Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([Mg]Br)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH3:5].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]>C1COCC1>[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([CH:23]([C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=2)[OH:24])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH3:5]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CCOc1cc([Mg]Br)ccc1OC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1cc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Grignard reagent was prepared in an oven-dried three necked flask outfitted with a reflux condenser, dropping funnel, and magnetic stirrer. Approximately ¼ of a solution of (3-ethoxy-4-methoxy-bromo)-benzene (10 g, 43.3 mmol) in anhydrous THF (60 mL) was added to a mixture of magnesium turnings (1.05 g, 43.3 mmol) in THF (10 mL) with a small piece of iodine. As soon as the solution became colorless (heating sometimes necessary), the remaining (3-ethoxy-4-methoxy-bromo)-benzene solution was added dropwise to the reaction mixture under mild reflux, over 30 min. The resulting mixture was refluxed for 3 h then cooled to room temperature for 30 min. The (3-ethoxy-4-methoxy-phenyl) magnesium bromide was then added slowly to a stirred solution of 4-methoxy-3-nitro-benzaldehyde (6.53 g, 36.1 mmol) in THF (60 mL) at 0° C. After complete addition, the reaction mixture was stirred at cold for 10 min and then at room temperature for 2 h. The solution was cooled to 0° C. and quenched with saturated NH4Cl solution (90 mL). The aqueous layer was extracted with ether (3×90 mL). The combined organic layers were washed with water (2×120 mL), brine (120 mL) and dried (MgSO4). Removal of solvent gave the crude (3-ethoxy-4-methoxy-phenyl)-(4-methoxy-3-nitro-phenyl) -methanol, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N+:10]([C:13]1[CH:20]=[CH:19]C(CO)=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[C:1]([O:7][CH2:8][C:9]1[CH:19]=[CH:20][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Product: CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 76.6 %

Procedure:
A mixture of ethyl acetoacetate (140 g, 1.08 mole) and p-nitrobenzyl alcohol (153 g, 1.00 mole; was washed with diethyl ether prior to use) in toluene (1 L) was slowly distilled, 900 ml of the solvent being collected over a period of 15 hours. After cooling, any insoluble material was removed by filtration over Celite, washed with toluene and evaporated in vacuo to obtain 280 g of a crude oil. This oil was crystallized at 5° C. from diethyl ether (280 ml) to yield 181.55 g (0.766 mole, 76.6% yield) of the title compound as off-white crystals: mp 40°-42° C.; ir (film) νmax : 1740 (ester), 1715 (C=O), 1515 and 1345 (NO2) cm-1 ; 1Hmr (CDCl3) δ: 1.98 (s, impurity), 2.32 (3H, s, CH3), 3.62 (2H, s, --COCH2CO2R), 5.08 (s, impurity), 5.28 (2H, s, --CO2CH2Ar), 7.53 (2H, "d", J=9 Hz, ArH's), and 8.23 ppm (2H, "d", J=9 Hz, ArH's); Rf 0.45 (diethyl ether). An analytical sample was obtained by recrystallization from toluene-hexanes: mp 47°-49° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10].[H-].[Na+].[C:13]1([N:19]2[CH2:24][CH2:23][N:22]([C:25](OC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:13]1([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:10][CH2:9][C@@H:3]3[CH2:4][N:5]([CH3:8])[CH2:6][CH2:7][N:2]3[CH3:1])=[O:26])[CH2:23][CH2:24]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN1CCN(C)[C@H](CO)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C)[C@H](COC(=O)N2CCN(c3ccccc3)CC2)C1
Temperature: 0 °C
Yield: 36.5 %

Procedure:
To a solution of 1,4-dimethyl-(S)-2-hydroxymethyl piperazine (Intermediate 3; 1.49 g, 10.3 mmol) in THF (20 mL) at 0° C. was added sodium hydride (1.24 g, 60% dispersion in mineral oil, 31.0 mmol). The reaction mixture was stirred for several minutes at 0° C. and then 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 3.72 g, 11.4 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 7 hours. The reaction mixture was then cooled to 0° C. and quenched with the drop-wise addition of sat aq NaHCO3 solution. The THF was removed in vacuo, the aqueous phase extracted with EtOAc (×3), combined organic phases washed with sat aq NaHCO3 solution (×6), dried (MgSO4) and concentrated in vacuo. The residue was suspended in water: formic acid solution [1:1] (20 mL), filtered and the filtrate was purified by reverse phase column chromatography (gradient eluting with methanol in water, with 1% formic acid in each solvent, 0-15%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give [(2S)-1,4-dimethylpiperazin-2-yl]methyl 4-phenylpiperazine-1-carboxylate (1.25 g, 36%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:15][S:16][C:17]1[C:22]2[CH:23]=[C:24]3[N:29]([C:21]=2[N:20]=[CH:19][CH:18]=1)[CH2:28][CH2:27][CH2:26][CH:25]3[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>ClCCCl>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH:25]1[C:24]2[N:29]([C:21]3[N:20]=[CH:19][CH:18]=[C:17]([S:16][CH3:15])[C:22]=3[C:23]=2[C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:28][CH2:27][CH2:26]1)[CH3:35]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC1CCCn2c1cc1c(SC)ccnc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)CC1CCCn2c1c(C(=O)c1ccc(Cl)cc1)c1c(SC)ccnc12
Reaction time: 4 h

