Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][S:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][S:27][C:28]4[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: Cn1ccnc1SCCCl
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCSc1nccn1C
Temperature: 90 °C
Yield: 18.1 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 0.9 mmol), (prepared as described for the starting material in Example 24), 2-(2-chloroethylthio)-1-methylimidazole hydrochloride (203 mg, 0.95 mmol) and potassium carbonate (303 mg 2.2 mmol) in NMP (20 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (100/0 increasing to 90/10) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-ylthio)ethoxy)quinazoline (75 mg, 17%) as a solid.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])=[CH:16][CH:15]=2)[CH2:9]1.C([N:28](CC)CC)C.[K].C1(=O)NC(=O)C2=CC=CC=C12.O.NN.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:28][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])=[CH:16][CH:15]=2)[CH2:9]1
Reactant: CCN(CC)CC
Reactant: O=C1CCCN1c1ccc(N2C[C@H](CO)OC2=O)cc1
Agent: CS(=O)(=O)Cl
Agent: NN
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: NC[C@H]1CN(c2ccc(N3CCCC3=O)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
At 0° C., methanesulfonyl chloride (1.79 g, 15.64 mmol) is added to a solution of (5R)-5-(hydroxymethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one (3.6 g, 13.0 mmol) and triethylamine (2.9 g, 28.7 mmol) in dichloromethane (160 ml). The reaction mixture is stirred at 0° C. for 1.5 hours and at room temperature for 3 hours and then washed with water, and the aqueous phase is reextracted with dichloromethane. The combined organic phases are dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue (1.67 g) is then dissolved in acetonitrile (70 ml), phthalimide potassium (2.62 g, 14.16 mmol) is added and the mixture is stirred in a closed vessel in a microwave oven at 180° C. for 45 min. Insoluble residue is removed from the mixture by filtration, the filtrate is evaporated under reduced pressure, the residue (1.9 g) is dissolved in methanol and hydrazine hydrate (0.47 g, 9.37 mmol) is added. The reaction mixture is heated under reflux for 2 hours and cooled, saturated sodium bicarbonate solution is added and the mixture is extracted six times with methylene chloride (2 1 in total). The combined organic phases are dried (magnesium sulfate), filtered and concentrated under reduced pressure.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])=[N:10][CH:9]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(S(C)(=O)=O)=CC=2)CCCC1.C(OC(=O)CCSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:16]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:9][N:10]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CCSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: CCOC(=O)CCSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CS(=O)(=O)c1ccc(NCC2CCCC2)cc1
Product: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCCC(=O)O)s2)cc1

Procedure:
The title compound was prepared via 3-{2-[3-cyclopentylmethyl-3-(4-methanesulfonylphenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].S(=O)(=O)(O)O.[F:19][C:20](I)([F:22])[F:21].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:19][C:20]([F:22])([F:21])[C:9]1[NH:10][C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c(=O)c2[nH]c(C(F)(F)F)nc2n(C)c1=O
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
0.18 g (1.0 mmol) of theophylline was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 8-trifluoromethyltheophylline (19F-NMR yield: 48%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 8-Trifluoromethyltheophylline was obtained as a white solid (0.086 g, yield: 35%) by column chromatography.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:17]([O:24][C:25](=[O:33])[CH2:26][C@@H:27]([NH2:32])[CH2:28][N:29]([CH3:31])[CH3:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25](=[O:33])[CH2:26][C@@H:27]([NH:32][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:28][N:29]([CH3:30])[CH3:31])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCc1ccccc1

