Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[O:18])[N:14]=2)[CH2:7]1)(=O)=O.[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[O:18])[N:14]=2)[CH2:9]1)(=[O:27])[CH3:25]
Reactant: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-[4-(thiophene-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (623 mg, 1.67 mmol) (obtained as described in Reference Example 66(3)) in dimethylformamide (18 ml) was added potassium thioacetate (1.14 g, 10.0 mmol) at room temperature, and the mixture was stirred in an oil bath (90° C.) for 4 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) ethyl acetate as the eluant to afford 3-acetylthio-1-[4-(thiophene-2-carbonyl-amino)methyl-1,3-thiazol-2-yl]azetidine (490 mg, yield 91%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:33]([F:34])=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C@H:19]([C:24]([O:26]C3CCCC3)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:10][C:9]=2[F:35])[C:6](=[O:36])[CH:5]=[CH:4][C:3]=1[C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1.[Li+].[OH-]>C1COCC1.O>[NH2:1][C:2]1[N:7]([C:8]2[C:9]([F:35])=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:32][C:33]=2[F:34])[C:6](=[O:36])[CH:5]=[CH:4][C:3]=1[C:37](=[O:45])[C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1
Reactant: CC(C)C[C@H](NCCCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)c(F)c1)C(=O)OC1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](NCCCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)c(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
From Example 55. To a solution of cyclopentyl N-(5-{4-[6-amino-5-(4-fluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenoxy}pentyl)-L-leucinate (33 mg, 0.05 mmol) in THF (1 ml) and water (1 ml) was added LiOH (25 mg, 1.05 mmol, 20 eq). The mixture was stirred at room temperature for 16 hours, before being heated at 80° C. for 10 hours. The mixture was concentrated under reduced pressure and water (5 ml) added. The pH was adjusted to 7 using 1M HCl and the aqueous layer extracted with 1-butanol (3×5 ml). The combined organic extracts were concentrated under reduced pressure. The solid residue was triturated with Et2O, collected by filtration and purified by preparative HPLC to provide the title compound as a white solid as the mono-TFA salt (7 mg, 24% yield). LC/MS: m/z 560 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ: 7.62-7.51 (3H, m), 7.34 (2H, m), 7.05 (2H, m), 5.72 (1H, d, J=9.8 Hz), 4.09 (2H, t, J=5.7 Hz), 3.23 (1H, m), 2.80 (2H, m), 1.79-1.43 (9H, m), 0.89 (6H, t, J=6.7 Hz).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][N:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:23])C(=O)C1>C(#N)C>[Br:23][C:2]1[S:1][C:10]2[CH2:9][CH2:8][CH2:7][N:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5][C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCCc2sccc2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)N1CCCc2sc(Br)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of Compound 1050 (1.53 g, 6.79 mmol) in acetonitrile (70 mL) at 0° C. was slowly added NBS (1.69 g, 9.48 mmol). The reaction was stirred at room temperature for 30 minutes, at which point HPLC analysis indicated disappearance of starting material. The reaction was quenched by addition of saturated sodium bicarbonate (50 mL) and stirred for one hour. The mixture was extracted with diethyl ether (3×100 mL), the volatiles removed under reduced pressure, and the residue purified by silica chromatography (0-30% ethyl acetate in hexanes) to give ethyl 2-bromo-7,8-dihydro-4H-thieno[3,2-c]azepine-5-carboxylate as a pale yellow oil (Compound 1051, 2.07 g, 86% yield); 1H NMR (300 MHz, CDCl3): δ 6.84-6.70 (m, 1H), 4.30 (d, J=15.4 Hz, 2H), 4.02 (q, J=6.7 Hz, 2H), 3.63 (s, 2H), 2.78 (dd, J=4.6, 5.7 Hz, 2H), 1.80 (s, 2H) and 1.16 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)[CH3:2].[CH2:10](I)[CH3:11].[CH3:13][NH:14][C:15]([C:17]1[C:21]2[CH:22]=[C:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([NH2:26])=[CH:25][C:20]=2[O:19][C:18]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:16]>C(#N)C>[CH3:13][NH:14][C:15]([C:17]1[C:21]2[CH:22]=[C:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([NH:26][CH2:1][CH3:2])=[CH:25][C:20]=2[O:19][C:18]=1[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)=[O:16].[CH3:13][NH:14][C:15]([C:17]1[C:21]2[CH:22]=[C:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([N:26]([CH2:10][CH3:11])[CH2:1][CH3:2])=[CH:25][C:20]=2[O:19][C:18]=1[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)=[O:16]
Reactant: CCI
Reactant: CCN(C(C)C)C(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(OC(C)C)cc12
Solvent: CC#N
Product: CCN(CC)c1cc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1OC(C)C
Product: CCNc1cc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1OC(C)C
Yield: 45 %
Yield: 27 %

