Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)Br.[P:38]([O:45]CC)([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([O:32][P:38]([O:42][CH2:43][CH3:44])([O:39][CH2:40][CH3:41])=[O:45])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Reactant: CCOP(OCC)OCC
Agent: BrC(Br)(Br)Br
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(N2CCC([C@@H](OP(=O)(OCC)OCC)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
A solution of (R)-ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 11A, 600 mg, 1.33 mmol), CBr4 (575 mg, 1.73 mmol), and pyridine (2 ml) at 0° C. was treated dropwise over a 10 minute period with triethyl phosphite (0.56 ml, 3.33 mmol). The solution was stirred at 0° C. for about 10 minutes and then the ice bath was removed. The reaction was stirred overnight at r.t. whereupon the excess pyridine was removed under reduced pressure and the concentrate was taken up in 50 ml of DCM. The organic layer was washed successively with 50 ml each of 0.5 N aq. HCl, saturated aqueous sodium bicarbonate, and water. The organic layers were dried over sodium sulfate, filtered and adsorbed onto silica gel. Purification by column chromatography (ISCO, 80 g silica gel column, eluting with 0→100% EtOAc/hexanes over 24 minutes) gave the title compound (500 mg, yield: 64%).
Reaction SMILES: [OH-].[K+].[CH2:3](Br)[CH:4]=[CH2:5].C1OCCOCCOCCOCCOCCOC1.[OH:25][CH:26]1[CH2:43][CH2:42][C:29]2([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH2:28][CH2:27]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:3]([O:25][CH:26]1[CH2:27][CH2:28][C:29]2([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:31][CH2:30]2)[CH2:42][CH2:43]1)[CH:4]=[CH2:5]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Yield: 92 %

Procedure:
KOH (257.46 mmol, 21.0 eq.), allyl bromide (36.8 mmol, 3.0 eq.) and 18-crown-6 (4.9 mmol, 0.4 eq.) were added to a solution of tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (12.26 mmol, 1.0 eq.) in toluene (65 ml) at 0° C. and then reaction mixture was heated at reflux for 1 h. Then the reaction mixture was diluted with ethyl acetate (150 ml) and washed with water (150 ml) and brine (150 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield the crude product which was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexanes to afford the desired product as a yellow oil. Yield: 92%
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[F:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cccc(F)c4F)c3O2)cc1
Product: CNCC1Cc2cc(Cl)cc(-c3cccc(F)c3F)c2O1

Procedure:
The title compound was prepared (0.068 g, 60%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.148 g, 0.329 mmol) and methylamine (0.102 g, 3.29 mmol). mp 177-179° C.
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+:6]=[N-:7])([CH3:4])[CH3:3].C([Li])CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[C:19](C#N)[C:20]#[N:21].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[C:19]([C:20]#[N:21])=[N:7][NH:6][C:5]=1[Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#CC(C#N)=Cc1cccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1[nH]nc(C#N)c1-c1cccs1
Reaction time: 0.33 h

Procedure:
After a solution of trimethylsilyldiazomethane in hexane (0.6 mol/L, 5 mL) was added to tetrahydrofuran (20 mL) under an argon atmosphere, to this reaction mixture was added a solution of n-butyl lithium in hexane (2.6 mol/L, 1.08 mL) in a dropwise manner over 5 minutes at −78° C., and this mixture was stirred at same temperature for 20 minutes. And then to this reaction mixture was added a solution of 2-thiophene-2-ylmethylene malononitrile (0.32 g) in tetrahydrofuran (5 mL) in a dropwise manner over 20 minutes. To this reaction mixture was added saturated aqueous ammonium chloride solution, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. This residue was washed with hexane to give 4-thiophene-2-yl-5-trimethylsilanyl-1H-pyrazole-3-carbonitrile (0.496 g). To the 4-thiophene-2-yl-5-trimethylsilanyl-1H-pyrazole-3-carbonitrile were added methanol (20 mL) and 1.0 mol/L aqueous sodium hydroxide solution (20 mL), and this mixture was heated to reflux for 2 hours. This reaction mixture was acidified (pH1) with adding 1.0 mol/L hydrochloric acid, the precipitated solid was collected by filtration. This obtained solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (0.154 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]([CH3:19])[CH2:16][CH2:17][OH:18])[CH2:7][CH2:6][CH2:5]2.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[OH:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[NH:27])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: CN(CCO)CCCN1CCCc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(CCO)CCCN1CCCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-((3-(6-amino-3,4-dihydroquinolin-1(2H)-yl)propyl)(methyl)amino)ethanol (67 mg, 0.254 mmol) in ethanol (4 ml) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (145 mg, 0.509 mmol). The resulting suspension was stirred overnight at room temperature. The reaction mixture was then diluted with water and aqeuous sodium carbonate (sat.) then extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed on silica gel eluting with ethyl acetate, followed by 5-10% (2M NH3 in methanol) in a 1:1 mixture of ethyl acetate and dichloromethane. 1H NMR (DMSO-d6) δ 7.67 (d, J=3.3 Hz, 1H), 7.55 (d, J=5.1 Hz, 7.07 (t, J=4.4 Hz, 1H), 6.55 (m, 2H), 6.48 (s, 1H), 6.23 (brs, 2H), 4.35 (t, J=5.4 Hz, 1H), 3.51-3.44 (m, 2H), 3.24-3.17 (m, 4H), 2.66 (t, J=6.45, 2H), 2.41-2.33 (m, 4H), 2.17 (s, 3H), 1.89-1.81 (m, 2H), 1.63 (quint, J=7 Hz, 2H). ESI-MS (m/z, %) 373 (MH+, 100), 258 (31), 187 (49), 127 (42). ESI-HRMS calculated for C20H29N40S (MH+), calculated: 373.2056, observed: 373.2052.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[N:23]1([CH:28]2[CH2:31][NH:30][CH2:29]2)[CH:27]=[N:26][CH:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][CH:28]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1ncn(C2CNC2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2CC(n3cncn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 94.4 %