Procedure:
To a solution of 4-chlorobenzoyl chloride (0.30 g, 1.7 mmol) in 1,2-dichloethane (6.0 mL) was added AlCl3 (0.24 g, 1.8 mmole). After a period of 5 min. a solution of ethyl [4-(methylthio)-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-6-yl]acetate from Example 1 Step 8 (0.15 g, 0.47 mmole) in 1,2-dichloroethane (6.0 mL) was added to the previous mixture. After a period of 4 h, at 80° C., the reaction mixture was partitioned between EtOAc and NaHCO3. The organic phase was separated, dried over Na2SO4 and evaporated. The title compound was purified by flash chromatography.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH2:14][OH:15])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:23]1([C:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:23]1([C:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:3]2[N:2]=[N:1][C:5]([C:6]3[CH:7]=[C:8]([CH:12]=[CH:13][CH2:14][OH:15])[CH:9]=[CH:10][CH:11]=3)=[N:4]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCC=Cc1cccc(-c2nnn[nH]2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCC=Cc1cccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-[3-(1H-tetrazol-5-yl)phenyl]-2-propenol (2.02 g) in dry dichloromethane (50 ml) was added triethylamine (1.5 ml) followed by triphenylchloromethane (2.8 g) in dry dichlormethane. The solution was stirred at room temperature for 90 minutes, washed with water (50 ml), followed by sodium bicarbonate solution (5%; 50 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a pale brown viscous oil which crystallised on standing to a cream solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].[C:7]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])([CH3:9])[CH3:8]>>[N:1]([CH2:4][CH2:5][O:6][Si:11]([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:13])[CH3:12])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [N-]=[N+]=NCCO
Product: CC(C)(C)[Si](C)(C)OCCN=[N+]=[N-]

Procedure:
protecting the hydroxy group of 2-azidoethanol with tert-butylchloro-dimethylsilane to produce 1-azido-2-(tertbutyl-dimethylsiloxy)ethane;
Reaction SMILES: [Br-].[N:2]1([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C([Li])CCC.[Br:33][C:34]1[C:39]2[O:40][CH2:41][C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3[C:44](=O)[C:38]=2[CH:37]=[CH:36][CH:35]=1>CCCCCC.O1CCCC1>[Br:33][C:34]1[C:39]2[O:40][CH2:41][C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3/[C:44](=[CH:8]/[CH2:7][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)/[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: O=C1c2ccccc2COc2c(Br)cccc21
Reactant: c1ccc([P+](CCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Brc1cccc2c1OCc1ccccc1/C2=C/CN1CCCC1

Procedure:
Anhydrous 2-(N-pyrrolidinyl)ethyltriphenylphosphonium bromide (20 g, 45 mmole), 45 mmole of n-butyl lithium in hexane (1.6 M), and 4-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (10 g, 35 mmole) were reacted in 550 mL dry tetrahydrofuran by the procedure in Example 1, Step a. This offered a (Z)/(E) (60:40) isomeric product as a light brown oil. pmr (DMSO-d6)δ: 7.28-7.56 (m, 5H, aromatic H); 7.15-7.26 (2 dd, 1H, H1); 6.88 (t, H3 of 60% Z); 6.84 (t, H3 of 40% E); 6.16 (t, CH= of 40% E): 5.86 (t, CH= of 60% Z); 5.30 (br s, 2H, ArCH2O); 2.28-2.54 (m, 6H, N(CH2)3); 1.66 (m, 4H, 2CH2).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N:22]1([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:28])=[CH:20][CH:19]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCNCC1
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (1.163 g) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid (˜4 mL). After 30 min, additional trifluoroacetic acid (5 mL) was added, and the mixture was stirred for a further 2 h. The mixture was diluted with diluted with saturated aquoues NaHCO3 and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to yield the title compound.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[O:12]1[CH2:13][CH2:14][N:9]([CH:3]([CH2:4][CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: CC/C=C/C(=O)OC
Product: CCC(CC(=O)OC)N1CCOCC1
Temperature: 100 °C

