Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.O.[CH2:18]=[C:19]([CH3:21])[CH3:20].O=P(Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C=C(C)C
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 6 h
Yield: 95.7 %

Procedure:
A 500-ml flask was charged with 50 ml of toluene and 53.42 g (0.25 mol) of 4′-methyl-2-biphenylcarboxylic acid, 0.45 ml (0.025 mol) of water and 32.63 g (0.58 mol) of isobutene. To this mixture was added dropwise 7.74 g (0.05 mol) of phosphorus oxytrichloride, and the mixture was stirred for 6 hours. The reaction mixture was added to 50 ml of a 10%-aqueous sodium hydroxide and washed. The organic layer was dried over anhydrous magnesium sulfate. Thereafter, the organic layer was concentrated by distilling off toluene by using a rotary evaporator, to give 64.2 g of tert-butyl 4′-methyl-2-biphenylcarboxylate as crystals (yield: 95% based on 4′-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Incidentally, the obtained compound had the same physical properties as those of the compound obtained in Example II-1.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[C:10]([O:19][CH3:20])[CH:9]=1)(=O)=O.O[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][S:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][O:5][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=2)=[CH:9][C:10]=1[O:19][CH3:20])(=[O:17])=[O:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1cc(CCOS(C)(=O)=O)ccc1OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(CCOc2ccc(C=O)cc2)ccc1OS(C)(=O)=O
Yield: 63 %

Procedure:
50 g (0.154 mole) 3-methoxy-4-(methylsulfonyloxy)phenethyl methanesulfonate, 48.8 g 0.4 mole) p-hydroxybenzaldehyde, 65.45 g 0.473 mole) potassium carbonate in 500 ml acetonitrile was refluxed for 4 hours. The precipitate was filtered off and the solvent was evaporated. Dichloromethane was added and the organic phase was washed with water, dried (magnesium sulfate), filtered and the solvent was evaporated to give 34 g (yield 63%) of 4-[2-(4-formylphenoxy)ethyl]-2-methoxyphenyl methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](OC)=O)=[CH:4][CH:3]=1.[Na].[N+]([O-])(O)=O.[NH2:21][NH:22][C:23]([NH2:25])=[NH:24]>CO>[NH2:25][C:23]1[N:24]=[C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:21][N:22]=1
Reactant: N=C(N)NN
Reactant: COC(=O)c1ccc(Cl)c2ccccc12
Agent: [Na]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: Nc1n[nH]c(-c2ccc(Cl)c3ccccc23)n1