Procedure:
The title compound, m/e=321.3 ([M+H]+), was produced in analogy with intermediate 1, steps 3 and 4. Thus, commercially available 6-phenylhexanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(6-phenyl-hexanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH:40]([CH2:44][OH:45])[CH2:39]1.C(OC(N1CCNCC1C(O)=O)=O)(C)(C)C.C(OC(N1CCNC[C@H]1C(O)=O)=O)(C)(C)C>ClCCl.O.C(N(CC)CC)C>[OH:45][CH2:44][CH:40]1[CH2:39][N:38]([CH3:37])[CH2:43][CH2:42][N:41]1[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1
Reactant: CN1CCNC(CO)C1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Agent: CC(C)(C)OC(=O)N1CCNCC1C(=O)O
Agent: CC(C)(C)OC(=O)N1CCNC[C@H]1C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(C)CC4CO)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 270 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 130 mg of (4-methylpiperazin-2-yl)methanol (synthesized starting from commercially available 1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid in one step in analogy to the synthesis of (2S)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid described in patent application WO2005/026152) in 10 ml dichloromethane is stirred at room temperature for 16 hours. 505 mg triethylamine is added and the reaction mixture is stirred additional 24 h at room temperature. Water (20 ml) is added to the mixture. After separation of the organic layer, the aqueous layer is extracted with dichloromethane (2×20 ml). The combined organic layers are dried over MgSO4. After filtration the solvent is removed under reduced pressure. The resulting residue is purified by flash chromatography [silica gel, eluent: ethyl acetate/methanol/aqueous solution of ammonia, 20/4/1 (v/v/v) and subsequently by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 65/35 to 15/85 (v/v)) to give the title product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2ncccc2[N+](=O)[O-])C1
Temperature: 110 °C

Procedure:
Tert-butyl(trans-3-aminocyclobutyl)carbamate (1.38 g, 7.41 mmol), 2-chloro-3-nitropyridine (1.25 g, 7.88 mmol) and potassium carbonate (0.655 ml, 10.85 mmol) were combined in dry dimethylsulfoxide (20 mL) and heated at 110° C. After 2 hours the reaction was cooled and partitioned between ethyl acetate (300 mL) and water (300 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired tert-butyl(trans-3-((3-nitropyridin-2-yl)amino)cyclobutyl)carbamate (1.45 g, 4.70 mmol, 63.5% yield).
Reaction SMILES: C([BH3-])#N.[CH3:4][C:5]1([N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[OH:29].C(O)(=O)C>C(Cl)Cl>[CH3:4][C:5]1([N:11]2[CH2:16][CH2:15][CH:14]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=3[OH:29])[CH2:13][CH2:12]2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: CC1(N2CCC(=O)CC2)CCOCC1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(N2CCC(Nc3cc(C(F)(F)F)ccc3O)CC2)CCOCC1
Temperature: 100 °C
Yield: 59.1 %

Procedure:
Polymer supported cyanoborohydride (191 mg, 0.82 mmol) was added to a solution of 1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinone (D12, 87 mg, 0.44 mmol), 2-amino-4-(trifluoromethyl)phenol (D7, 74 mg, 0.42 mmol, 4.3 mmol/g) and acetic acid (0.12 mL, 2.09 mmol) in DCM (2.5 mL). The mixture was heated by microwave at 100° C. for 10 min before being filtered and concentrated by rotary evaporation to give a yellow oil, which was purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM) to give 2-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}-4-(trifluoromethyl)phenol (D14, 89 mg, 60%) as an off-white solid.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.[Pd+2].ClC1C=C[C-](P(C(C)(C)C)C(C)(C)C)C=1Cl.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[NH2:6][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([C:18]2[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=2)=[C:8]([F:9])[CH:7]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P([c-]1ccc(Cl)c1Cl)C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2cc([N+](=O)[O-])c(N)cc2F)cc1
Temperature: 60 °C
Yield: 93.1 %