Procedure:
A suspension of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (75 mg, 0.25 mmol) and 100 mg (0.5 mmol) of 3-(1,2,4-triazol -1-yl)azetidine hydrochloride in 3 ml of dry pyridine, in the presence of 152 mg (1 mmol) of DBU was heated under nitrogen at 75° C. overnight. The suspension was then evaporated to dryness and to the residue water was added and solid collected, washed with water and dried to give 95 mg (94%) of the desired product as a yellow solid. m.p. 293°-295° C. 1H NMR (TFA) δ: 9.79 (s, 1H), 9.1 (s, 1H), 8.88 (s, 1H), 6.12-5.88 (m, 1H), 5.45-5.05 (m, 4H), 4.44-4.16 (m, 1H), 1.53-1.18 (m, 4H). Anal. calcd. for C18H16F2N6O3 : C, 53.74; H, 4.01; N, 20.88. Found: C, 53.60; H, 4.08; N, 20.91.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:5][CH:4]([C:6]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=O)[CH2:3]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([NH2:30])[CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH2:5][CH:4]([CH:6]([NH:30][C:22]2[CH:21]=[N:20][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:3]1
Reactant: CCOC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Reactant: Nc1cnc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1ccc(C(Nc2cnc3ccccc3c2)C2CC(C)(C)C2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 3.1 %

Procedure:
A flask containing ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate (397 mg, 1.53 mmol) was charged with toluene (13.9 mL), quinolin-3-amine (200 mg, 1.39 mmol), and para-toluene sulfonic acid (26.8 mg, 0.139 mmol). The reaction was refluxed with a Dean-Stark for 24 h. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 508 mg of crude material. To this crude material was added anhydrous methanol (6.47 mL) and the solution was cooled to 0° C. Sodium borohydride (147 mg, 3.88 mmol) was then added. After 5 h, the reaction was partly concentrated and quenched with saturated aqueous ammonium chloride. The reaction mixture was extracted three times with ethyl acetate. The combined organic layers were then dried over sodium sulfate, filtered, and concentrated to give 560 mg of crude material. Purification by column chromatography (0-50% ethyl acetate in heptane) provided ethyl 4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzoate (17.0 mg, 3.4% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ: 8.47 (d, J=2.9 Hz, 1H), 8.03-7.97 (m, 2H), 7.90-7.86 (m, 1H), 7.46-7.42 (m, 2H), 7.42-7.30 (m, 3H), 6.69 (d, J=2.7 Hz, 1H), 4.40-4.31 (m, 2H), 4.27 (dd, J=9.2, 4.3 Hz, 1H), 2.58-2.47 (m, 1H), 2.03 (ddd, J=11.2, 7.6, 4.2 Hz, 1H), 1.79-1.67 (m, 2H), 1.67-1.55 (m, 1H), 1.36 (t, J=7.1 Hz, 3H), 1.14 (s, 3H), 1.09 (s, 3H). MS (M+1): 389.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:15][CH3:14])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(SC)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
A mixture of 4,6-Dichloro-2-methylthio-5-nitropyrimidine (5.25 g, 21.88 mmol) in methanol (40 mL) was treated with sodium methoxide (1.3 g, 24.06 mmol). The mixture was stirred at room temperature for 3 h. At this point the reaction was poured onto ice to give a brown solid which was filtered and washed with water. The solid was dried under vacuo to give 4-Chloro-6-methoxy-2-methylthio-5-nitropyrimidine (4.40 g, 85%) as a brown solid. LRMS for C6H6Cl1N3O3S (M+H)+ at m/z=235. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][C:8]=1[CH2:21][N:22]([CH3:24])[CH3:23].[CH3:25][Si:26]([CH3:29])([CH3:28])Cl.O>C1COCC1>[CH3:23][N:22]([CH2:21][C:8]1[CH:9]=[C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH:12][C:7]=1[Si:26]([CH3:29])([CH3:28])[CH3:25])[CH3:24]
Reactant: CN(C)Cc1cc(NC(=O)OC(C)(C)C)ccc1Br
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cc(NC(=O)OC(C)(C)C)ccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At −78° C., n-butyl lithium (2.5 ml/L, 3 ml) was slowly added dropwise into a solution of tert-butyl 4-bromo-3-((dimethylamino)methyl)phenylcarbamate (compound 28) (2.7 g, 8 mmol) in THF. The reaction mixture was stirred at low-temperature for 30 minutes, followed by adding trimethylchlorosilane (1.1 g, 9.6 mmol). And then the reaction mixture was stirred at low-temperature for 1 hour. After the mixture was warmed to RT and stirred overnight, three times of water was added into the reaction solution. The reaction mixture was extracted by ethyl acetate. The solvent was dried and evaporated to give a crude product, which can be directly used for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:12]([CH2:26][NH2:27])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:12]([CH2:26][NH:27][C:29](=[O:31])[CH3:30])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Solvent: ClCCl
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CNC(C)=O)cc1
Temperature: 0 °C
Yield: 85.3 %

