Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([OH:21])=[O:20])=[C:8]([CH2:11]OC(=O)CC(=O)C)[CH2:9][S:10][C@H:5]12)=[O:2].[N:24]1[N:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=[CH:26][CH:25]=1>>[CH:1]([NH:3][C@@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([CH2:11][C:26]3[CH:25]=[NH+:24][N:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=34)[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reactant: c1ccn2nccc2c1
Product: O=CN[C@@H]1C(=O)N2C(C(=O)[O-])=C(Cc3c[nH+]n4ccccc34)CS[C@H]12

Procedure:
7β-Formamido-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid and pyrazolo[1,5-a]pyridine are reacted in the same manner as described in Example 5 to give the above-identified compound.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][Cl:18])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7].[ClH:37].[CH3:38][CH:39]1[CH2:44][O:43][CH2:42][CH2:41][NH:40]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[ClH:18].[ClH:37].[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH:39]2[CH3:38])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCCl)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CC1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOCC3C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.4 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-chloro-2-butynyl)piperazine (0.49 g), 3-methylmorpholine hydrochloride (0.15 g), potassium carbonate (0.39 g) and potassium iodide (10 mg) in dry N,N-dimethylformamide (5 ml) was stirred for 5 hours at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3-methylmorpholino)-2-butynyl]piperazine dihydrochloride (0.28 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[N:12][C:11]=1[C:19]([OH:21])=O.Cl.[NH2:23][O:24][CH2:25][C@@H:26]([OH:28])[CH3:27].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[OH:28][C@@H:26]([CH3:27])[CH2:25][O:24][NH:23][C:19]([C:11]1[N:12]=[CH:13][C:14]2[N:15]([CH:16]=[N:17][CH:18]=2)[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: C[C@H](O)CON
Reactant: O=C(O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](O)CONC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.8 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (85 mg, 0.21 mmol) in anhydrous DMF (1.0 mL) was added (S)-1-aminooxy-propan-2-ol hydrochloride (32.7 mg, 0.26 mmol, 1.2 eq.), DIPEA (0.13 mL, 0.77 mmol, 3.6 eq.), HOBt (36.0 mg, 0.26 mmol, 1.2 eq.) and EDCI (51.2 mg, 0.26 mmol, 1.2 eq.), and the reaction mixture was stirred at ambient temperature under N2 for 16 hours. The reaction mixture was poured into ethyl acetate, and the organic layer was washed with a saturated solution of sodium bicarbonate, 50% brine and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 40%, methanol in ethyl acetate) to give an oil. Crystallization from dichloromethane—ether—hexane afforded the title compound as a yellow solid (10.7 mg, 10.6%). 1H NMR (MeOD, 400 MHz) δ ppm 8.76 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.64 (dd, J=10.13, 1.84 Hz, 1H), 7.55-7.50 (m, 1H), 6.72 (t, J=8.49 Hz, 1H); LCMS (method E1): RT=5.14 min, [M+H]+=472.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N+:15](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-:16]>S(Cl)(Cl)=O>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[N+:15]=[N-:16])[C:4]([C:3]1[C:2]([Cl:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=1)=[O:6])[CH3:22]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1ccc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
2-Chloro-6-trifluoromethylnicotinic acid (10.0 g, 44.3 mmol) was suspended in thionyl chloride (85 ml) and heated under reflux for 2 h. The mixture was allowed to cool to ambient temperature, the solvent was removed in vacuo, toluene (50 ml) was added and the solution concentrated to afford a brown residue. This residue was cooled to −10° C. before ethyl diazoacetate (12.7 g, 110 mmol) was added dropwise over 30 min (maintaining the internal temperature below −5° C.). On complete addition the mixture was allowed to stir at 0° C. for 1 h then heated at 55° C. for 18 h. The mixture was allowed to cool to ambient temperature then evaporated. The residue was purified by dry flash chromatography on silica eluting with isohexane on a gradient of ethyl acetate (10–30%). Collecting the appropriate fractions gave 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-2-diazo-3-oxo-propionic acid ethyl ester (13.7 g, 96%) as a yellow oil: δH (400 MHz, CDCl3) 1.17 (3H, t, J7), 4.15 (2H, q, J7), 7.68 (1H, d, J8), 7.78 (1H, d, J8), CHN2 absent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:23][N:24]=[C:25]=[S:26].[Cl-].[NH4+]>O1CCCC1.CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][C:25](=[S:26])[NH:24][CH3:23])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CN=C=S
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=S)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a dry tetrahydrofuran-dimethylformamide (1:1 v/v, 1 ml) solution of 50 mg (0.15 mmol) of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]-methanol (Compound I-8) was added 6.6 mg (0.17 mmol) of 60% sodium hydride under nitrogen atomosphere, and the mixture was stirred at room temperature for 30 minutes. Then, 22 mg (0.3 mmol) of methylisothiocyanate was added under ice-cooling. The mixture was stirred at the same temperature for 30 minutes, and at room temperature for 30 minutes. To the reaction mixture, an aqueous ammonium chloride solution was added to terminate the reaction. The mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:1) to give 37 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-(N-methylthiocarbamoyl)oxymethyl-1H-imidazole (Compound I-44) (yield 60%). mp 119-121° C.
Reaction SMILES: C([Mg]Cl)C.Br[C:6]1[S:10][C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:8][C:7]=1[CH3:28].[CH2:29]([O:31][C:32](C#N)=[O:33])[CH3:30]>C1COCC1>[CH2:29]([O:31][C:32]([C:6]1[S:10][C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:8][C:7]=1[CH3:28])=[O:33])[CH3:30]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1Br
Reactant: CCOC(=O)C#N
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
Ethylmagnesium chloride (10.9 ml, 2M in THF) is added over 30 minutes to a solution of 3-(5-bromo-4-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (10.0 g, Example 1, step D) in THF (15 ml) at 0° C. After 1 hour at room temperature, a solution of ethylcyanoformate (2.81 g) in THF (15 ml) is added to the reaction mixture. After 40 minutes, the reaction is quenched with a saturated aqueous solution of NH4Cl in water. The mixture is extracted three times with MTBE. The organic phases are combined, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid ethyl ester (5.6 g) as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.C(O)(=O)C.CO>[C:17]1([NH:23][C:24](=[O:25])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC(C(=O)c2cccc(NC(=O)Nc3ccccc3)c2)CC1
Yield: 73.4 %