Procedure:
The synthesis method of Example 7-(2) was applied. The compound (1.90 g) obtained in (3) above, methanol (20 ml), metallic sodium (810 mg) and aminoguanidine nitrate (4.8 g) were used as reagents to give a brown solid (2.27 g). The obtained compound was used as it was in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:28])[C:24]([NH:26][NH2:27])=[O:25])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:24]3[O:25][C:34](=[O:35])[NH:27][N:26]=3)=[O:28])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)NN
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-hydrazinyl-2-oxoacetamido)butanoate, intermediate 12, (289 mg, 0.72 mmol) in THF (8.5 mL) is added CDI (139 mg, 0.86 mmol) at room temperature. After stirring for 18 hour at room temperature, the reaction is quenched with H2O and 1M HCl, and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) and then lyophilized to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)butanoate (100 mg). HPLC retention time=1.67 minutes (condition A); MS (m+1)=430.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.1 Hz, 3H) 2.52-2.70 (m, 2H) 2.84 (dd, J=13.7, 8.4 Hz, 1H) 2.90 (dd, J=13.7, 8.4 Hz, 1H) 4.02 (q, J=7.1 Hz, 2H) 4.42-4.58 (m, 1H) 7.30 (d, J=8.1 Hz, 2H) 7.37-7.43 (m, 1H) 7.47 (t, J=7.8 Hz, 1H) 7.57-7.66 (m, 3H) 7.70 (t, J=1.9 Hz, 1H) 8.98 (d, J=8.8 Hz, 1H) 12.94 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=4)[C:23](=[O:25])[N:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].[CH3:39]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]3[N:20]([CH3:39])[CH:21]=[C:22]([CH2:26][C:27]4[CH:32]=[N:31][C:30]([O:33][CH3:34])=[N:29][CH:28]=4)[C:23](=[O:25])[N:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:35]([F:37])([F:38])[F:36]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1
Solvent: ClCCl
Solvent: CI
Product: COc1ncc(Cc2cn(C)c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
To a solution of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4-oxo-1,4-dihydro-2-pyrimidinyl)thio]methyl}benzonitrile (100 mg, 0.179 mmol) and Hunig's base (0.062 mL, 0.357 mmol) in DCM (3 mL) was added MeI (0.013 mL, 0.214 mmol). The mixture was stirred at room temperature overnight, and quenched by ice water. Purification via MDAP afforded the title compound (8 mg, 7.80% yield). LCMS: rt=3.29 min, [M+H+]=575
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([CH2:7][S:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[NH:3]1.N.CO>C1COCC1.[Ni]>[NH2:25][CH2:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][S:8]([CH2:7][C:4]3[NH:3][C:2](=[O:1])[NH:6][N:5]=3)(=[O:9])=[O:10])=[CH:13][CH:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1cccc(-c2ccc(CS(=O)(=O)Cc3n[nH]c(=O)[nH]3)cc2)c1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cccc(-c2ccc(CS(=O)(=O)Cc3n[nH]c(=O)[nH]3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A suspension of 4′-({[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]sulfonyl}methyl)biphenyl-3-carbonitrile obtained in Reference Example 110 (0.250 g, 0.705 mmol), Raney-nickel (0.250 g) and 28% aqueous ammonia (5 mL) in THF (5 mL)-methanol (5 mL) was stirred at room temperature for 4 hr under hydrogen atmosphere (1 atm). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitated solid was collected by filtration to give the title compound as a pale-blue powder (0.250 g, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:18]([C:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27])([CH3:22])[CH3:21])#[N:19].Cl.C(N=C=NCCCN(C)C)C.CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:18]([C:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:10]=1)=[O:27])([CH3:22])[CH3:21])#[N:19]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Nc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cc3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a solution of 3-(4-nitrophenoxy)aniline (4.69 g, 20.4 mmol) and 3-(1-cyano-1-methylethyl)benzoic acid (3.98 g, 21.0 mmol) produced in Example A7(ii) in pyridine (100 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.69 g, 24.5 mmol) and N,N-dimethylpyridine-4-amine (151 mg, 1.24 mmol), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added methanol (50 mL) and the mixture was further stirred at the same temperature for 30 min. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with dilute hydrochloric acid (150 mL×2) and saturated aqueous sodium hydrogencarbonate solution (150 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (8.10 g, 99%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:11][C:12]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[N:19][C:18]=2Cl)=[O:16])=[NH:13])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].O.Cl>CN(C=O)C>[Cl:23][C:21]1[N:20]=[N:19][C:18]2[N:13]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:14][C:15](=[O:16])[C:17]=2[CH:22]=1
Reactant: N=C(COCCc1cccc(Cl)c1)NC(=O)c1cc(Cl)nnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(COCCc2cccc(Cl)c2)nc2nnc(Cl)cc12
Temperature: 100 °C
Yield: 0.6 %

Procedure:
A mixture of crude 3,6-dichloro-pyridazine-4-carboxylic acid{2-[2-(3-chloro-phenyl)-ethoxy]-1-imino-ethyl}-amide (170 mg) and K2CO3 (121 mg, 0.877 mmol) in DMF (2 ml) was heated to 100° C. for 2 h. Then water was added and the pH was adjusted to 2 by addition of 0.1 N HCl. The resulting mixture was extracted two times with CH2Cl2 and the combined extracts were washed with water and brine, dried (Na2SO4) and evaporated. The remaining residue was purified by column chromatography (silica gel, CH2Cl2/MeOH 100:0 to 98:2) to give the title compound as light yellow solid (1 mg, 0.5%). MS: m/e=351.1 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:10]=O)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[NH2:1][C:2]1[C:3]([CH:10]=[N:21][NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Product: Nc1nc(Cl)c(Cl)nc1C=NNC(=O)c1ccccc1

