 moles (5g) was heated under reflux with an excess of SOCl2 for 60 minutes at a temperature of 75-80° C. After the reaction was completed, the excess SOCl2 was eliminated by vacuum evaporation, using a water pump (40-50° C.). This process was repeated two to three times, each time adding benzene to aid in elimination of SOCl2 and yielding phenylacetyl chloride (PAC). Then, 0.018 mole of 2-hydrazino-2-imidazoline.HBr (3.5 g) was suspended in ether and shaken with 2N NaOH (2-5 equivalents) on an ice bath, until it was completely dissolved. The PAC was then added dropwise very slowly from a funnel with vigorous shaking. Excess NaOH was present to drive the reaction to completion. After the addition of PAC, the mixture was stirred at 0C for an additional 15-30 minutes. The ether layer was washed with water, then with saturated NaHCO3. It was then dried over Na2SO4, filtered and was brought to complete dryness. The solid residue from the ether layer was then crystallized from an ethanol-water mixture (70-80% ethanol). The yield, was approximately 55% without subjecting the residual amide to further separation from the aqueous layer.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:17]=[C:12]([CH3:11])[CH:13]=[CH:14][CH:15]=2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1O
Reactant: Cc1cccc(B(O)O)c1
Solvent: ClCCl
Product: COc1cc(Br)ccc1Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-2-methoxyphenol (1.0 g, 0.0049 mol), 3-methylbenzeneboronic acid (1.7 g, 0.012 mol), TEA (4.1 mL, 0.030 mol), cupric acetate (1.4 g, 0.0079 mol) and DCM (50 mL) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=2.31 (s, 3H), 3.83 (s, 3H), 6.68-6.77 (m, 2H), 6.82 (d, J=8.34 Hz, 1H), 6.87 (d, J=7.58 Hz, 1H), 7.03 (dd, J=8.46, 2.15 Hz, 1H), 7.11 (d, J=2.27 Hz, 1H), 7.17 (t, J=7.83 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19]([C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:24]=2[CH:25]=1)=[O:20]>CO>[NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:30][C:27]3[CH:28]=[CH:29][C:23]4[O:22][C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:25][C:24]=4[CH:26]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Solvent: CO
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(N)c4)n3)ccc2o1
Temperature: 100 °C

