Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:9]=[C:8]([N:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH3:11])[N:7]=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:5]=1/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[CH2:26][C@@H:27]([OH:32])[CH2:28][C:29]([OH:31])=[O:30])[CH3:3].[K].[Ca:35].[Cl-].[Ca+2].[Cl-].C([O-])(=O)C.[Ca+2].C([O-])(=O)C.[OH-].[Ca+2].[OH-]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH3:3])[C:4]1[C:5](/[CH:23]=[CH:24]/[C@H:25]([CH2:26][C@H:27]([CH2:28][C:29]([O-:31])=[O:30])[OH:32])[OH:33])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:7]=[C:8]([N:10]([CH3:11])[S:12]([CH3:15])(=[O:13])=[O:14])[N:9]=1.[CH3:1][CH:2]([CH3:3])[C:4]1[C:5](/[CH:23]=[CH:24]/[C@H:25]([CH2:26][C@H:27]([CH2:28][C:29]([O-:31])=[O:30])[OH:32])[OH:33])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:7]=[C:8]([N:10]([CH3:11])[S:12]([CH3:15])(=[O:13])=[O:14])[N:9]=1.[Ca+2:35]
Reactant: [Ca]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-]

Procedure:
The rosuvastatin potassium salt obtained is further treated with mixture of toluene and ethyl acetate followed by treatment with suitable calcium source like calcium chloride, calcium acetate, calcium hydroxide and the like. In particular, calcium acetate is used to obtain rosuvastatin calcium salt. The isolated rosuvastatin calcium is in amorphous form.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH:18]([CH2:25][C:26](=[O:36])[NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=3[CH3:35])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[N:6][O:7][C:8]=2[CH:9]2[CH2:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10]2)[CH2:3][CH2:2]1.Br.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:1]1([C:4]2[C:5]([CH:18]([CH2:25][C:26](=[O:36])[NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=3[CH3:35])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[N:6][O:7][C:8]=2[CH:9]2[CH2:12][CH:11]([CH2:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:10]2)[CH2:3][CH2:2]1
Reactant: COC(=O)CCC(CC(=O)Nc1ccc(C)cc1C)c1noc(C2CC(CC(C)(C)C)C2)c1C1CC1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)CC(CCC(=O)O)c2noc(C3CC(CC(C)(C)C)C3)c2C2CC2)c(C)c1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Methyl 4-{4-cyclopropyl-5-[3-(2,2-dimethylpropyl)cyclobutyl]isoxazol-3-yl}-5-(2,4-dimethylphenylcarbamoyl)valerate (115 mg) and acetic acid (1.2 mL) were mixed. To the mixture was added 47% hydrobromic acid (0.6 mL) at 10° C. The mixture was stirred at RT and further stirred at 60° C. To the reaction mixture was added sodium acetate (492 mg) at ice temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: methanol/chloroform/acetic acid=1/20/0.05) to give the title compound (109 mg). The resulting title compound was analyzed using a chiral column. The retention time of the title compound was 24.7 min., and the optical purity thereof was 94.9% ee.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2cccc(F)c2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1cccc(F)c1

Procedure:
From 2-amino-4-(3-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:38][CH2:39][CH2:40][CH3:41])[N:17]([CH2:18][CH2:19][CH2:20][N:21]([CH2:26][C:27]3[CH:28]=[C:29]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:23][CH2:24]Cl)[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1.[I-].[Na+]>C1COCC1.CN(C=O)C>[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:38][CH2:39][CH2:40][CH3:41])[N:17]([CH2:18][CH2:19][CH2:20][N:21]([CH2:26][C:27]3[CH:28]=[C:29]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:23][CH2:24][N:2]([CH3:3])[CH3:1])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CNC
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCCl)Cc1cccc(CC(=O)OC)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCN(C)C)Cc1cccc(CC(=O)OC)c1
Temperature: 55 °C