Procedure:
In a similar manner, 0.96 gram (0.005 mole) of 3-amino-5,6-dichloropyrazinaldehyde, 0.08 gram (0.005 mole) of benzoic hydrazide and 100 milliliters of ethanol were mixed together and refluxed for 10 minutes to obtain a benzoic acid 2-[(3-amino-5,6-dichloropyrazinyl)methylene]hydrazide product. The product was recovered and recrystallized three times from ethanol to obtain yellow crystals which after drying 2 hours at 100° C. had the following elemental analyses.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[N:8]1([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][CH:28]([C:24]3[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=3)[CH2:29][CH2:30]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: ClCCCCCCn1ccc2ccccc21
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCn3ccc4ccccc43)CC2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
1-(6-Chlorohexyl)-1H-indole (23.6 mg, 0.100 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (24.6 mg, 0.100 mmol), K2CO3 (27.6 mg, 0.200 mmol), NaI (22.5 mg, 0.150 mmol) and DMF (1.00 mL) were combined and stirred overnight at 100° C. The reaction mixture was cooled to room temperature and the crude material was purified by preparative TLC using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product as a yellow solid (40 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 8.08-6.52 (m, 11H) 4.17 (t, 2H, J=7.2 Hz), 3.26 (d, 2H, J=11.6 Hz), 2.74-2.52 (m, 4H), 2.44-2.28 (m, 2H), 2.20-2.02 (m, 2H), 1.98-1.82 (m, 4H), 1.78-1.62 (m, 2H), 1.43-1.28 (m, 4H), 1.28 (d, 6H, J=6.8 Hz); ESMS m/e: 446.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH:13]=[O:14])=[CH:5][NH:6]2.[CH3:15][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH:13]([OH:14])[CH3:15])=[CH:5][NH:6]2
Reactant: C[Mg+]
Reactant: O=CCc1c[nH]c2c(F)ccc(Br)c12
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)Cc1c[nH]c2c(F)ccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a solution of (4-bromo-7-fluoro-1H-indol-3-yl)-acetaldehyde (358 mg, 1.40 mmol) in THF (10 mL) was added a solution of MeMgBr (4.0 mL of 1.4 M in toluene-THF (75:25), 5.59 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with H2O and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, 30% EtOAc in hexanes) to give 158 mg (42%) of the title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 8.97 (bs, 1H), 7.11 (dd, J=8.10, 4.20 Hz, 1H), 6.70 (dd, J=10.2, 8.10 Hz, 1H), 4.18 (m, 1H), 3.29(dd, J=14.5, 3.93 Hz, 1H), 2.87 (dd, J=14.5, 8.43 Hz, 1H), 2.16 (bs, 1H), 1.29 (d, J=6.18 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:11])[C:3]=1[C:4]#[N:5].[NH4+:20].[OH-]>CO.CCO>[NH2:20][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:11])[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(S(=O)c2cccc(F)c2C#N)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: COc1cccc(S(=O)c2cccc(N)c2C#N)c1
Temperature: 130 °C

Procedure:
To a solution of 0.73 g (2.7 mmol) of 2-fluoro-6-[(3-methoxyphenyl)sulfinyl]benzonitrile (Example 16) in 65 ml of MeOH/EtOH (2.5:4) was added 20 mL of concentrated NH4OH. This mixture was sealed in a glass-lined bomb and heated at 130° C. for 3 h. After solvent removal, the resultant concentrate was purified by flash column chromatography on silica gel with 5% MeOH in methylene chloride as the eluent. This resulted in 0.36 g (53%) of 2-amino-6-[(3-methoxyphenyl)sulfinyl]benzonitrile as a solid: mp 110°-114° C.; NMR. (Me2SO-d6, 200 MHz): δ 3.8 (s, 3H), 6.5 (br s, 2H); 7.1 (apparent d, 1H), 7.0 (apparent d, 2H), 7.2-7.3 (m, 2H), 7.5 (apparent t, 2H); mass spec (CI) 273 (M+ +1, 100%). Anal. Calc. for C14H12N2O2S: C, 61.75; H, 4.44; N, 10.29; S, 11.77. Found: C 61.65; H, 4.46; N, 10.21; S, 11.69.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=[O:31])[CH:28]=4)[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>C(OCC)C>[F:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([CH:30]([OH:31])[C:2]5[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=5)[CH:28]=4)[CH2:23][CH2:22]3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: Brc1cccnc1
Solvent: CCOCC
Product: OC(c1cccnc1)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 68.8 %

Procedure:
3-Bromopyridine (0.44 ml), 1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-formylindoline (0.4 g) and diethyl ether employed as the solvent were treated as in Example 93 to give the title compound (0.337 g) as a yellow oil (yield: 68.8%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[CH:14]=O)([CH3:10])([CH3:9])[CH3:8].CC(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:7]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[CH:14]=[CH2:1])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
Dry tetrahydrofuran (80 ml) was added to a mixture of potassium t-butoxide (6.740 g, 60.06 mmoles) and methyltriphenylphosphonium bromide (24.276 g, 60.06 mmoles) and stirred at room temperature for 30 minutes. A solution of 3,5-di-t-butylbenzaldehyde (10.087 g, 46.20 mmoles) in dry tetrahydrofuran (30 ml) was then added and the reaction mixture was stirred at room temperature for 17 hours. Acetone (50 ml) was then added and then all of the solvent was removed under vacuum. Pet. ether (60-80, 150 ml) was then added to the residue and the mixture was stirred vigorously for 30 minutes. The solution was then filtered through silica, rinsing thoroughly with pet. ether (60-80) and the solvent removed under vacuum to give 3,5-di-t-butylstyrene (9.302 g, 93%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:19]2[CH2:20][C:21](=[O:23])[CH2:22]2)=[CH:14][CH:13]=1
Reactant: OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6.3 mL (71.42 mmol) of oxalyl chloride in 250 mL of methylene chloride was added slowly 10.15 mL (142.84 mmol) of DMSO at −78° C. and stirred for 20 minutes. To this was added a solution of 11 g (35.7 mmol) of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol in 30 mL of methylene chloride and the mixture was stirred for 30 minutes at −78° C. Then 24.7 mL (178.56 mmol) of triethylamine was added at −78° C. and the mixture was stirred for 1 h at −78° C. before warming to rt. The solution was poured into 500 mL of ether and washed with 50 mL of aq NaHCO3. The organic layer was dried over Na2S04 and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]([CH:13]=[CH:14][CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[C:11]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:36]>CCO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:36]
Reactant: CC(C)n1c(C=CC(O)CC(O)CC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 50 °C
Reaction time: 2.25 h
Yield: 62 %

