Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].Br[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1)[OH:6]
Reactant: COc1cccc(C=O)c1OC
Reactant: COc1cc(Br)cc(OC)c1
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2cccc(OC)c2OC)c1
Yield: 88.8 %

Procedure:
2,3-Dimethoxybenzaldehyde (0.84 g, 5.03 mmol), 1-bromo-3,5-dimethoxybenzene (1.20 g, 5.53 mmol), and n-butyl lithium (2.20 ml, 5.53 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 50% EtOAc in hexane in about 40 min.) to give (2,3-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol as a greenish yellow oil (1.36 g, 89%): 1HNMR (CDCl3) 7.08-7.01 (m, 1H, Ar), 6.93-6.85 (m, 2H, Ar), 6.57 (d, J=2 Hz, 2H, Ar), 6.35 (t, J=2 Hz, 1H, Ar), 5.94 (d, J=6 Hz, 1H, CHOH), 3.86 (s, 3H, OCH3), 3.76 (s, 6H, 2OCH3), 3.66 (s, 3H, OCH3), 3.05 (d, J=6 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][CH3:12])#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][CH3:12]
Reactant: COc1ccc(OC)c(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(OC)c(CN)c1
Yield: 93.8 %

Procedure:
A sample of 3.12 g of 2-cyano-1,4-dimethoxybenzene was reduced by 1 g of lithium aluminum hydride in 20 mL of THF at 0° C. to yield 3 g of 2-aminomethyl-1,4-dimethoxybenzene. This was then refluxed in a 1:1 (v/v) mixture of acetic acid and 48% aqueous hydrobromic acid overnight. The volatile components were removed under reduced pressure, and the crude 2-aminomethyl-1,4-hydroquinone HBr salt was used “as is” without further purification. Triethylamine (0.4 mL) was added to a mixture of 50 mg of compound (1) and 0.6 mmole of 2-aminomethyl-1,4-dihydroquinone HBr salt in 2 mL of dichloroethane, and stirred overnight. The crude dihydroquinone was then oxidized to the desired quinone compound (11) with ceric ammonium nitrate in a water/acetonitrile mixture.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C@H:9]1[CH2:13][S:12][C:11](=[O:14])[NH:10]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25].[Cl-].[NH4+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:14]=[C:11]1[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[C@@H:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:13][S:12]1
Reactant: O=C1N[C@@H](COC2CCCCO2)CS1
Reactant: N#CCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: N#CCCCCCCN1C(=O)SC[C@@H]1COC1CCCCO1
Temperature: 50 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of 3-4 (0.73 g, 3.4 mmol) in 10 mL DMF was added 60% sodium hydride (140 mg, 3.5 mmol) and the resulting solution was stirred for 1 hour at 50° C. whereupon 7-bromoheptanonitrile (1.1 mL, 6.8 mmol) and tetrabutylammonium iodide (50 mg) were added. The solution was stirred at 50° C. overnight afterwhich it was cooled to room temperature, slowly poured into saturated aqueous ammonium chloride solution and was extracted with ether. The organic phases were then combined and sequentially washed with H2O, brine and dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 40–50% ethyl acetate/hexanes to yield 970 mg of 4-1 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.63 (m, 1H), 4.04–3.68 (m, 3H), 3.68–3.58 (m, 1H), 3.55 (m, 2H), 3.42 (dd, 1H), 3.22–3.04 (m, 2H), 2.36 (t, 2H), 1.86–1.44 (m, 12H), 1.38–1.30(m, 2H); MS (+ESI): m/z 327.2 (M+1)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH3:9])([CH3:3])[CH3:2].N1CCN=C1>[Co]>[CH:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH3:9])([CH3:3])[CH3:2]
Reactant: CC1=NCCN1C(C)C
Agent: [Co]
Agent: C1=NCCN1
Product: Cc1nccn1C(C)C
Yield: 14 %

Procedure:
The procedure of Example 1 was followed except that 26.2 g of 1-isopropyl-2-methylimidazoline and 3.0 g of a cobalt hydrogenation catalyst was charged. GLC analysis show that a 14% yield of 1-isopropyl-2-methylimidazole was obtained with 19% conversion of imidazoline.