Procedure:
Diisopropylethylamine (407 μL, 2.34 mmol) and ethyl iodine (187 μL, 2.34 mmol) were added to a solution of 6-amino-2-(4-fluoro-phenyl)-5-isopropoxy-benzofuran-3-carboxylic acid methylamide, prepared according to Example 16 (200 mg, 584 μmol) in dry acetonitrile (8 mL). The reaction was monitored under analytical LC/MS conditions and quenched by addition of water (4 mL). After concentration to dryness, the crude product was purified by preparative HPLC (reverse phase C18, acetonitrile/water plus 0.1% acetic acid), affording 97 mg (45%) of the 6-ethylamino-2-(4-fluoro-phenyl)-5-isopropoxy-benzofuran-3-carboxylic acid methylamide and 63 mg (27%) of 6-diethylamino-2-(4-fluoro-phenyl)-5-isopropoxy-benzofuran-3-carboxylic acid methylamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(CCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(CCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-1H-pyrazol-4-yl]propionate (1.08 g), 1 N aqueous sodium hydroxide solution (4.2 ml), tetrahydrofuran (3 ml), and ethanol (3 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-ethoxy-1-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-1H-pyrazol-4-yl]propionic acid (880 mg, yield: 88%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 110–111° C.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH3:21])=[CH:12][CH:11]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[ClH:1].[CH3:21][NH:20][CH2:19][CH2:18][CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([OH:9])=[CH:15][CH:14]=1
Reactant: CNCCCOc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CNCCCOc1ccc(O)cc1
Reaction time: 0.4 h
Yield: 80 %

Procedure:
A solution of 1-benzyloxy-4-(3-methylaminopropoxy)benzene hydrochloride (8.4 g) in acetic acid (250 ml) was hydrogenated over 0.5 g of 10% palladium on carbon in a Parr apparatus (50°; initial pressure 50 psi). The reaction was completed within 0.4 hours and after the catalyst was removed by filtration, the solvent was distilled in vacuo. The residue was crystallized from methanol-ethyl acetate to give 4.8 g (80% of 4-(3-methylaminopropoxy)phenol hydrochloride, mp 167°-169°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9](N(C)C2C=CC=CC=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[OH:19]S(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]([OH:10])=[O:19])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1c(C(=O)N(C)c2ccccc2)ccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(C(=O)O)ccnc1Cl
Temperature: 130 °C
Yield: 54 %