Procedure:
A 100 ml round bottom flask was loaded with fluvastatin tert-butyl ester (2.0 g, 4.28 mmole), EtOH (20 ml) and NaOH (0.18 g). The mixture was heated to 50° C. and stirred for 2.25 h then cooled to room temperature and the EtOH was evaporated. The volume of the water was completed to 8 vol. and the mixture was extracted with EtOAc (2×20 ml). The aqua solution was evaporated to obtain 4.22 g and ACN (30 ml) was added. The solution was stirred at room temperature over the weekend. The product was isolated by filtration under nitrogen, washed with ACN (20 ml) and dried at 40° C. in a vacuum oven for 24 h to obtain 1.15 g (62%) of fluvastatin sodium crystal form LXXIX.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[N:12][NH:13][C:14]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:24]>C(#N)C>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[N:12][N:13]=[C:14]2[Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]ncc2c1OCc1ccccc1
Solvent: CC#N
Product: COc1ccc2c(Cl)nncc2c1OCc1ccccc1
Yield: 97.4 %

Procedure:
A suspension of 5-benzyloxy-6-methoxy-2H-phthalazin-1-one (4 g, 14.17 mmoles), prepared as described in example 69, in acetonitrile (40 ml), and POCl3 (6.5 ml, 70.8 mmoles) was heated at 80° C. under stirring up to dissolution. After 30 minutes the solution was evaporated and the residue taken up in CH2Cl2 (100 ml), washed with a cold solution of NaOH (20 ml) and water (200 ml) and extracted in ethyl ether (twice) and ethyl acetate (once) checking the pH to be around 7. The organic phase was washed with a saturated NaCl solution, anhydrified and concentrated to give 4.15 g of the title compound (yield: 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH2:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[S:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])(=[O:24])=[O:23]>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])(=[O:24])=[O:23])=[CH:6][CH:7]=1
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: NCCOCCc1ccc(F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCS(=O)(=O)NCCOCCc1ccc(F)cc1
Yield: 85.3 %

Procedure:
The subtitle compound (8.32 g) was prepared according to the method of Example 3d) using 2-[2-(4-fluorophenyl)ethoxy]ethanamine (5.36 g), triethylamine (4.6 ml) and methyl 3-(chlorosulphonyl)propanoate (5.6 g) in diethyl ether (150 ml).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.C(O)(=O)C.[CH2:13]([NH:15][C:16](=[O:18])[O-:17])[CH3:14].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]2[CH:24]([CH3:32])[CH:25]3[CH2:29][NH:28][CH2:27][CH:26]3[C:30]=2[CH:31]=1>ClCCCl.C(Cl)Cl.O>[CH2:13]([NH:15][C:16](=[O:17])[O-:18])[CH3:14].[CH3:19][C:20]1[C:21]([Cl:8])=[CH:22][C:23]2[CH:24]([CH3:32])[CH:25]3[CH2:29][NH:28][CH2:27][CH:26]3[C:30]=2[CH:31]=1
Reactant: Cc1ccc2c(c1)C1CNCC1C2C
Reactant: O=C1CCC(=O)N1Cl
Agent: CCNC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc2c(cc1Cl)C(C)C1CNCC21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
NCS (27 mg, 0.2 mmol) and acetic acid (1 mL) were added to a solution of N-Ethylcarbamate-5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (50 mg, 0.2 mmol) in DCE (1 mL). The reaction solution was stirred for 3 hours at 60° C. The reaction was diluted with CH2Cl2 (3 mL) and H2O (3 mL) and filtered through an Extrelut column. The column was washed with CH2Cl2 and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2) using a 0-60% ethyl acetate-hexanes gradient to afford the subtitle compound. MS calculated for C16H20ClNO2+H: 294, observed: 294.