Reaction SMILES: [F:1][C@:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].Cl.[CH3:22][NH:23][OH:24]>>[F:18][C:17]([F:20])([F:19])[S:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C@@:2]([F:1])([CH3:6])[C:3]([N:23]([OH:24])[CH3:22])=[O:4])=[CH:8][CH:9]=1)(=[O:16])=[O:15]
Reactant: C[C@@](F)(C(=O)O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: CNO
Agent: Cl
Product: CN(O)C(=O)[C@@](C)(F)c1ccc(OS(=O)(=O)C(F)(F)F)cc1

Procedure:
Following the same procedure described for 4 and starting from 2 (1.6 mmol) and N-methylhydroxylamine hydrochloride (2 mmol), after workup compound 5 was isolated as a colourless oil (0.34 g, yield 63%). [α]D=+10.5 (c=0.5; CH3OH). 1H-NMR (CDCl3) δ 7.65 (d, 2H, J=7 Hz), 7.30 (d, 2H, J=7 Hz), 2.90 (s, 3H), 1.94 (d, 3H, J=23 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.C([O:31][CH2:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]([F:48])=[CH:35][C:34]=1[N:49]1[CH2:61][CH2:60][N:52]2[C:53]3[CH2:54][CH2:55][CH2:56][CH2:57][C:58]=3[CH:59]=[C:51]2[C:50]1=[O:62])(=O)C.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1.O>[F:48][C:36]1[CH:37]=[C:38]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:19][CH2:20][N:21]([CH:24]5[CH2:27][O:26][CH2:25]5)[CH2:22][CH2:23]4)=[CH:14][N:13]=3)[C:5]3[N:9]=[CH:8][NH:7][C:6]=3[CH:10]=2)[C:33]([CH2:32][OH:31])=[C:34]([N:49]2[CH2:61][CH2:60][N:52]3[C:53]4[CH2:54][CH2:55][CH2:56][CH2:57][C:58]=4[CH:59]=[C:51]3[C:50]2=[O:62])[CH:35]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nc[nH]c2c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1c2cc3c(n2CCN1c1cc(F)cc(-c2cc(Nc4ccc(N5CCN(C6COC6)CC5)cn4)c4nc[nH]c4c2)c1CO)CCCC3
Temperature: 110 °C
Yield: 10.1 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 116c (300 mg, 0.78 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 101k (545 mg, 1.13 mmol), potassium carbonate (414 mg, 3.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (68 mg, 0.075 mmol), tricyclohexyl phosphine (210 mg, 0.75 mmol), water (0.2 mL), and dioxane (10 mL). After bubbling nitrogen through the suspension for 10 minutes, the sealed vial was heated at 110° C. overnight. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 116 as a white solid (52 mg, 10%). MS-ESI: [M+H]+ 663.3. 1H NMR (500 MHz, DMSO) δ 8.23 (bs, 1H), 8.11 (s, 1H), 7.88 (d, J=4.5 Hz, 1H), 7.35-7.31 (m, 1H), 7.23-7.17 (m, 2H), 7.13-7.09 (m, 2H), 6.52 (s, 1H), 4.57-4.45 (m, overlap, 4H), 4.31 (d, J=7.5 Hz, 2H), 4.11-4.01 (m, 4H), 3.51-3.47 (m, 1H), 3.10-3.06 (m, 4H), 2.59-2.41 (m, 8H), 1.81-1.68 (m, 4H)
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH3:22][C:23]([CH3:28])=[CH:24][C:25](Cl)=[O:26].N1C=CC=CC=1.O>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:25](=[O:26])[CH:24]=[C:23]([CH3:28])[CH3:22])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)=CC(=O)Cl
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: ClCCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)=CC(=O)N1CC(NC(=O)OC(C)(C)C)C(=O)Nc2cc(C)ccc21
Yield: 63.2 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (40 ml), 3,3-dimethylacryloyl chloride (941 mg) and pyridine (626 mg) were added, the mixture was refluxed for one hour. The reaction mixture was allowed to cool, water (100 ml) was added, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Isopropylether was added to the residue for trituration, collected by filtration, to thereby obtain 1.62 g of the titled compound.