Procedure:
A solution of dimethylamine in THF (2M, 6 mL) was added to a mixture of the product from step (ix) (1.17 mmol) and sodium iodide (250 mg) in DMF (5 mL) at rt. The mixture was heated at 55° C. in a sealed vessel for 24 h, cooled, filtered and the filtrate purifed by RPHPLC. The fractions containing the desired compound were evaporated to dryness and the residue triturated with ether/isohexane, 270 mg.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Si]([O:18][CH2:19][C@@H:20]1[C:24]([C:25]2[N:26]=[C:27]([SH:30])[S:28][CH:29]=2)=[CH:23][CH2:22][N:21]1[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])(C(C)(C)C)(C)C.O(P(OC1C=CC=CC=1)O[C:46]1[C@H:52]([CH3:53])[C@H:51]2[N:48]([C:49](=[O:61])[C@@H:50]2[C@H:54]([O:56][Si](C)(C)C)[CH3:55])[C:47]=1[C:62]([O:64][CH2:65][CH:66]=[CH2:67])=[O:63])C1C=CC=CC=1.C(#N)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[CH2:34]([O:33][C:31]([N:21]1[CH2:22][CH:23]=[C:24]([C:25]2[N:26]=[C:27]([S:30][C:46]3[C@H:52]([CH3:53])[C@H:51]4[N:48]([C:49](=[O:61])[C@@H:50]4[C@H:54]([OH:56])[CH3:55])[C:47]=3[C:62]([O:64][CH2:65][CH:66]=[CH2:67])=[O:63])[S:28][CH:29]=2)[C@H:20]1[CH2:19][OH:18])=[O:32])[CH:35]=[CH2:36]
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Reactant: C=CCOC(=O)N1CC=C(c2csc(S)n2)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [F-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@@H]3CO)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 0.16 ml, 0.16 mmol) was added at 0–5° C. to a solution of allyl (2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(2-mercapto-1,3-thiazol-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (67 mg, 0.16 mmol) in THF (0.3 ml) and the mixture was stirred for 20 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 0.62 g, 0.32 mmol) and the solution was allowed to stand in a refrigerator for 12 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 1/5→1/3) to give a mixture of a coupling compound and POCA (Starting material). To the mixture in THF (2.4 ml) were added at 0–5° C. acetic acid (92 μl) and tetrabutylammonium fluoride in THF (1M, 0.96 ml, 0.96 mmol). After reaction for 20 hours, to the reaction mixture was added ice water and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 1/3→10% methanol/chloroform) to give allyl (4R,5S,6S)-3-({4-[(2S)-1-[(allyloxy)carbonyl]-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1,3-thiazol-2-yl}sulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (83 mg, 95%).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]=[O:5].C(N(CC)CC)C.[CH2:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[CH2:15][CH2:14]1.Cl>O1CCCC1>[OH:22][C:17]1[C:18]([CH:4]=[O:5])=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][CH2:13]2
Reactant: Oc1cccc2c1CCC2
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=Cc1ccc2c(c1O)CCC2
Temperature: 72.5 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirred suspension Magnesium chloride (71.0 gm, 0.745 mole) and Para-formaldehyde (33.6 gm, 1.12 mole) in Tetrahydrofuran (200 ml), Triethylamine (104 ml, 0.745 mole) was added at room temperature and stirred for 30 minutes. To the reaction mixture; the solution of Indan-4-ol (50 gm, 0.373) in Tetrahydrofuran (100 ml) was added at room temperature and heated to 70-75° C. for 6 hours. To the reaction mixture, 2N Hydrochloric acid (600 ml) was added and extracted with Ethylacetate (2×500 ml). The Ethylacetate layer was washed with water (300 ml), dried over Sodium sulphate and further it was distilled under vacuum to give viscous oil (52.0 gm) which becomes solid upon keeping.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=3[CH3:13])[CH2:22][CH2:23]2)=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: COc1cc(Br)ccc1C(=O)O
Product: COc1cc(Br)ccc1C(=O)N1CCN(c2ccc(C)cc2C)CC1
Yield: 81.3 %

Procedure:
Methyl 4-bromo-2-methoxybenzoate (10 g) was dissolved in methanol (80 mL), 1N aqueous sodium hydroxide solution (80 mL) was added, and the mixture was refluxed for 3 hr. After cooling, 1N hydrochloric acid (80 mL) was added, and the mixture was filtered to give 4-bromo-2-methoxybenzoic acid (9.2 g). By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-methoxybenzoic acid (3.1 g) and 1-(2,4-dimethylphenyl)piperazine (2.7 g), the title compound (4.4 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([CH3:10])=[C:5]([C:7]([O-:9])=O)[N:6]=1.[Li+].Cl.Cl.[NH2:20][CH2:21][CH:22]([OH:38])[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[Cl:37])[CH2:26][CH2:25]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[Cl:37][C:31]1[C:32]([Cl:36])=[CH:33][CH:34]=[CH:35][C:30]=1[N:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH:22]([OH:38])[CH2:21][NH:20][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[N:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH3:10])=[O:9])[CH2:25][CH2:26]1
Reactant: Cc1nc(C(=O)[O-])c(C)n1-c1ccccc1
Reactant: NCC(O)CN1CCN(c2cccc(Cl)c2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc(C(=O)NCC(O)CN2CCN(c3cccc(Cl)c3Cl)CC2)c(C)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 39.8 %