Procedure:
A mixture of N4-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidineamine (10 mg, 0.06 mmol) and 2-methoxycarbonyl-5-aminobenzofuran (36 mg, 0.18 mmol) in dry MeOH (0.5 ml) was refluxed for 2 days (100° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3:Acetone, 9:1) to give N4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.24 (s, 1H), 7.96 (dd, 1H, J=1.7, 3.5 Hz), 7.46-7.59 (m, 3H), 6.93-6.99 (m, 2H), 6.84 (d, 1H, J=8.2 Hz), 6.35 (m, 1H), 3.84 (s, 3H); LCMS purity: 97.8%; MS (ES), m/e 394.02 (M+, 70).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].[CH2:21]([NH2:23])[CH3:22]>>[NH2:1][C:2]1[N:10]=[C:9]([NH:23][CH2:21][CH3:22])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Yield: 71 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and aqueous ethylamine (50 ml) were heated at 120° C. for 20 hours in autoclave. The reaction mixture was condensed in vacuo. To the residue was added 5N aqueous sodium hydroxide and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (147 mg, yield 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.Cl.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=2[C:40]([F:43])([F:42])[F:41])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:25][CH2:26][CH:27]([O:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[N:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=5)[CH:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:36])=[CH:33][C:32]=2[C:40]([F:41])([F:42])[F:43])[CH2:28][CH2:29]1
Reactant: CN1CCC(Oc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(OC3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
This compound was prepared in the same manner as in Example 1, except that 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (Patent Document 1) and 4-(1-methylpiperidin-4-yloxy)-3-trifluoromethylbenzoyl chloride hydrochloride (Reference Example 11) were used.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[O:9][CH:8]2OCC)([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20].C(O)(=O)C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:9])[NH:20][N:19]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC1OC(=O)c2ccc(C(C)(C)C)cc21
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2c(=O)[nH]ncc2c1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
2.9 g (12 mmol) of 5-tert-butyl-3-ethoxy-3H-isobenzofuran-1-one was weighed into a 50 mL round bottom flask fitted with a stir bar and cap. Added 10 mL (130 mmol) of hydrazine monohydrate. Added 15 mL of glacial acetic acid. Stirred at 100° overnight. Poured the reaction mixture into 200 mL of stirred water. Collected the solids by filtration and washed with water. Dried under high vacuum to obtain 2.24 g of the title compound as an off-white solid. MS (ESI) 203 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH3:24])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)=[C:4]([Cl:25])[CH:3]=1.[CH3:26][C:27]([CH3:29])=[O:28].CO>C1COCC1>[Cl:25][C:4]1[CH:3]=[C:2]([C:27]([OH:28])([CH3:29])[CH3:26])[CH:7]=[CH:6][C:5]=1[CH:8]1[S:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]([CH3:24])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:9]1=2
Reactant: CC(C)=O
Reactant: Cn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(Br)cc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(C)(C)O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a degassed solution of 4-(4-bromo-2-chloro-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.255 g, 0.59 mmol, see Ex.#3 step D) in anhydrous THF (2.5 mL) was added dropwise isopropylmagnesium chloride lithium chloride complex solution (2.25 mL, 1.3 M in THF, 2.93 mmol) at about 0° C. After complete addition, the mixture was stirred at rt for about 4 h, then cooled to about −40° C. and acetone (0.3 mL, 4.1 mmol) was added dropwise. Subsequently, the mixture was warmed to rt, treated with methanol (2 mL) and concentrated in vacuo. The residue was dissolved in ethyl acetate (40 mL), washed with saturated aqueous ammonium chloride (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, diethyl ether) to give 2-[3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]phenyl]propan-2-ol (0.095 g, 0.23 mmol, 39%) as a white foam: LC-MS (Table 1, Method e) Rt=6.53 min; m/z 415 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 1.52 (3 H, s) 1.53 (3 H, s) 1.69 (1 H, s) 2.71 (1 H, ddd, J=15.0, 5.2, 2.0 Hz) 2.88 (1 H, ddd, J=15.0, 9.3, 2.6 Hz) 3.21-3.29 (1 H, m) 3.57-3.66 (1 H, m) 3.79 (1 H, dd, J=3.8, 5.4 Hz) 3.83 (3 H, s) 6.84 (1 H, s) 7.08 (1 H, ddd, J=7.5, 4.8, 1.1 Hz) 7.20 (1 H, dd, J=8.1, 1.8 Hz) 7.27 (1 H, d, J=8.1 Hz) 7.52 (1 H, d, J=1.8 Hz) 7.59 (1 H, td, J=7.9, 1.8 Hz) 7.73 (1 H, dt, J=7.9, 1.1 Hz) 8.53 (1 H, ddd, J=4.8, 1.8, 1.0 Hz); and 4-(2-chlorophenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.035 mg, 0.10 mmol, 17%) as a white foam: LC-MS (Table 1, Method e) Rt=7.62 min; m/z 357 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.72 (1 H, ddd, J=15.1, 6.1, 2.2 Hz) 2.87 (1 H, ddd, J=15.1, 9.1, 2.5 Hz) 3.23-3.32 (1 H, m) 3.57-3.66 (1 H, m) 3.81 (1 H, br s) 3.84 (3 H, s) 6.82 (1 H, s) 7.05-7.13 (3 H, m) 7.25-7.31 (1 H, m) 7.36-7.42 (1 H, m) 7.59 (1 H, td, J=7.7, 1.5 Hz) 7.72 (1 H, dt, J=8.0, 1.1 Hz) 8.52 (1 H, ddd, J=4.8, 1.5, 0.8 Hz).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:25])[N:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:28][C@H:29]([C:36]([NH:38][C@@H:39]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH:40]([OH:47])[C:41]([O:43][CH:44]([CH3:46])[CH3:45])=[O:42])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:25])[N:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]([NH:28][C@H:29]([C:36]([NH:38][C@@H:39]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH:40]([OH:47])[C:41]([O:43][CH:44]([CH3:45])[CH3:46])=[O:42])=[O:37])[CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(O)C(=O)OC(C)C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(C)C)C(O)C(=O)OC(C)C
Yield: 10.3 %