Reaction SMILES: [OH-:1].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1>O>[CH:6]12[CH2:7][CH:4]([CH:4]=[CH:5]1)[CH2:5][CH:6]2[C:7]([OH:3])=[O:1]
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
19.0 g (58.5 mmol) of the Diels-Alder adduct was dissolved in 115 ml of tetrahydrofuran, 12.9 g (300 mmol) of sodium hydroxide in 140 ml of water was added on ice cooling, the mixture was stirred at room temperature for 24 hours. After distilling off tetrahydrofuran, the product was neutralized with 27 ml of concentrated hydrochloric acid and extracted with a mixture solvent of hexane-methylene chloride (98:2) (100 ml×4). The extract was dried over anhydrous magnesium sulfate, the solution was filtered, and the solvent was distilled off to obtain 8.3 g of crude 5-norbornene-2-carboxylic acid.
Reaction SMILES: [C:1]1([C@@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([C@@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:25][C:26]#[N:27])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCBr
Reactant: Oc1cccc2c1c1cccc3c1n2[C@@H](c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1cccc3c1n2[C@@H](c1ccccc1)CO3
Temperature: 70 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of (S)-(+)-1-Phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol 0.161 g, 0.534 mmol), bromoacetonitrile (0.074 mL, 1.07 mmol), potassium carbonate (0.148 g, 1.07 mmol), and DMF (2 mL) is stirred at 70° C. for 4 h. Additional bromoacetonitrile (0.074 mL) and potassium carbonate (0.074 g) are then added and the mixture is stirred overnight. Bromoacetonitrile and potassium carbonate (0.074 mL and 0.074 g, respectively) are then added and the temperature is increased to 90° C. The mixture is heated at that temperature for 5.5 h and then allowed to cool and stir overnight, after which the mixture is partitioned between ethyl acetate, aq. ammonium chloride, and brine. The organic layers are dried over magnesium sulfate, concentrated, and the residue is chromatographed on silica gel gel (40 mL) using first CH2Cl2/hexane (1:1) to elute unreacted starting material, and then ethyl acetate/CH2Cl2/hexane (5:45:50) to give 0.113 g of (S)-(+)-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[CH:15]([C:17]3([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH2:20][CH2:19][CH2:18]3)[N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(N(CC)CC)C.[CH2:42]([S:45](Cl)(=[O:47])=[O:46])[CH2:43][CH3:44].Cl>N1C=CC=CC=1.ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]2([CH:15]3[C:16]4[N:4]([CH2:3][CH2:2][NH:1][S:45]([CH2:42][CH2:43][CH3:44])(=[O:47])=[O:46])[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[C:11]=4[CH2:12][CH2:13][NH:14]3)[CH2:20][CH2:19][CH2:18]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)C1C1(c2ccc(Cl)cc2)CCC1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCCn1c2c(c3ccccc31)CCNC2C1(c2ccc(Cl)cc2)CCC1

Procedure:
tert-Butyl 9-(2-aminoethyl)-1-[1-(4-chlorophenyl)cyclobutyl]-1,3,4,9-tetrahydro-2H-b-carboline-2-carboxylate (90 mg, 0.187 mmol) was dissolved in pyridine (2 mL). Triethylamine (38 mg, 0.375 mmol) followed by propane-1-sulfonyl chloride (40 mg, 0.280 mmol) were added. The reaction mixture was stirred over night. The solvent was evaporated in vacuo. The residue was treated with dichloromethane (10 mL) and washed successively with saturated ammonium chloride solution (2×10 mL) and water (10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude intermediate was purified by flash chromatography (silica, dichloromethane, methanol). The obtained compound (58 mg, 0.099 mmol) was dissolved in dichloromethane (2 mL) and excess 5M isopropanolic hydrochloric acid was added. The reaction mixture was stirred over night at room temperature. The solvent was evaporated in vacuo. Yield: 35 mg (0.067 mmol, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2
Reactant: Brc1ccc2nc(CN3CCCC3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)CCC(CN1CCCC1)N2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Under an argon atmosphere 0.69 mL (6.87 mmol) borane-pyridine complex are added to a solution of 500 mg (1.72 mmol) 6-bromo-2-pyrrolidin-1-ylmethyl-quinoline (see 3.45b) in 10 mL acetic acid at RT. The mixture is stirred for 7 h at RT, again combined with 0.35 mL (3.46 mmol) borane-pyridine complex and stirred for another hour at RT. It is cooled to 0° C. and the solution is made basic with 8% NaOH solution. The aqueous phase is extracted with EtOAc and the solvent is eliminated i.vac. The residue is taken up with water and acidified with 12% HCl. The aqueous phase is extracted with EtOAc and then made basic with 20% NaOH solution while cooling with ice. The aqueous phase is extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)[C:6](=[O:21])[C:5]2([C:24]1[C:32](O)=[CH:31][C:27]2[O:28][CH2:29][O:30][C:26]=2[CH:25]=1)[CH2:22][OH:23].C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[O:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=1)[C:6](=[O:21])[C:5]12[C:24]2=[CH:25][C:26]3[O:30][CH2:29][O:28][C:27]=3[CH:31]=[C:32]2[O:23][CH2:22]1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccc(F)cc2C1(CO)c1cc2c(cc1O)OCO2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccc(F)cc2C12COc1cc3c(cc12)OCO3
Reaction time: 1 h
Yield: 34.2 %

Procedure:
To a solution of 5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one (3.34 g, 7.18 mmol) in anhydrous tetrahydrofuran (80.0 mL) was added tributylphosphine (2.18 g, 2.70 mL, 10.8 mmol) under nitrogen. A solution of di-tert-butyl azodicarboxylate (2.49 g, 10.8 mmol) in anhydrous tetrahydrofuran (25.0 mL) was added over 10 min. The reaction solution was stirred for 1 h, and quenched with saturated ammonium chloride (30.0 mL). After the solvent was removed under reduced pressure, the gummy material was extracted with ethyl acetate (3×75.0 mL). The organic layer was washed with 10% aqueous HCl solution (2×25.0 mL), saturated aqueous sodium hydrogen carbonate (3×25.0 mL), brine (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (30%) to afforded the title compound (1.10 g, 34%) as a colorless solid: mp 139-141° C.; 1H NMR (300 MHz, CDCl3) δ 7.02-6.96 (m, 1H), 6.93-6.89 (m, 2H), 6.74-6.73 (m, 1H), 6.50 (s, 1H), 6.38 (d, 1H), 6.09 (s, 1H), 5.87 (dd, 2H), 4.95 (ABq, 2H), 4.78 (Abq, 2H); 13C NMR (75 MHz, CDCl3) δ 176.9, 161.5, 158.3, 155.9, 151.7, 149.2, 142.6, 137.1, 137.1, 133.7, 118.6, 115.6, 115.3, 112.7, 112.4, 112.0, 109.7, 109.6, 109.4, 102.8, 101.7, 93.8, 80.1, 58.6, 37.1; MS (ES+) m/z 448.2 (M+1).