Procedure:
To a mixture of lithium 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (compound 13a, 150 mg, 0.67 mmol), 1-amino-3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propan-2-ol dihydrochloride (compound 41, 300 mg, 0.80 mmol), EDCI (260 mg, 1.34 mmol) and HOBt (180 mg, 1.34 mmol) in anhydrous DMF (7 mL) was added NMM (370 μl, 3.35 mmol). The reaction mixture was stirred at room temperature for 15 hrs. The mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (purification system, Gilson) to provide the title compound (134 mg, 40%) as a white solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](OCC)=[O:7])#[N:2].N>CO.[Ni]>[C:11]1([C:5]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:4][CH2:3][CH2:1][NH:2][C:6]2=[O:7])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(CCC#N)(c1ccccc1)c1ccccc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: O=C1NCCCC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Example 1B (14.4 g, 49.1 mmol) and 7 M ammonia in methanol (150 mL) were added to solvent-washed Raney®-nickel (72.0 g, 1227 mmol), and the mixture was stirred at room temperature for 24 hours under hydrogen (30 pounds per square inch). The mixture was filtered through a nylon membrane, and the filtrate was concentrated. The residue was dissolved in dichloromethane/methanol (1:1) and filtered through diatomaceous earth to remove a greenish residue. The filtrate was concentrated to obtain a solid which was slurried in methanol, filtered, and dried to obtain the title compound. MS (DCI+) m/z 251 (M+H)+.
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[Cl:8][C:9]1[N:15]=[CH:14][C:13]2[NH:16][C:17](=O)[CH2:18][NH:19][C:12]=2[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.CC(C)([O-])C.[K+]>C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:8][C:9]1[N:15]=[CH:14][C:13]2[N:16]([CH3:17])[C:7](=[O:6])[CH2:18][NH:19][C:12]=2[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1
Reactant: O=C1CNC2=C(C=NC(Cl)=CN2c2ccccc2)N1
Reactant: COS(=O)(=O)OC
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1C(=O)CNC2=C1C=NC(Cl)=CN2c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dimethylsulfate, 1.15g (9mmol), was added to a solution of 1.2g (4.4mmol) of 7-chloro-1,3-dihydro-5-phenyl-2H-pyrazino[2,3-f] [1,4] diazepin-2-one and 1g (9mmol) of potassium t-butoxide in 30 ml of ethanol. After stirring for 10 min at room temperature, the reaction mixture was diluted with 10% aqueous sodium carbonate solution and was extracted with methylene chloride. The extracts were washed with water, dried over sodiumsulfate and evaporated. The residue was chromatographed over 40g of silica gel (Merck, 70-230 mesh) using 10% ethylacetate in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ether/hexane to yield the above-named product, with mp. 105°-107°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:24]1([C:27]([NH2:29])=[O:28])[CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:29][C:27]([CH:24]3[CH2:26][CH2:25]3)=[O:28])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OS(=O)(=O)C(F)(F)F)c2c1C
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1oc2cccc(NC(=O)C3CC3)c2c1C
Yield: 98 %

Procedure:
To 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (300 mg, 0.85 mmol, 1 eq, prepared according to Example 20, Step 1) in 8 mL of dioxane under nitrogen were added cyclopropyl carboxamide (87 mg, 1.02 mmol, 1.2 eq), Pd2 (dba)3 (16 mg, 0.017 mmol, 0.02 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (30 mg, 0.051 mmol, 0.06 eq), and cesium carbonate (390 mg, 1.19 mmol, 1.4 eq). The reaction mixture was heated at reflux for 72 h. After work up and column chromatography (dichloromethane/hexanes), 4-(cyclopropanecarbonyl-amino)-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 98% yield (238 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (m, 4 H) 1.3 (t, J=7.1 Hz, 3 H) 1.8 (s, 1 H) 2.6 (s, 3 H) 4.4 (q, J=7.2 Hz, 2 H) 7.2 (d, J=7.1 Hz, 1 H) 7.5 (m, 1 H) 7.5 (m, 1 H) 10.1 (s, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:16]2[CH:17]=[C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:19](COCC[Si](C)(C)C)[C:15]=2[C:14](=[O:33])[N:13]([CH3:34])[N:12]=1.[C:35]1([OH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:34][N:13]1[C:14](=[O:33])[C:15]2[NH:19][C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:17][C:16]=2[C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[O:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:12]1
Reactant: CCOC(=O)c1cc2c(-c3cc([N+](=O)[O-])ccc3F)nn(C)c(=O)c2n1COCC[Si](C)(C)C
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccccc3)nn(C)c(=O)c2[nH]1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A mixture of Example 74f (0.26 g, 0.53 mmol), phenol (0.060 g, 0.64 mmol) and cesium carbonate (0.21 g, 0.63 mmol) in dimethylsulfoxide (5 mL) was heated at 110° C. for 6 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was then treated with 15 mL of ethanol and 1 mL of concentrated H2SO4. The mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 40-80% ethyl acetate to afford 0.14 g (61%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[N:18]1([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:29][CH2:28]1
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1)C1CC1
Yield: 69.8 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (210 mg, 0.680 mmol) was reacted with 4-(pyrrolidin-1-ylmethyl)piperidine (229 mg, 1.36 mmol) to afford the desired product (210 mg, 70%) as a yellow semisolid: ESI MS m/z 443 [C23H28BrN3O+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH2:12][O:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:8][CH:9]=1)([O-])=O>C1(C)C=CC=CC=1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH2:12][O:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:8][CH:9]=1
Reactant: O=C(OCCSc1ccc([N+](=O)[O-])cn1)c1cccc(Cl)c1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1ccc(SCCOC(=O)c2cccc(Cl)c2)nc1
Reaction time: 1 h