Procedure:
A mixture of 171 g of methyl 2-trans-pentenoate and 130.5 g of morpholine was heated for 46 hours at 100° C. After distillation of the reaction mixture over a Vigreux column, 179 g (59% of theory) of methyl 3-morpholinovalerate of boiling point 85° C./0.4 mbar, nD20 =1.4610, were obtained.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:14]([CH2:30][S:31][C:32]2[NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[N:33]=2)=[N:15][CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:12][C:13]1[C:14]([CH2:30][S:31]([C:32]2[NH:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)=[O:9])=[N:15][CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCCOCc2ccccn2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(OCCOCc2ccccn2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
0.16 g of m-chloroperbenzoic acid was added to a solution of 0.38 g of 2-[{3-methyl-4-(2-pyridylmethoxyethoxy)pyridine-2-yl}methylthio]-1H-benzimidazole in 20 ml of dichloromethane at -60° C. in a nitrogen atmosphere to obtain a mixture. This mixture was stirred for 0.5 hour. After the completion of the reaction, 0.16 g of triethylamine was added to the reaction mixture. The obtained mixture was heated to -10° C., followed by the addition of 30 ml of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was stirred at a room temperature for 0.5 hour and extracted with 50 ml of dichloromethane thrice. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and dried in a vacuum to obtain a crude product. This crude product was crystallized from dichloromethane/diethyl ether to obtain 0.31 g of 2-[{3-methyl-4-(2-pyridylmethoxyethoxy)pyridine-2-yl}methylsulfinyl]-1H-benzimidazole as a white crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[N:6][CH:7]=1.Cl[C:17]1[C:26]2[C:21](=[C:22]([Cl:27])[CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH3:28])[C:18]=1[CH3:29].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:17]3[C:26]4[C:21](=[C:22]([Cl:27])[CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]([CH3:28])[C:18]=3[CH3:29])[CH2:9][C:8]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc2c(Cl)cccc2c(Cl)c1C
Reactant: Brc1cnc2c(c1)NCC21CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c(Cl)cccc2c(N2CC3(CCOCC3)c3ncc(Br)cc32)c1C

Procedure:
Prepared according to procedure M by using 6′-bromo-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (150 mg, 0.56 mmol), 4,8-dichloro-2,3-dimethylquinoline (126 mg, 0.56 mmol) and NaH (48.6 mg, 1.11 mmol, 55% dispersion in oil) in DMF (2.5 mL) while heating the reaction at 60° C. for 14 h. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 6′-bromo-1′-(8-chloro-2,3-dimethylquinolin-4-yl)-1′,2,2′,3,5,6-hexahydrospiro-[pyran-4,3′-pyrrolo[3,2-b]pyridine]. Mass Spectrum (ESI) m/e=458.0 [(M+1) (79Br)] and 460.0 [(M+1) (81Br)].
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([CH3:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[S:19]([OH:22])(=O)=[O:20])(=[O:3])[CH3:2].S1(CCCC1)(=O)=O.P(Cl)(Cl)([Cl:32])=O>>[C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([CH3:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[S:19]([Cl:32])(=[O:22])=[O:20])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)O)ccc12
Solvent: O=S1(=O)CCCC1
Product: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Temperature: 40 °C
Yield: 81 %

Procedure:
100 g of 1-acetoxy-5-acetaminonaphthalene-2-sulfonic acid was added to 500 ml of sulfolane, and 200 ml of phosphorus oxychloride was dropwise added thereto at 40° C. while stirring. After continuing stirring for about 1 hour, the reaction mixture was poured into 2 liters of ice water, and the precipitated crystals were collected by filtration, washed with water until the filtrate did not show acidity, and air-dried as such for 24 hours to obtain 70 g (81% yield) of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12].C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[Cl:21][C:11]([C:10]1[CH:9]=[C:8]([CH:16]=[CH:15][CH:14]=1)[CH2:7][S:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:17])=[O:12]
Reactant: COC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
Into a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-((3-methoxy-3-oxopropylthio)methyl)benzoic acid (61.6 mg, 0.24 mmol, 1.00 equiv) in dichloromethane (5 mL). This was followed by dropwise addition of oxalyl dichloride (121.76 mg, 0.96 mmol, 4.00 equiv) with stirring at room temperature. Then a few drops of N,N-dimethylformamide were added as catalyst. The resulting solution was heated to reflux for 30 min. The resulting mixture was concentrated under vacuum to yield 60 mg (crude) of methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate as yellow oil. The crude was used directly in the next step.
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].CC(C)=O>C(O)C>[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: CCO
Solvent: CC(C)=O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 75.6 %