Procedure:
A suspension of 4-bromo-5-fluoro-2-nitroaniline (0.8 g, 3.8 mmol), 4-cyanophenylboronic acid (0.58 g, 3.87 mmol) and sodium carbonate (1 g, 9.50 mmol) in THF/water (15 mL/2 mL) was degassed with nitrogen for 10 minutes. To the suspension was added dichloro [1,1′ bis(di-tert-butylphosphino)]ferrocene palladium (II) (80 mg, 0.095 mmol) and the reaction was heated to 60° C. for 18 hours. The reaction was filtered through celite and the filtrate diluted with water and EtOAc. The organic layer was collected and concentrated in vacuo to afford the title compound as a yellow solid (0.91 g, 91%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH3:10][N:11](C=O)C>CO.O.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([C:10]#[N:11])=[N:7][C:6]=1[CH3:8]
Reactant: CN(C)C=O
Reactant: Cc1nc(Br)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CO
Product: Cc1nc(C#N)ccc1N
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-2-methylpyridin-3-amine (compound 1, 500 mg, 2.69 mmol) in DMF (10 mL) was added Zn(CN)2 (943 mg, 8.06 mmol) and Pd(PPh3)4 (288 mg, 0.3 mmol) at room temperature. The reaction was stirred at 110° C. in microwave reactor for 1 h. After it was cooled to room temperature, the mixture was filtered and purified by reverse phase chromatography (X bridge Prep C18OBD, 40-60% MeOH in water with 10 mmol NH4HCO3 modifier) to afford the compound as an oil.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7]1[CH:12]2[C:13]([CH3:15])([CH3:14])[CH:10]([CH2:11]2)[CH2:9][CH:8]=1>C(Cl)CCl.[Cl-].[Zn+2].[Cl-]>[C:13]([C:10]12[CH2:11][CH:12]([C:7]([CH3:6])=[CH:8][CH2:9]1)[C:1](=[O:4])[CH2:2][CH2:3]2)([CH3:15])=[CH2:14]
Reactant: C=CC(=O)Cl
Reactant: CC1=CCC2CC1C2(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: C=C(C)C12CC=C(C)C(C1)C(=O)CC2
Yield: 0.8 %

Procedure:
A mixture of 20.0 g acryloyl chloride (0.22 mol) and 3.01 g zinc chloride (0.02 ml, 0.1 eq.) in 150 ml ethylene chloride was treated with a soln. of 350 ml α-pinene ((1S-(−)/(1R)-(+) 90:10, 2.20 mol, 10 eq.) in 250 ml ethylene chloride and the resulting mixture was stirred 1 h at 25° C. and 4 h at 50° C. After cooling, the reaction mixture was washed with aq. sat. NaCl soln. and aq. sat. NaHCO3 soln. The aq. phases were extracted with Et2O, dried (Na2SO4), and concentrated. The crude product (48 g) was filtered (SiO2, hexane/Et2O 200:6→200:10) and the residue (1.42 g) treated with 300 mg LiOH.H2O in 15 ml MeOH at 25° C. for 7 h. The resulting mixture was poured into aq. sat. NaCl soln., extracted with hexane and the org. phases dried with Na2SO4, FC (SiO2, hexane/Et2O 30:1) gave 347 mg (0.8%) of compound 10. Boiling point: 80° C. at 0.07 torr (0.09 mbar).
Reaction SMILES: [I-:1].[I-].[I-].CO[CH2:6][CH2:7][N:8]([CH2:26][CH2:27]OC)[C:9]1[CH:10]=[C:11]([CH3:25])[C:12]2[C:21]([CH:22]=1)=[S+:20][C:19]1[C:14](=[C:15]([CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=1)[N:13]=2.[CH3:30][O:31][CH2:32][CH2:33][N:34](C1C=C(C)C2C(C=1)=[S+]C1C(=C(CC)C=CC=1)N=2)[CH2:35][CH2:36]OC.COC[CH2:59][N:60](C1C=C(C)C2C(C=1)=[S+]C1C(=C(CC)C=CC=1)N=2)CCOC.CN1CCNCC1.[CH3:89][OH:90]>>[I-:1].[CH3:89][O:90][CH2:36][CH2:35][N:34]([CH2:33][CH2:32][O:31][CH3:30])[C:17]1[CH:16]=[C:15]([CH2:23][CH3:24])[C:14]2[C:19]([CH:18]=1)=[S+:20][C:21]1[C:12](=[C:11]([CH3:25])[CH:10]=[C:9]([N:8]3[CH2:7][CH2:6][N:60]([CH3:59])[CH2:27][CH2:26]3)[CH:22]=1)[N:13]=2
Reactant: CO
Reactant: CCc1cccc2[s+]c3cc(N(CCOC)CCOC)cc(C)c3nc12
Agent: CN1CCNCC1
Agent: [I-]
Product: CCc1cc(N(CCOC)CCOC)cc2[s+]c3cc(N4CCN(C)CC4)cc(C)c3nc12