Procedure:
To a solution of 50 mg of 2-(1-naphthylmethyl)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionic acid and 70 mg of isopropyl(2RS,3S)-3-(L-histidyl)amino-2-hydroxy-5-methylhexanoate dihydrochloride in 4 ml of N,N-dimethylformamide were added 0.036 ml of diphenylphosphoryl azide and 0.064 ml of triethylamine with stirring under ice-cooling, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol=5/1 by volume; Rf2 =0.36) to obtain 10 mg of isopropyl(2RS,3S)-3-{N-[2-(1-naphthylmethyl)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[C:6]=1[O:17][CH3:18].C([Li])CCC.CN([CH:27]=[O:28])C.O>CCOCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([O:17][CH3:18])=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[C:10]=1[CH:27]=[O:28]
Reactant: COCOc1cc(OC)c(OC)c(OC)c1OC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COCOc1c(C=O)c(OC)c(OC)c(OC)c1OC
Temperature: -20 °C

Procedure:
6.2 g of 1-methoxymethyloxy-2,3,4,5-tetramethoxybenzene prepared in Referential Example 13 was dissolved in 50 ml of anhydrous ether, and 18 ml of n-butyllithium (1.6M n-hexane solution) was dropwise added thereto at -20° C. while stirring. After the mixture was stirred at 0° C. for 30 min, the temperature was returned to -20° C. and 3.5 ml of DMF was dropwise added thereto. After 100 ml of water was added thereto, the mixture was extracted with ethyl acetate, and the organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=7:3) to prepare 5.6 g of the product compound as a light yellow oleaginous substance.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]([CH3:20])[N:4]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][N:5]1[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:7][C:3]([CH2:2][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]3[CH:7]=[C:6]([C:8]4[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=4)[N:5]([CH3:20])[N:4]=3)[CH2:23][CH2:22]2)=[N:4]1
Reactant: COc1cc(-c2cc(CCl)nn2C)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2cc(CN3CCCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)n(C)n4)CC3)nn2C)cc(OC)c1OC

Procedure:
3-Chloromethyl-1-methyl-5-(3,4,5-trimethoxy-phenyl)pyrazole (119 mg) and homopiperazine (20 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5](=[C:6]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=[CH:13][C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH2:4][CH2:3]1.[H][H]>C(O)(=O)C.C(O)C.[Pt]=O>[CH:11]1[C:12]2[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:6](=[C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:22][CH2:21]3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Yield: 94.2 %

Procedure:
Dissolved cyproheptadine (22.2 g, 0.077 mol) in 150 mL of glacial acetic acid and 20 mL of ethanol. Added platinum oxide catalyst (1.0 g), and hydrogenated on Paar shaker at 57 psi of hydrogen pressure for 5 hours. Filtered, and evaporated filtrate to give a solid. Recrystallized crude product from ether-pet ether to give 21.0 g (94% yield) of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1.[CH2:24]=[O:25].C([N-]C(C)C)(C)C.[Li+].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([C:8]2([CH2:24][OH:25])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1
Reactant: C=O
Reactant: CCCCCN1C(=O)C(c2cc(F)ccc2O)c2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(CO)(c2cc(F)ccc2O)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(5-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one (2.10 g, 6.70 mmol) in THF (20.0 mL) were added paraformaldehyde (1.76 g, 58.8 mmol) and lithium diisopropylamide (7.35 mL, 2.0 M in THF, 14.7 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs followed by the addition of ammonium chloride solution (10.0 mL) and ethyl acetate (100 mL). The organic layer was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to dryness to give the title compound: 1H NMR (300 MHz, CDCl3) δ 9.55-9.10 (br, 1H), 7.53-6.86 (m, 6H), 6.57-6.49 (m, 1H), 4.74-4.30 (br, 1H), 4.18-4.07 (m, 2H), 3.79-3.60 (m, 2H), 1.77-1.61 (m, 2H), 1.41-1.24 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 326 (M−17), 366 (M+23).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[CH3:15][NH:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:15][N:16]([C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[N:3]=1)[NH2:17]
Reactant: Cc1nc(Cl)cc(-c2ccccc2)n1
Reactant: CNN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1nc(-c2ccccc2)cc(N(C)N)n1

