Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:12][C:3]=1[NH:4][NH:5][C:6](=[NH:11])[C:7]([F:10])([F:9])[F:8].C(N(CC)CC)C.[C:28](Cl)(Cl)=[O:29].Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:12][C:3]=1[N:4]1[C:28](=[O:29])[NH:11][C:6]([C:7]([F:10])([F:8])[F:9])=[N:5]1
Reactant: O=C(Cl)Cl
Reactant: CC(C)Oc1cc(NNC(=N)C(F)(F)F)c(Cl)cc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(-n2nc(C(F)(F)F)[nH]c2=O)c(Cl)cc1Cl
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 81.5 %

Procedure:
Under a dry nitrogen atmosphere a stirred solution of 2.1 g (0.0062 mole) of N-[2,4-dichloro-5-(1-methylethoxy)anilino]trifluoroacetamidine in 130 mL of toluene was cooled in an ice bath. To this was added 5.2 mL (0.037 mole) of triethylamine followed by the dropwise addition of 45.6 mL of a 2.9% (0.013 mole) phosgene in toluene solution. After complete addition the mixture was heated quickly to 65° C. and stirred at that temperature for 45 minutes. The mixture was allowed to cool to room temperature and stir for approximately 18 hours. The mixture was diluted with 25 mL of water and stirred vigorously for a brief period. Sufficient concentrated hydrochloric acid was added to make the aqueous phase acidic (pH 2). The acidic aqueous phase and the organic phase were shaken briskly after which the organic phase was separated from the mixture and saved for further purification. The aqueous phase was extracted with methylene chloride and the extract evaporated to leave a yellow solid. This solid was dissolved in toluene and the resultant solution added to the saved organic phase from above. The combined organic phase was stirred at room temperature with decolorizing carbon and filtered through a celite pad. The filtrate was extracted with a 1N sodium hydroxide solution. This extract was washed with toluene and acidified with concentrated hydrochloric acid to pH 2. Sodium chloride was added to the acidic solution to the point of saturation. A precipitate formed upon cooling this solution and was collected by filtration. The filter cake was rinsed with several portions of ice cold water and dried under reduced pressure to yield 1.8 g of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3-trifluoromethyl-4,5-dihydro-1,2,4-triazol-5(1H)-one (mp 160°-161° C.), Compound 36.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.C(O[C@@H:32]1[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]1[O:34][C:35](=[O:37])[CH3:36])(=O)C.P(O)(OC1C=CC([N+]([O-])=O)=CC=1)(OC1C=CC([N+]([O-])=O)=CC=1)=O>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:32]3[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]3[O:34][C:35](=[O:37])[CH3:36])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1ncc2sc(=O)[nH]c2n1
Agent: O=[N+]([O-])c1ccc(OP(=O)(O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 150 °C
Yield: 39.9 %

Procedure:
Compound 86 (62 mg, 0.4 mmol), 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose tetraacetate (128 mg, 0.4 mmol), and catalytic bis(p-nitrophenyl) hydrogen phosphate (13 mg, 0.04 mmol) were mixed and placed in a 500 ml flask. The reaction vessel was carefully placed under vacuum (˜5.0 mmHg) and lowered into an oil bath heated at 150° C. for 10 minutes. After cooling to room temperature, the solids were washed with ethyl acetate. The crude product was purified by flash column. (silica, 5 to 35% ethyl acetate gradient in chloroform) to yield 68 mg of compound 79 (40%) as a white solid as a white powder identical in all respects to material isolated in Example 38, step 2.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C@@H:11]1[C@H:17]2[C@H:18]3[C@H:27]([CH2:28][CH2:29][C@:14]2([CH2:15][CH3:16])[C:13](=[O:31])[CH2:12]1)[C@@H:26]1[C:21](=[CH:22][C:23](=[O:30])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3.O>N1C=CC=CC=1.C(Cl)Cl>[C:1]([O:10][C@@H:11]1[C@H:17]2[C@H:18]3[C@H:27]([CH2:28][CH2:29][C@:14]2([CH2:15][CH3:16])[C:13](=[O:31])[CH2:12]1)[C@@H:26]1[C:21](=[CH:22][C:23](=[O:30])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
At 0° C., 5 ml of benzoyl chloride is added dropwise to 5 g of 15α-hydroxy-18-methyl-4-estrene-3,17-dione in 20 ml of pyridine. After 45 minutes, 2 ml of water is added, the mixture is stirred for another 30 minutes, and then the reaction mixture is poured into ice/water. The thus-precipitated product is suctioned off, dissolved in methylene chloride, washed with water, and dried over sodium sulfate. After chromatography of the crude product on silica gel with an acetone-hexane gradient, 5.6 g of 15α-benzoyloxy-18-methyl-4-estrene-3,17-dione is obtained as a foam.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]([C:15]4[C:19]5=[N:20][C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=[C:18]5[N:17]([CH3:28])[CH:16]=4)=[CH:14][C:7]=23)[CH2:3][CH2:2]1.[OH-].[K+]>CO.O.ClCCl>[CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13]([C:15]4[C:19]5=[N:20][C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=[C:18]5[N:17]([CH3:28])[CH:16]=4)=[CH:14][C:7]=23)[CH2:2][CH2:3]1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CC4)ccnc3[nH]1)cn2C
Yield: 96 %