Procedure:
A solution of 3-(bis(2-methoxyethyl)amino)-9-ethyl-1-methylphenothiazin-5-ium triiodide (150 mg, 0.2 mmol) in methanol (10 mL) and 1-methylpiperazine (30 mg, 0.3 mmol) was stirred for 2 h at room temperature. The resulting mixture was concentrated to dryness and purified by flash chromatography using the methanol-chloroform gradient to provide the title compound.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:6]([O:8][C@@H:9]1[C@@H:14]2[C@@H:15]([CH2:20][CH2:21][C@@H:22](O)[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([O-:28])=[O:27])[C@@H:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[CH:12][C@H:11]([CH3:31])[CH2:10]1)=O)([CH3:5])[CH3:4].[NH4+].S([O-])(O)(=O)=O.[K+].[OH2:39]>C(#N)C>[CH3:1][CH2:2][C:3]([C:6]([O:8][C@@H:9]1[C@@H:14]2[C@@H:15]([CH2:20][CH2:21][C@H:22]3[O:28][C:26](=[O:27])[CH2:25][C@H:24]([OH:29])[CH2:23]3)[C@@H:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[CH:12][C@H:11]([CH3:31])[CH2:10]1)=[O:39])([CH3:4])[CH3:5]
Reactant: O
Reactant: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [NH4+]
Solvent: CC#N
Product: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Temperature: 42.5 °C
Reaction time: 3.5 h

Procedure:
Simvastatin ammonium salt (25 g) was taken in acetonitrile (100 ml) under nitrogen atmosphere. To the reaction mixture, potassium hydrogen sulfate (18.7 g) taken in water (50 ml) was added. The reaction mixture was stirred for 3-4 hours at 40-45° C. Water (250 ml) was added to the reaction mixture under stirring. The resulting lactonized product obtained was filtered and washed with water, dried under vacuum to yield crude simvastatin. The crude simvastatin was recrystallized from methanol and water to obtain pure simvastatin.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][CH:7]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[C:9]=2[O:8]1>>[Cl:1][S:2]([C:13]1[CH:14]=[C:15]([C:16]([OH:18])=[O:17])[C:9]2[O:8][CH:7]([CH3:6])[CH2:11][C:10]=2[CH:12]=1)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: CC1Cc2cccc(C(=O)O)c2O1
Product: CC1Cc2cc(S(=O)(=O)Cl)cc(C(=O)O)c2O1
Temperature: 0 °C

Procedure:
630 g of chlorosulphonic acid were introduced into a 1-liter round-bottomed flask. The contents were cooled to 0° C. and 160 g of finely ground 2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid were then added in portions, maintaining the temperature between 0° and 5° C. by cooling in an ice bath.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:16])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2.C([O-])([O-])=O.[K+].[K+].[SH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].O>CO>[CH3:16][N:3]1[C:4]2[C:9](=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2)[C:10]2[CH:11]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[S:23][C:2]1=2
Reactant: Cn1c(Cl)c(C=O)c2cc([N+](=O)[O-])ccc21
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2c3cc([N+](=O)[O-])ccc3n(C)c2s1
Reaction time: 8 h