Procedure:
N-methyl-N-(2-methyl-6-phenyl-pyrimidin-4-yl)-hydrazine was prepared from 4-chloro-2-methyl-6-phenylpyrimidine (500 mg, 2.4 mmol), methylhydrazine (0.52 mL, 9.8 mmol) and potassium carbonate (506 mg, 3.7 mmol) in 5 mL of 1,4 dioxane by a procedure similar to example 3, step 1 yielding 392 mg (75%) of a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[F:19][C:20]([F:40])([F:39])[C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:25](B(O)O)[CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:23]2[CH:22]=[C:21]([C:20]([F:40])([F:19])[F:39])[CH:26]=[CH:25][C:24]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Product: CCOC(=O)c1cc(F)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using [5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.
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]>ClCCl>[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: ClCCl
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Yield: 61.8 %

Procedure:
Fluvastatin methyl ester (3.0 g) was dissolved in dichloromethane (35 ml). NaOH (0.29 g) was added and the mixture was stirred at room over night. The product was isolated by filtration under nitrogen, washed with dichloromethane (20 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 1.89 g (62%) of fluvastatin sodium Form C.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]2=[N:4][C:3]=1[C:14]([O:16]CC)=O.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:14]([C:3]2[N:4]=[C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:6]3[C:7](=[O:8])[C:2]=2[OH:1])=[O:16])=[CH:22][CH:21]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2C
Product: CN1C(=O)Cn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Yield: 61.1 %

Procedure:
Reaction of intermediate 13, ethyl 6-hydroxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.050 g, 0.197 mmol) with 4-fluorobenzylamine (0.11 g, 0.87 mmol) as described in the preparation of example 1 gave 0.040 g (60% yield) of the title amide as white crystals. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.15 (3H, s, NCH3), 4.49 (2H, s, CH2), 4.5 (2H, d, J=6.5 Hz, CH2), 7.18 (2H, m, aromatics), 7.38 (2H, m, aromatics), 9.49 (1H, broad t, NH), 12.28 (1H, s, OH). MS (ESI+) m/z 333 [M+H+].
Reaction SMILES: [C:1]([C:3](=[C:9](SC)[S:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[NH2:14][NH2:15]>CC(O)C>[NH2:2][C:1]1[NH:15][N:14]=[C:9]([S:10][CH3:11])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Reactant: NN
Solvent: CC(C)O
Product: CCOC(=O)c1c(SC)n[nH]c1N
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of ethyl 2-cyano-3,3-bis(methylthio)acrylate (2.2 g, 10.1 mmol) and hydrazine (0.325 mL, 10.1 mmol) in 2-propanol (20 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (1:1) to give ethyl 5-amino-3-(methylthio)-1H-pyrazole-4-carboxylate (1.2 g, 59%) as a solid. m/z (APCI-pos) M+1=202.0.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=O)(C)(C)C.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[ClH:24]>CN(C)C=O.ClCCl.O1CCOCC1>[ClH:24].[CH2:6]([NH:8][C@H:9]([CH3:10])[C:11]([O:13][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C[C@@H](NCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-(tert-butoxycarbonyl)-D-alanine (3 g) in dimethylformamide (5 ml) was added dropwise to a stirred solution mixture of 60% sodium hydride (1.4 g) in dimethylformamide (5 ml) at ice-bath temperature. After stirring for 30 minutes at the same temperature, benzyl bromide (4.14 ml) was added and then the mixture was stirred for 1 hour at the same temperature and then for 6 hours at room temperature. The reaction mixture was poured into a mixture of dilute hydrochloric acid and ice-water, and extracted with diisopropyl ether. The extract was washed with aqueous sodium bicarbonate solution and brine successively and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1) to give an oily product, which was dissolved in dichloromethane (40 ml). To the solution was added 4N hydrogen chloride in dioxane solution (7 ml) at ice-bath temperature. The resulting mixture was stirred for 1.5 hours at room temperature and then concentrated under reduced pressure to give benzyl (2R)-2-(N-benzylamino)propionate hydrochloride (2.2 g).