Procedure:
2-chloro-N,3-dimethyl-N-phenylpyridine-4-carboxamide (2.2 g, 8.5 mmol) was treated with a mixture of concentrated H2SO4 (23.2 ml) and water (16.8 ml) and then heated to 130° C. for 46 hours. After which time, the reaction mixture was allowed to reach room temperature and poured onto ice (200 ml) and stirred until the ice had melted. The mixture was made alkaline (pH 8) by the addition of solid Na2CO3 (50.3 g) portionwise. The suspension was filtered and the filtrate acidified to pH 3 by the addition of 6M HCl (aq) (˜1.5 ml). The resulting solid was collected by filtration, washed with water (20 ml) and dried in-vacuo at 40° C. for 10 hours to give the title compound (779 mg, 54%) as a pink solid. LC-MS 100%, m/z=171.9, 173.9; 1H NMR (500 MHz, MeOD) δ ppm 8.30 (d, J=4.89 Hz, 1H) 7.64 (d, J=5.04 Hz, 1H) 2.58 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[N:22]=3)[CH3:20])=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][NH:29][S:30]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:32])=[O:31]>>[ClH:27].[CH3:28][NH:29][S:30]([CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:23]2[N:22]=[C:21]([N:19]([C:17]3[CH:16]=[CH:15][C:12]4[N:13]([CH3:14])[C:9]([NH:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:10][C:11]=4[CH:18]=3)[CH3:20])[CH:26]=[CH:25][N:24]=2)=[CH:39][CH:40]=1)(=[O:31])=[O:32]
Reactant: CNS(=O)(=O)CCc1ccc(N)cc1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccccc1)n2C)c1ccnc(Cl)n1
Product: CNS(=O)(=O)CCc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCc3ccccc3)n4C)n2)cc1
Product: Cl
Yield: 33 %

Procedure:
The title compound was prepared following the procedure of Example 1 with N2-benzyl-N5-(2-chloropyrimidin-4-yl)-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (95 mg, 0.25 mmol) and 2-(4-amino-phenyl)-ethanesulfonic acid methylamide (54 mg, 0.25 mmol) to give the desired product as a white solid (49 mg, 33%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.97 (br s, 1H), 9.34 (br s, 1H), 7.85 (d, J=6.6 Hz, 1H), 7.49-7.59 (m, 5H), 7.25-7.37 (m, 4H), 7.17 (d, J=8.1 Hz, 3H), 7.03 (q, J=5.4 Hz, 1H), 5.77 (d, J=6.6 Hz, 1H), 4.74 (d, J=5.1 Hz, 2H), 3.72 (s, 3H), 3.46 (s, 3H), 3.21-3.27 (m, 2H), 2.85-2.91 (m, 2H), 2.58 (d, J=4.8 Hz, 3H). MS (ESI) m/z=557 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH2:17][CH:18]=[CH2:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.Br[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][C:46]([O:48][CH3:49])=[O:47].[I-].[K+]>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:45]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:39]=2)[C:46]([O:48][CH3:49])=[O:47])=[C:12]([CH2:17][CH:18]=[CH2:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
To a suspension of KH (1.3 eq) in DMF (1 mL) was added a solution of the product of Step C (157 mg, 0.566 mmol) in DMF (1 mL), followed by 18-crown-6 (30 mg; 0.2 eq). The reaction mixture was stirred for 5 minutes at room temperature. A solution of methyl 2-bromophenylacetate (168 mg, 0.735 mmol) in DMF (1 mL) was added, followed by a catalytic amount of potassium iodide. The reaction was heated to 80° C. for 0.5 hours then stirred at room temperature for 16 hours. After concentration in vacuo, the residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water, brine, then dried (MgSO4). After filtration and concentration in vacuo, the residue was chromatographed on silica (MPLC, ethyl acetate/hexanes (5/95)) to afford 158 mg (66%) of the title compound (Rf =0.22, 5% ethyl acetate/hexanes).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[C:18]4[N:17]5[CH2:19][CH2:20][N:21]=[C:22]([CH3:23])[C:16]5=[CH:15][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CO.O.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[C:18]4[N:17]5[CH2:19][CH2:20][NH:21][CH:22]([CH3:23])[C:16]5=[CH:15][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1=NCCn2c1cc1c2-c2ccc(C3CCCCC3)cc2CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC1NCCn2c1cc1c2-c2ccc(C3CCCCC3)cc2CC1
Yield: 27 %