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in ethanol (15 ml). The mixture was stirred at about 70EC for 1.75 h, after which the starting material was not detected by HPLC. Then, acetone (40 ml) was dripped into the solution and the mixture was cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.54 g (75.6%) of fluvastatin sodium Form VI.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]([CH2:22][CH2:23][CH3:24])[C:19]([NH2:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:18]([CH2:22][CH2:23][CH3:24])[CH2:19][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCCC(C(N)=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(CN)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a stirred solution of the crude 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-propyl-3-phenylpropanamide in anhydrous THF (10 mL) was added 1.0M lithium aluminum hydride in diethyl ether (2.0 mL, 2.0 mmol) portionwise at RT under nitrogen. After stirring at RT for 24 hr, the mixture was carefully quenched with MeOH, poured into brine (100 mL), extracted with ethyl acetate (2×100 mL), dried (Na2SO4) and concentrated to give 45 mg (94% yield, 3 steps) of 2((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)pentan-1-amine.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH:17]([CH3:22])[CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=2)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.O.[NH2:25][NH2:26]>C(O)C>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]([CH3:22])[CH2:18][C:19](=[O:21])[NH:25][N:26]=3)=[CH:14][CH:15]=2)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(CC(=O)O)C(=O)c1ccc(-n2cnc3c2CCCC3)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(-n2cnc3c2CCCC3)cc1
Yield: 43.7 %

Procedure:
A mixture of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-1-yl)-β-methyl-γ-oxobenzenebutanoic acid (7.3 g, 0.023 mol), 80% hydrazine hydrate (1.75 g, 0.028 mol) in ethanol (75 ml) is heated under reflux for six hours. The solution is concentrated to a small volume and filtered. The residue is washed with 2-propanol, followed by ether to give 3.1 g of 4,5-dihydro-6-[4-(4,5,6,7-tetrahydro-1H-benzimidazol-1-yl)phenyl]-5-methyl-3(2H)-pyridazinone, mp 199°-200° C.
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[BrH:18]>>[Br:18][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Br
Reactant: OC(c1ccccc1)(c1ccccc1)C1CC1
Product: BrCCC=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A mixture of 26.5 g of α-cyclopropyl-α-phenylbenzenemethanol and 150 ml of 48% HBr was stirred at ambient temperature for 3 h. After addition of ice water, the mixture was extracted twice with diethyl ether, washed, dried and concentrated to obtain 33 g (97.3%) of 4-bromo-1,1-diphenyl-1-butene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[O:14])=[CH:8][CH:7]=1.[CH2:16]([OH:19])[CH2:17][OH:18]>O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:18][CH2:17][CH2:16][OH:19])=[O:14])=[CH:8][CH:7]=1
Reactant: OCCO
Reactant: COC(=O)COc1ccc(N=C=O)cc1
Solvent: O
Product: COC(=O)COc1ccc(NC(=O)OCCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
(4-Isocyanatophenoxy)-acetic acid methyl ester 4 (15 g, 72.46 mmol) was added to ethylene glycol (30 ml) at room temperature. The reaction was exothermic and the temperature rose to 42° C. Later the reaction mixture was stirred at room temperature for 16 hours. Water (100 ml) was added and crude 5 was filtered, dried and purified by column chromatography on silica gel using chloroform as eluant to get pure 5 (16.17 g, 82.9%) as an off-white powder with an m.p between 85.5-87.5° C.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:21])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(C(=O)Cl)cc1
Temperature: 80 °C

Procedure:
To a mixture of 4-isopropylbenzoic acid (191 mg, 1.16 mmol) and pyridine (0.12 mL, 1.5 mmol) in toluene (10 mL) was added thionyl chloride (0.11 mL, 1.5 mmol). After heating at 80° C. for 3 h, the reaction mixture was cooled and concentrated in vacuo to give 4-isopropylbenzoyl chloride. A solution of this material (1.16 mmol) in methylene chloride (10 mL) was added to a mixture of 2-amino-N-(4-methoxyphenyl)benzamide (200 mg, 0.83 mmol) and pyridine (0.07 mL, 0.87 mmol) in methylene chloride (15 mL) cooled to 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction was partitioned between methylene chloride (25 mL) and 1 N hydrochloric acid (10 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo to give 262 mg (81%) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH2:29]([NH2:31])[CH3:30]>>[CH2:29]([NH:31][C:19]([C:17]1[S:16][C:14]2[N:15]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)[N:11]=[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:13]=2[CH:18]=1)=[O:21])[CH3:30]
Reactant: CCN
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Agent: Cl
Product: CCNC(=O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to ethylamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 31.8 mg of 129. MS (Q1) 409.2 (M)+.