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and phenyl isocyanate (37 μL, 0.344 mmol) in methylene chloride (2 mL) were mixed for 72 h at ambient temperature. The solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was stirred with 5N sodium hydroxide solution (1 mL). The solvent was removed under vacuum and the residue was purified by silica gel chromatography (methylene chloride:methanol:ammonium hydroxide, 97.5:2.5:0.25 then 95:5:0.5). The solvent was evaporated to give 28.5 mg (74%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH3:17][O-:18].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH3:17])[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and sodium methylate in methanol. EI-MS m/e (%): 216 (M+, 100), 215 ([M—H]+, 36).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([CH2:20][CH:21]=O)[C:16]2=O)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][CH2:14][C:15]3[CH:20]=[CH:21][N:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:16]=3[C:17]=2[CH:18]=1
Reactant: CC(=O)NCCN
Reactant: O=CCC1CCc2ccc(Cl)cc2C1=O
Solvent: ClCCl
Product: CC(=O)NCCn1ccc2c1-c1cc(Cl)ccc1CC2
Yield: 54.1 %

Procedure:
N-Acetylethylenediamine (2.9 g) was dissolved in 50 ml of methylene chloride under argon, treated in succession with 4.5 g of molecular sieve 4 Å and a solution of 5.7 g of 7-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde in 20 ml of methylene chloride and heated to reflux for 16 hours while stirring. The reaction mixture was cooled, filtered over a Celite® pad and the filtrate was freed from solvent. The crude product, 6.6 g of brown solid, was dissolved in a 6-fold amount of hot ethyl acetate and, after the addition of an 8-fold amount of hexane, boiled briefly. There were obtained 4.0 g (55%) of N-[2-(8-chloro-4,5-dihydro-1H-benzo[g]indol-1-yl)ethyl]acetamide; m.pt.: 144°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[N:22]([C:31](=[O:32])[CH2:30][OH:33])[CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc(OC[C@@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: O=C(O)CO
Product: COc1cc(OC[C@@H]2C[C@H](O)CN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 81 %