Procedure:
3-Cyclohexyl-5,6,10,11-tetrahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole (0.34 g) was dissolved in a mixture of 15 ml of methanol and 1,5 ml of water under argon. The solution was treated portionwise with 0.15 g of sodium borohydride while stirring and stirred at room temperature for 3 hours. Thereafter, the methanol was removed in a vacuum and the residue was stirred with 20 ml of ether and 20 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 20 ml of ether each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 0.35 g of colourless oil, was dissolved in a 20-fold amount of ethanol and boiled briefly with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.11 g (27%) of 3-cyclohexyl-5,6,8,9,10,11-hexahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole fumarate (2:1); m.pt.: 199°-202° C. (dec.).
Reaction SMILES: C(N(CC)CC)C.C(O)(C)(C)C.[CH2:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1)[CH2:14][CH3:15].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])=[O:29]>C1C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28](=[O:29])[CH2:27][CH2:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:13][CH2:14][CH3:15])=[CH:22][CH:21]=1)=[O:25]
Reactant: O=C(CBr)c1ccccc1Cl
Reactant: CCCOc1ccc(C(C)=O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: CCCOc1ccc(C(=O)CCC(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 37.4 %

Procedure:
To a solution of 11.7 gm (85.6 mmol) of fused ZnCl2 in 20 mL of benzene was 10 added 8.50 mL (64 mmol) of triethylamine and 6.12 mL (64 mmol) of dry t-butanol. After dissolution at room temperature 11.45 gm (64 mmol) of 1-(4-propoxyphenyl) ethanone 100 and 10.0 gm (42.8 mmol) of 2-bromo-1-(2-chlorophenyl) ethanone 99. The mixture was allowed to stir at room temperature for 6 days. The solvents were removed at reduced pressure and the residue added to 100 mL of water. The aqueous phase was extracted with ethyl acetate (200 mL) twice. The combined organic layers were washed with water (150 mL), saturated brine, dried (Na2SO4) and the solvents removed at reduced pressure. Column chromatography of the residue using 2%-4%-8% ethyl acetate-hexanes yielded 5.3 gm (37%) of a light yellow solid. This was recrystallized from hot hexanes-ethyl acetate. 1H NMR (400 MHz, CDCl3) δ: 1.04 (t, 3H, J=7.42 Hz), 1.82 (m, 2H), 3.36 (m, 2H), 3.42 (m, 2H), 3.98 (t, 2H, J=6.5 Hz), 6.92 (d, 2H J=8.9 Hz), 7.38 (m, 3H), 7.64 (m, 1H), 7.97 (m, 2H).
Reaction SMILES: C[Si](C)(C)CCOCN1C=C([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][N:13]=2)C=N1.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[S:22]([O:18][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][CH:17]=1)(=[O:23])=[O:21]
Reactant: C[Si](C)(C)CCOCn1cc(-c2cc(O)ccn2)cn1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Oc1ccncc1)C(F)(F)F
Reaction time: 1 h
Yield: 123.3 %

Procedure:
To solution of 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-4-ol (0.67 g, 2 mmol) in DCM was added TEA (0.69 g, 7 mmol) and the mixture was stirred at OC, (Tf)2O (0.843 g, 3 mmol) was added slowly. The resulting reaction mixture was steered at r.t. for one hour. Solvent was removed under vacuo. And the residue was purified by silicone gel column to afford 2414(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-4-yl trifluoromethanesulfonate (0.56 g, 58%) LCMS-ESI+ (m/z): [M+H]+ calcd. for C26H30N5O3: 424.48; found: 424.05.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:30]([O:32]C)=O)[CH2:13][C@H:14]1[N:18](C(OC(C)(C)C)=O)[C@H:17]([C:26]([O:28][CH3:29])=[O:27])[CH2:16][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:13][C@H:14]2[N:18]([C@H:17]([C:26]([O:28][CH3:29])=[O:27])[CH2:16][CH2:15]2)[C:30]1=[O:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C[C@@H]1CC[C@@H](C(=O)OC)N1C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CC[C@H]2CC(NC(=O)OCc3ccccc3)C(=O)N21
Temperature: 95 °C
Reaction time: 0.75 h