Procedure:
2-Amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (141 mg, 0.25 mmol, prepared as described in Example 1) and diisopropypethylamine (75 μl, 0.43 mmol) were dissolved in dichloromethane (10 ml) with stirring. The flask was then flush with nitrogen and sealed with a rubber septum before being cooled to 0° C. Acetyl chloride (20 μl, 0.28 mmol) was added dropwise to the solution, which was then warmed slowly to room temperature. After 2 hours of stirring, the reaction was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of hexane/ethyl acetate (3:1) as eluent, which afforded 95 mg (86%) of 7-(acetylamino-methyl)-2-amino-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:5])[CH3:4].C([Si](C)(C)[O:11][CH:12]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:26]2[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[C:28]([CH3:35])[CH:27]=2)([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:17][C:16]=1[CH3:36])(C)(C)C.F>C(#N)C>[CH3:1][O:2][C:3](=[O:5])[CH3:4].[CH2:22]([C:21]([C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[C:28]([CH3:35])[CH:27]=1)([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH:12]([OH:11])[C:37]([CH3:39])([CH3:40])[CH3:38])=[C:16]([CH3:36])[CH:17]=1)[CH2:24][CH3:25])[CH3:23]
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Agent: F
Solvent: CC#N
Solvent: COC(C)=O
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a solution of [5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonylamine]-acetic acid methyl ester (380 mg, 0.59 mmol) in acetonitrile (10 ml) at 0° C. is added hydrofluoride solution (3 ml, 48% in water). After stirring at RT for 2 h, the reaction is concentrated and partitioned between EtOAc and 1N HCl. The organic layer is washed successively with 1N HCl and brine. Tle organic layer is concentrated and chromatographed (Hex to 25% EtOAc/Hex) to give the title compound (250 mg, 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH:20]([CH3:25])[CH2:19]1.Cl>C1COCC1>[CH:9]([O:8][C:4]1[CH:3]=[C:2]([C:20]2([CH3:25])[CH:21]([OH:24])[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19]2)[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC1CN(C)CCC1=O
Reactant: CC(C)Oc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(C2(C)CN(C)CCC2O)c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 662.3 %