Procedure:
The procedure described in Example 20 was repeated using (3S,5S)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (157 mg) with glycolic acid (31 mg) to give the title compound as a white solid in 81% yield; NMR spectrum (DMSO-d6) 10.01 (s, 1H), 8.48 (s, 1H), 8.22 (dd, 1H), 7.74-7.69 (m, 1H), 7.43 (t, 1H), 6.84 (d, 1H), 6.78 (d, 1H), 5.29-5.28 (m, 1H), 4.73-4.68 (m, 1H), 4.64-4.59 (m, 2H), 4.44-4.42 (m, 1H), 4.34-4.31 (m, 1H), 4.06-4.05 (m, 2H), 3.93 (s, 3H), 3.64 (dd, 1H), 3.45 (s, 1H), 2.25-2.12 (m, 1H), 1.99-1.95 (m, 1H); Mass spectrum MH+ 477.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.CN(C)C=O.[OH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]=[C:19]=[S:20]>C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[N:3]([C:19]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][OH:12])=[S:20])[N:4]=[CH:5][N:6]=1
Reactant: OCCCCCN=C=S
Reactant: Nc1nc[nH]n1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ncnn1C(=S)NCCCCCO
Yield: 18.9 %

Procedure:
The synthesis method of Example 1-(3) was applied. 3-Amino-1H-1,2,4-triazole (4.00 g), dimethylformamide (25 ml) and 5-hydroxypentyl isothiocyanate (9.24 g) were used as reagents. After the reaction, silica gel column chromatography (chloroform-methanol) was applied to give 2.06 g of white crystals (yield 19%). The crystals were subjected to recrystallization from chloroform to give white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[NH2:13]OS(O)(=O)=O.[O-]S([O-])(=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[C:3]2[O:12][N:13]=[CH:5][C:4]=2[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)c(O)c1Cl
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2cnoc2c1Cl

Procedure:
3-chloro-2-hydroxy-4-methoxybenzaldehyde (1.48 g) is suspended in 15 ml of H2O and hydroxylamine-O-sulfonic acid (1.08 g) is added, along with 0.1 g of Na2SO4. After three hours an additional 15 ml of H2O is added. After a total of four hours the reaction mixture is treated with 8% NaHCO3 solution and then extracted into ether. Evaporation and trituration with hexane gives a solid product. Recrystallization from toluene/hexane gives 7-chloro-6-methoxy-1,2-benzisoxazole, mp 115°-118° C.
Reaction SMILES: Cl.[N:2]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:24]([C:25]5[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=5)=[CH:23][NH:22][C:19]4=[N:20][CH:21]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].CCOC(C)=O>CO>[C:41]([N:5]1[CH2:4][CH2:3][N:2]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:24]([C:25]5[CH:26]=[CH:27][C:28]([C:29]([NH2:31])=[O:30])=[CH:32][CH:33]=5)=[CH:23][NH:22][C:19]4=[N:20][CH:21]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6]1)(=[O:43])[CH3:42]
Reactant: NC(=O)c1ccc(-c2c[nH]c3ncc(-c4ccc(C(=O)N5CCNCC5)cc4)cc23)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)c2ccc(-c3cnc4[nH]cc(-c5ccc(C(N)=O)cc5)c4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a solution of 4-{5-[4-(piperazine-1-carbonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-benzamide, hydrochloride salt (19 mg, 0.041 mmol) in MeOH (2 ml) was added triethylamine (400 μl, 2.88 mmol) and acetic anhydride (100 μl, 1.06 mmol). The mixture was stirred for 1 hr at room temperature. EtOAc was added and washed with saturated aqu. NaHCO3, water, brine and dried and evacuated. Purification on silica gel employing 0-10% MeOH:DCM provided 4.7 mg (25%) of the title compound. MS ESI (m/z): 468.3 (M+1)+, calc. 467.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br.BrC[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[C:13]([CH3:15])=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]=2[CH:21]([CH3:22])[CH3:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1c(C)[nH]c(Sc2cc(Cl)cc(Cl)c2)c1C(C)C
Reactant: BrCc1ccncc1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Product: CCOC(=O)c1c(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n(-c2ccncc2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.1 %