Procedure:
1.4 g of (66) was added to a slurry of excess K2CO3 in 100 ml of MeOH. 2 ml of methyl 2-mercaptoacetate was added and the mixture left with stirring overnight. Addition of water precipitated the product, which was washed with MeOH and water to give 640 mg of (67). M. p. 269°-71° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]1([CH:15]2[CH2:20][CH2:19][CH:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.BrCCCl.C1C[O:31][CH2:30][CH2:29]1>CN1C(=O)N(C)CCC1>[C:21]([CH:18]1[CH2:19][CH2:20][CH:15]([C:9]2[CH:14]=[CH:13][C:12]([C:30](=[O:31])[CH3:29])=[CH:11][CH:10]=2)[CH2:16][CH2:17]1)(=[O:23])[CH3:22]
Reactant: CC(=O)C1CCC(c2ccccc2)CC1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCBr
Solvent: CN1CCCN(C)C1=O
Product: CC(=O)c1ccc(C2CCC(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of freshly prepared LDA (132 mL of n-butyl lithium, 2.5 M in hexane, 51 mL of diisopropylamine) in THF (anhydrous, 420 mL), DMPU (200 mL) at −78° C. was added a solution of A1 (60 g, 300 mmol) in THF (60 mL) at −78° C. After stirring for 40 min, 1-bromo-2-chloroethane (24.9 mL, 300 mmol) was added. After stirring for another 20 min at −78° C., the dry ice-acetone bath was removed and the reaction was slowly warmed up to rt. After stirring for an additional hour, the reaction mixture was cooled back to −78° C. and a solution of DMPU (200 mL) in THF (420 mL) was added. Another portion of freshly prepared LDA (120 mL of n-butyl lithium, 2.5 M in hexane, 47 mL of di-isopropylamine in THF (anhydrous, 420 ml)) was added into the reaction mixture by cannula at −78° C. After stirring for 1.5 h at −78° C., the dry ice-acetone bath was removed and the reaction was slowly warmed up to rt. After 5-6 h, the reaction was quenched with saturated aqueous ammonium chloride (300 mL) and concentrated. The residue was diluted with H2O (480 mL) and extracted with ethyl acetate/hexane (1:5 (v/v), 3×360 mL). The combined organic layers were washed with brine (500 mL) and then dried, filtered, and concentrated. The resulting crude product was purified by silica gel flash column chromatography (Hexanes/EtOAc=10/1 (v/v)) to provide A2 (35 g).
Reaction SMILES: C([N:4]1[CH2:11][CH:10]2[CH:6]([CH2:7][CH2:8][CH2:9]2)[C:5]1(C(OCC)=O)[C:12]([O:14]CC)=[O:13])(=O)C.[BrH:22]>CC(O)=O>[BrH:22].[CH:6]12[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:11][NH:4][CH:5]2[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C1(C(=O)OCC)C2CCCC2CN1C(C)=O
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)C1NCC2CCCC21
Yield: 93 %

Procedure:
A solution of N-acetyl-3-azabicyclo[3.3.0]octane-2,2-dicarboxylic acid, diethyl ester (1.9 g, 6.3 mmol) in aqueous HBr (48%, 10 mL) and HOAc (2 mL) was heated at 120° C. under nitrogen for 18 h. The reaction mixture was cooled, concentrated in vacuo, and the residue was azeotroped with acetonitrile (2×) and Et2O/toluene (1×) to yield 3-azabicyclo[3.3.0]octane-2-carboxylic acid, hydrobromide (1.4 g, 93%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[H-].[Na+].F[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][C:22]2[N:26]([CH3:27])[N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:20]=1)[C:16]#[N:17].O>CC(N(C)C)=O>[CH3:27][N:26]1[C:22]([O:21][C:19]2[CH:18]=[C:15]([CH:14]=[C:13]([N:5]3[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]3)[CH:20]=2)[C:16]#[N:17])=[CH:23][C:24]([C:28]([F:31])([F:30])[F:29])=[N:25]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cc(F)cc(C#N)c1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(C#N)cc(-n2ccc(C(F)(F)F)n2)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
Under an atmosphere of nitrogen, 0.131 g (0.96 mmol) of 3-trifluoromethylpyrazole was initially charged in 5 ml of dimethylacetamide, and 0.033 g (1.1 mmol) of sodium hydride (80%) was added at 0° C. The mixture was allowed to warm to room temperature, and 0.250 g (0.88 mmol) of 3-fluoro-5-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)benzonitrile was added, the mixture was heated at 140° C. for 8 h and cooled to room temperature, water was added to the reaction solution and the solution was stirred for a number of minutes. The mixture was extracted twice with heptane/ethyl acetate (1:1) and twice with ethyl acetate. The combined phases were washed with water and then dried over magnesium sulfate, filtered and concentrated. Column chromatography of the crude product gave 0.240 g of 3-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-5-(3-trifluoromethylpyrazol-1-yl)benzonitrile in the form of white crystals of melting point of 116-117° C.