Reaction SMILES: [Na+:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:18]([CH3:20])[CH3:19])[C:10]=2[CH2:21][CH2:22][CH:23]([OH:31])[CH2:24][C:25]([OH:30])=[CH:26][C:27]([O-:29])=[O:28])=[CH:5][CH:4]=1>C(O)C>[CH3:20][CH:18]([N:11]1[C:10](/[CH:21]=[CH:22]/[C@@H:23]([OH:31])[CH2:24][C@@H:25]([OH:30])[CH2:26][C:27]([O-:29])=[O:28])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:19].[Na+:1]
Reactant: CC(C)n1c(CCC(O)CC(O)=CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Solvent: CCO
Product: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
2 g of fluvastatin sodium (prepared according to Example 8 of U.S. Pat. No. 4,739,073 and Example 14D of U.S. Pat. No. 5,354,772 A) heated to boiling in 35 ml of ethanol until the material goes into solution. The hot solution obtained is filtered into 80 ml of boiling 2-propanol and allowed to cool to room temperature, while the precipitation of the anhydrous amorphous form of fluvastatin sodium salt begins. The suspension obtained is allowed to stand at 40° C. for 4 hours, and then filtered, washed with cold ethanol (4° C.) and dried in vacuum at room temperature. Thus 1.4 g of anhydrous amorphous fluvastatin sodium salt is obtained (yield 70%). X-ray powder diffraction examination (FIG. 3 as shown in the accompanied drawings) confirmed the amorphous nature of the product.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1.[OH-:14].[Na+]>C1COCC1.O.Cl.CCOC(C)=O>[Cl:1][C:2]1[N:11]=[C:10]([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1
Reactant: [OH-]
Reactant: Clc1nc(Cl)c2cc(I)ccc2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1nc(Cl)nc2ccc(I)cc12
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 2,4-dichloro-6-iodoquinazoline (10 g, 30.8 mmol) in THF (8 ml) and water (8 ml) was treated with aqueous NaOH (1 N, 4 ml). The solution was stirred for 1 h, then diluted with aqueous HCl (1 N) and EtOAc. The organic phase was separated and washed with brine then dried over Na2SO4. Filtration and removal of the volatiles afforded the title compound (9.4 g, 100%) as a solid. LCMS (ES+) m/z 307 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18].[CH3:19][S-:20].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[CH2:8][S:20][CH3:19]
Reactant: Fc1ccc(Oc2ccc(CBr)cc2Br)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Yield: 99.9 %

Procedure:
A mixture of Example 52C (1.512 g, 4.00 mmol) and sodium thiomethoxide (0.280 g, 4.00 mmol) in dimethylformamide (8 mL) was stirred at room temperature for 6 hours. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride twice, dried with anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (1.38 g, 100%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:56]([CH2:59][CH3:60])=[C:57]=[O:58]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:59]([NH:56][C:57](=[O:58])[O:39][C@H:36]1[CH2:37][CH2:38][C@@H:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]3[N:22]=[C:21]4[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]5[CH2:15][O:14][C@@H:13]6[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]56)=[N:19][C:20]4=[CH:25][C:24]=3[Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)[CH3:60]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)O[C@H]1CC[C@@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Reaction time: 6 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol (50 mg), 4-dimethylamino-pyridine (DMAP, 1 mg) and triethylamine (30 μL) are dissolved in tetrahydrofurane (1 mL), treated with isocyanatoethane (11 μL) and stirred for 6 hours. Triethylamine (60 μL) and isocyanatoethane (22 μL) are added and the mixture is stirred for 12 hours at 70° C. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is used directly in the next step. LC (method 4): tR=1.20 min; Mass spectrum (ESI+): m/z=787 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:49])([F:48])[C:22]1[C:26]([CH2:27]O)=[CH:25][N:24]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:23]=1.C(Br)(Br)(Br)[Br:51]>ClCCl>[Br:51][CH2:27][C:26]1[C:22]([C:21]([F:49])([F:48])[F:20])=[N:23][N:24]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1CBr
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 42.4 %

Procedure:
Triphenylphosphine (0.54 g, 2.1 mmol) was added to a solution of (3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl)-methanol (0.6 g, 1.5 mmol) in dichloromethane (25 mL). The resulting solution was cooled to −20° C. and a solution of carbon tetrabromide (0.54 g, 1.6 mmol) in dichloromethane (5 mL) was added in four portions. The solution was stirred for 5 min at −20° C. and then at for 3 h at 0° C. Further portions of triphenylphosphine (0.17 g, 0.65 mmol) and carbon tetrabromide (0.24 g, 0.72 mmol) were added. The solution was stirred for 3 h, and further portions of triphenylphosphine (0.54 g, 2 mmol) and carbon tetrabromide were added. The solution was stirred for 30 min and then the solvent was evaporated and the residue purified by flash chromatography, eluting with 5-10% ethyl acetate/petroleum ether to give 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole (0.30 g, 43%) as a white solid.