Procedure:
A mixture of 2-[(5-nitro-2-pyridinyl)thio]ethyl 3-chlorobenzoate (5) (0.24 g, 0.71 mmol) and 10% Pd/C (0.10 g) in toluene or methanol was agitated under a hydrogen atmosphere (40 PSI) for 1 h. The reaction mixture was filtered through Celite® and concentrated to give 2-[(5-amino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (51), LCMS: purity: 99%; MS (m/e): 309 (MH+), which was used without further purification. Acetyl chloride (4.6 μL, 0.064 mmol) was added to a room temperature solution of 2-[(5-amino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (51) (18.9 mg, 0.061 mmol) and triethylamine (18 μL, 0.13 mmol) in anhydrous dichloromethane (1.0 mL), After 16 h, the reaction mixture was diluted with dichloromethane and washed with 1N HCl and brine and then dried over anhydrous MgSO4. Purification by silica gel chromatography provided 2-[(5-acetylamino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (52), LCMS: purity: 99%; MS (m/e): 351 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][O:23][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of methanesulphonylchloride (7.7 ml) in dichloromethane (50 ml) was added dropwise to a stirred solution of 1-benzyloxycarbonyl-4-hydroxymethylpiperidine (23.4 g) in dichloromethane (350 ml) cooled to 5° C. Stirring was continued for 1 hour, then the solution was washed with water (4×150 ml) and saturated aqueous sodium chloride (100 ml), dried and concentrated. The residue was crystallised from tetrachloromethane (250 ml) to give 1-benzyloxycarbonyl-4-methanesulphonyloxymethylpiperidine (20 g) as colourless prisms, m.p. 72°-74° C. NMR (CDCl3): δ 1.1-1.4(2H,m); 1.7-1.8(2H,d); 1.9-2.1(1H,m); 2.7-2.9(2H,t); 3.0(3H,s); 4.05(2H,d); 4.1-4.4(2H,d); 5.1(2H,s); 7.3(5H,m); m/e 328(M+H)+ 350 (M+Na)+ ; calculated for C15H21N5O5 : C, 55.0; H, 6.5; N, 4.3; found: C, 54.8; H, 6.6; N, 4.2%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([NH2:34])[CH:6]=1)[CH3:2].[H-].[Na+].I[CH3:39].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([NH:34][CH3:39])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(N)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(NC)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1
Reaction time: 48 h

Procedure:
5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-aminobenzoic acid ethyl ester (210 mg, 0.43 mmol), sodium hydride (17 mg, 0.43 mmol), iodomethane (0.027 mL, 0.43 mmol), in 3 mL of DMF were stirred at room temperature for 24 hrs, then another 0.027 mL of iodomethane were added and the reaction mixture was stirred for another 48 hrs. The mixture was then poured into water and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), and concentrated. Purification was carried out on SPE using iso-hexane containing a gradient of ethylacetate (20–30%) to give the required product as a yellow oil. (85 mg, 39%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH:12]1([NH2:16])[CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH:12]1([NH:16][C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCC1)OCc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl chloroformate (5.2 mL, 36.4 mmol) was added dropwise to an ice-cold solution of cyclobutylamine (2 g, 28.1 mmol) in dichloromethane (20 mL), with stirring. Triethylamine (4.7 mL, 33.7 mmol) was added dropwise to the ice-cold solution, and once the addition was complete the reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was washed with saturated sodium bicarbonate solution (×2), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane as eluant to afford the title compound, 3.72 g. 1H NMR (CDCl3, 300 MHz) δ: 1.68 (m, 2H), 1.82 (m, 2H), 2.35 (m, 2H), 4.19 (m, 1H), 4.92 (m, 1H), 5.14 (s, 2H), 7.25-7.39 (m, 5H). MS TSP+ m/z 223.2 [MH]+