Procedure:
The 3-bromo-i-propoxybenzene (200 g, 0.08703 mol) was combined with THF (540 ml) under nitrogen and cooled to about -75° C. n-Butyl lithium (565 ml, 0.8306 mol) was added dropwise while maintaining the mixture at less than -70° C. After 2 hours 1,3-Dimethyl-4-piperidone (106.7 g, 0.8389 mol) was added while maintaining the temperature of the mixture between -80° C. and -70° C. After stirring 2 hours at -70° C., the reaction mixture was then added to 6N HCl (280 ml) while maintaining the temperature at 20°-25° C. The pH was adjusted to 1 with 12N HCl. The aqueous layer containing product was separated and heptane (320 ml) was added along with 50% NaOH (48 ml, pH=13-14) and the resulting mixture allowed to stand overnight. The mixture was heated to 45°- 50° C. and the upper layer was separated. The remaining aqueous layer was extracted with heptane (320 ml) at 45°-50° C. The combined organic fractions were washed with de-ionized water (120 ml) at 45°-50° C. The resulting organic layer was vacuum distilled at a pot temperature of about 55° C. at 100 mmHg. Crystallization from heptane and drying provided 151.8 g of 3-(3-i-propoxyphenyl)-1,3-dimethyl-4-hydroxypiperidine. Melting point 75.0°-76.0° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C-:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][N:11]([CH3:13])[CH3:12])[CH3:3].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19].C([Li])CCC.[CH2:25]=[O:26]>C(OCC)C>[OH:26][CH2:25][C-:9]1[CH:8]=[CH:7][C:6]([CH2:10][N:11]([CH3:13])[CH3:12])=[C:5]1[CH2:4][N:2]([CH3:1])[CH3:3].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]
Reactant: C=O
Reactant: CN(C)Cc1ccc[c-]1CN(C)C
Agent: [Fe+2]
Agent: [Li]CCCC
Agent: c1cc[cH-]c1
Solvent: CCOCC
Product: CN(C)Cc1cc[c-](CO)c1CN(C)C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a stirred solution of 1,2-bis-(dimethylaminomethyl) ferrocene (Example 9, 0.70 g, 2.32 mmol) in diethyl ether (15 cm3) under argon is added 1.2 equivalents n-butyl lithium (Aldrich, 1.75 mL, 1.6M in diethyl ether) and the mixture stirred for three hours to yield a red solution. The reaction mixture is cooled in a dry ice/acetone bath, calcined paraformaldehyde added in 2:1 excess, and the resultant mixture stirred at room temperature overnight. The mixture is quenched with water and extracted with diethyl ether. The ethereal extracts are dried over MgSO4, filtered over celite and the solvent removed in vacuo, to yield the title compound (0.7 g, 2.12 mmol, 91%) as an orange oil., which partially crystallized on cooling.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:32]=[CH:31][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=[CH:21][N:20]=3)[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[CH2:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:34]>C(O)C>[CH2:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:3][C:4]2[CH:32]=[CH:31][C:7]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:22]=[CH:21][N:20]=4)[CH:12]=3)=[O:9])=[CH:6][CH:5]=2)[CH2:37][CH2:36]1)[CH3:34]
Reactant: CCN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Agent: Cl
Solvent: CCO
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1
Temperature: 25 °C

Procedure:
A suspension of 466 mg (1 mmol) of 4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide hydrochloride in 25 ml of dry ethanol is treated with 381 μl (3 mmol) N-ethylpiperazine and then heated under reflux for 16 hours. The yellow solution is cooled to room temperature and decanted from a small amount of a brown insoluble residue which forms on the wall of the flask. The solvent is evaporated and the residue taken up in citric acid solution (10% w/w) and washed with dichloromethane. The aqueous layer is made basic by addition of sodium bicarbonate and sodium carbonate solution and extracted three times with 150 ml of dichloromethane containing 2 ml of ethanol. The combined organic extracts are washed with conc. sodium chloride solution, dried over sodium sulfate, and evaporated. The residue was stirred with 3 ml of ethyl acetate and the crystalline product filtered and washed with a small amount of ethyl acetate to obtain 4-(4-ethyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; m.p. 209.5-210.5° C.; tR(HPLC)1) 6.62 min.
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].C(#N)C.[OH-].[Na+:36]>CO>[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+:36]
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: CO
Solvent: CC#N
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 40 °C
Yield: 81.1 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to acetonitrile (60 ml) and dissolved by heating the mixture to reflux. The solution was then cooled to about 40° C. and NaOH (1 eq.) dissolved in MeOH (7.5 ml) was added. Turbidity appeared immediately. After 30 minutes an oil residue separated from the mixture. The mixture was heated again to about 55° C. for 3 h to dissolve the oil. The product was isolated by filtration under nitrogen, washed with acetonitrile (40 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 2.48 g (81.1%) of fluvastatin sodium Form LV.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([I:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[Si:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([I:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(I)c2cccnc12
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)c2cccnc12
Reaction time: 8 h
Yield: 80.5 %

Procedure:
8-Hydroxy-5-iodoquinoline (7.0 g, 25.8 mmol), imidazole (1.85 g, 27.2 mmol) and tert-butyldimethylsilyl chloride (4.28 g, 28.4 mmol) are dissolved in anhydrous CH2Cl2 (40 ml) under N2. The mixture is stirred vigorously overnight, then diluted with CH2Cl2 (60 ml) and washed with 5% aqueous HCl (2×30 ml) and water (40 ml). The organic phase is dried over sodium sulfate, and the solvent is distilled off under reduced pressure, leaving a brown liquid. This crude product is purified by flash chromatography on silica (heptane:ethyl acetate 5:1). The end product is isolated as pale-yellow solid (8 g, 80%).