Procedure:
1500 mg of 1-tert-butyl 2-methyl (2S,5S)-5-(2-benzyloxycarbonylamino-2-methoxycarbonylethyl)pyrrolidine-1,2-dicarboxylate were mixed with 0.2 ml of thioanisole. Then 10 ml of trifluoroacetic acid were added, and the mixture was stirred for 45 min. The solvents were then removed in vacuo, and the residue was taken up in 10 ml of pyridine. 1.1 ml of diisopropylethylamine were added, and the mixture was heated at 95° C. for 3 h. The solvents were removed in vacuo, and the residue was chromatographed on silica gel.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[C:16]([CH3:30])=[C:17]([CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:18][NH:19]C(=O)C(F)(F)F)=[N:10]2)=[CH:5][CH:4]=1.[OH-].[K+]>C1COCC1>[NH2:19][CH2:18][C:17]1[C:16]([CH3:30])=[C:15]([C:11]2[NH:12][C:13](=[O:14])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=3)[N:10]=2)[C:28]([CH3:29])=[CH:27][CH:26]=1
Reactant: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1-c1nn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(CN)c(C)c1-c1nn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31.7 %

Procedure:
To a solution of N-(3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)-2,2,2-trifluoroacetamide (Example-106, 0.800 g, 1.74 mmol) in THF (10 mL), aqueous solution of KOH was added and the reaction mass was stirred at RT for 3-4 h. After completion of the reaction, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.200 g of the desired product. MS (m/z): 362.86 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][Cl:19])[C:4]=2[CH:3]=1.[F:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:19].[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:30]3[CH2:31][CH2:32][CH:27]([C:25](=[O:26])[C:24]4[CH:23]=[CH:22][C:21]([F:20])=[CH:34][CH:33]=4)[CH2:28][CH2:29]3)[C:4]=2[CH:3]=1
Reactant: ClCCCN1c2ccccc2Sc2ccc(Br)cc21
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: O=C(c1ccc(F)cc1)C1CCN(CCCN2c3ccccc3Sc3ccc(Br)cc32)CC1

Procedure:
A stirred mixture of 8.86 g. (0.025 mole) of 2-bromo-10-(3-chloropropyl)phenothiazine, 5.18 g. (0.025 mole) of 4-(p-fluorobenzoyl)piperidine and 10 g. of potassium carbonate in 100 ml. of dry dimethylformamide was heated at 90°-100° C. for 24 hours. The cooled reaction mixture was filtered, the dimethylformamide removed at reduced pressure and the residue mixed with dry ether and the ether mixture filtered to remove solids. The dry ether solution was treated with ethereal hydrogen chloride to give the 2-bromo-10-[3-(4-p-fluorobenzoylpiperidinyl)propyl]phenothiazine hydrochloride.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:19](=[O:21])[CH3:20])[CH:10]=[C:11]([S:13]([F:18])([F:17])([F:16])([F:15])[F:14])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br-:22].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)Cl>CO.C1COCC1>[Br:22][CH2:20][C:19]([C:9]1[CH:10]=[C:11]([S:13]([F:15])([F:14])([F:16])([F:17])[F:18])[CH:12]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:8]=1)=[O:21]
Reactant: [Br-]
Reactant: CC(=O)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CBr)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 27 h
Yield: 109.5 %

Procedure:
1-[3-Morpholin-4-yl-5-(pentafluorosulfanyl)phenyl]ethanone (O2.044; 1.1 g) was dissolved in methanol/THF (20/20 ml) and admixed while stirring with phenyltrimethylammonium tribromide (1.25 g). After stirring at RT for 27 h, 50 ml of 20% citric acid were added and the mixture was stirred for 1 h. After adding DCM (100 ml), the DCM phase was removed, dried and concentrated. The residue was dissolved in acetonitrile (100 ml), and 2 N sulfuric acid (20 ml) was added to the solution. After stirring at RT for 24 h, the mixture was admixed with water and extracted with EA. The EA phase was washed with saturated sodium hydrogencarbonate solution, dried and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/EA gradient of 0-60% within 40 min). 866 mg of the title compound were obtained.