Procedure:
A solution of 0.1 g of ethyl 5-(3,5-dichlorophenylsulphanyl)-4-isopropyl-2-methyl-1H-pyrrole-3-carboxylate in 2 ml of anhydrous tetrahydroftiran was stirred at room temperature under nitrogen and treated with 65 mg of 4-bromomethylpyridine hydrobromide, 5 mg of tetra-n-butylammonium bromide and 24 mg of powdered sodium hydroxide. The mixture was stirred at room temperature for 20 h then diluted with 20 ml of water and extracted three times with 10 ml of ethyl acetate. Combined extracts were washed with 10 ml of brine, then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/isohexane (1:1) for the elution to give 0.104 g of ethyl 5-(3,5-dichlorophenylsulphanyl)-4-isopropyl-2-methyl-1-pyridin-4-yl-1H-pyrrole-3-carboxylate as a colourless gum. Mass spectrum (ESI) m/z 463 [M+H]+. 1H NMR (CDCl3) 1.32 (d, 6H), 1.40 (t, 3H), 2.45 (s, 3H), 3.61 (m 1H), 4.34 (q, 2H), 5.16 (s, 2H), 6.69 (d, 2H), 6.76 (m, 2H), 7.01 (t, 1H), 8.47 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][S:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl.O>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH:2][C:3]2([C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:5][S:6][CH2:7][CH2:8]2)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1(N)CCSCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1(NS(=O)(=O)c2ccc(OC)cc2)CCSCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-amino-4-carbomethoxy-tetrahydrothiopyran hydrochloride (3.1 g, 15.0 mmol) in methylene chloride (75 mL) containing triethylamine (3.5 g, 330.0 mmol) is added 4-methoxybenzenesulfonyl chloride (4.1 g, 20.0 mmol) at room temperature. The reaction mixture is stirred at room temperature for 18 hours. The mixture is diluted with water and the organic layer is removed. The aqueous layer is extracted with diethyl ether and the organic extracts are washed with brine, dried (MgSO4) and the solvent is evaporated. The product is purified by silica gel chromatography (50% ethylacetate/hexanes) to provide 4-[[4-methoxybenzenesulfonyl]amino]-4-carbomethoxy-tetrahydrothiopyran.
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].[F:6][C:7]([F:23])([C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:8][OH:9]>CCN(C(C)C)C(C)C>[OH:3][C@H:2]([CH2:1][O:9][CH2:8][C:7]([F:23])([F:6])[C:10]([F:21])([F:22])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])[CH2:4][OH:5]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OC[C@@H]1CO1
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@H](O)COCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 58.2 %

Procedure:
(S)-2-hydroxy-3-(2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyloxy)-propanol was prepared by the following modification of a procedure described in U.S. Pat. No. 3,470,258 (Teroso et al.). (R)-glycidol (5.0 g, 67.5 mmol) was added dropwise to a 120° C. solution of 2,2,3,3,4,4,5,5,6,6,6-undecafluorohexanol (30 g, 101 mmol) and N,N'-diisopropylethylamine (0.47 ml, 2.7 mmol). The resulting mixture was then stirred for one hour. The resulting product was distilled (79-81° C. at 0.4 mm Hg) from the mixture to give 14.7 g of (S)-2-hydroxy-3-(2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyloxy)-1-propanol as a clear liquid. (R)-2-fluoro-3-(2,2,3,3,4,4,5,5,6,6,6-undecafluorohexane-1-p-toluenesulfonate was then prepared using essentially the procedure described in Example 1.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:26][N:25]([CH3:27])[CH2:24][CH2:23][C:9]=3[N:10]([CH2:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)(O)[CH3:15])[C:11]=2[CH:12]=1)([CH3:3])[CH3:2]>O=S(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:26][N:25]([CH3:27])[CH2:24][CH2:23][C:9]=3[N:10](/[CH:13]=[C:14](/[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)\[CH3:15])[C:11]=2[CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2c3c(n(CC(C)(O)c4ccncc4)c2c1)CCN(C)C3
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3ccc(C(C)C)cc31)CN(C)CC2)c1ccncc1

Procedure:
1-(7-Isopropyl-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-4-yl-propan-2-ol (100 mg, 0.2 mmol) was dissolved in SOCl2 (1.0 mL) and stirred the reaction at RT for 2 h. After completion of starting material by monitoring TLC reaction mixture was concentrated under reduced pressure and saturated bicarbonate was added, extracted with EtOAc, organic layer was washed with water, dried over sodium sulfate and concentrated, and purified by reverse phase Chromatography. Yield: 68 mg. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.62 (d, 2H), 7.70 (d, 2H), 7.48 (s, 1H), 7.42 (d, 1H), 7.05 (m, 2H), 4.40 (m, 2H), 3.58 (m, 2H), 3.05 (m, 3H), 2.95 (s, 3H), 1.95 (s, 3H), 1.25 (d, 6H).