Procedure:
To a solution of 0.11 g of cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine in 20 cm3 of methanol, at a temperature in the region of 20° C., is added 1 cm3 of 5N potassium hydroxide. The reaction medium is refluxed for 24 hours. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 20 cm3 of water. The solid formed is filtered off on a sinter funnel. The solid obtained is taken up in 80 cm3 of dichloromethane and 3 cm3 of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give 0.075 g of cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine with the following characteristics:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:9]1([CH2:15][N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:21][CH2:20]2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CN1CCCNCC1
Product: CN1CCCN(C2CCN(Cc3ccccc3)CC2)CC1
Yield: 35 %

Procedure:
Prepared analogously to Example A11a) from hexahydro-1-methyl-1H-1,4-diazepine and 1-(phenylmethyl)-4-piperidinone in a yield of 35% of theory. Colourless viscous oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:13][CH:14]=O>C(O)C.O.N>[N:1]1[CH:13]=[CH:14][N:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=12
Reactant: COC(=O)c1cccnc1N
Reactant: O=CCCl
Agent: N
Solvent: CCO
Solvent: O
Product: COC(=O)c1cccn2ccnc12

Procedure:
A mixture of methyl 2-aminonicotinate (prepared according to the method of WO 89/01488 at page 33, prep 17) (1 g, 6.56 mmol), and chloroacetaldehyde (1.05 mL, 6.56 mmol) in ethanol (5 mL) was heated under reflux for 18 hours. The cooled mixture was diluted with water (10 mL), 0.88 ammonia (1 mL) added and the solution concentrated in vacuo. The residue was dissolved in methanol and the dark solution treated with charcoal, the mixture filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:2.5:0.5) as eluant, and the product triturated with ether, to afford the title compound, 768 mg.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3.[CH2:29]([O:31][CH:32](OCC)[O:33][CH2:34][CH3:35])[CH3:30]>B(F)(F)F.CCOCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:29]([O:31][CH:32]([O:33][CH2:34][CH3:35])[C@@H:21]1[CH2:22][C@@:23]2([CH3:24])[C@@H:18]([CH2:17][CH2:16][C@@H:15]3[C@@H:25]2[CH2:26][CH2:27][C@@:10]2([CH3:11])[C@H:12]3[CH2:13][CH2:14][C@@H:9]2[OH:8])[CH2:19][C:20]1=[O:28])[CH3:30]
Reactant: CCOC(OCC)OCC
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: FB(F)F
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(OCC)[C@@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)CC1=O
Yield: 71 %

Procedure:
By the method of part A of Example 20 (5α,17β)-17-hydroxyandrostan-3-one trifluoroacetate (ester) (0.344 mole) was diethoxymethylated using triethylorthoformate (126 ml.) and boron trifluoride etherate (140 ml.). The product was crystallized from methanol, affording (2α,5α,17β)-2-(diethoxymethyl)-17-hydroxyandrostan-3-one trifluoroacetate (ester) (118.7 g., 71% yield, m.r. 122°-123° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([N:14](C(OC(C)(C)C)=O)[CH3:15])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:24]>ClCCl.C(O)(C)C>[ClH:24].[CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:14][CH3:15])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(COCc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CNC(COCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Benzyloxy-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid methyl ester (0.6 g, 1.86 mmol) was dissolved in dichloromethane and then added slowly into a mixture of hydrochloric acid in isopropyl alcohol ([5M], 3 mL). The reaction mixture was stirred for 2 hours at room temperature. The solvent was then evaporated and the residue was kept on high vacuum atmosphere overnight to yield a crude product as an oil. The crude product was stored in the freezer as an oil.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH:14]=[CH:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.[N:21]1C(C)=CC=C[C:22]=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CN>C(Cl)Cl>[CH3:22][NH:21][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH:14]=[CH:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1
Reactant: OCCCn1c(C=Cc2ccsc2)cc2ccccc21
Reactant: Cc1cccc(C)n1
Agent: CN
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CNCCCn1c(C=Cc2ccsc2)cc2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A solution of 1-(3-hydroxypropyl)-2-[2-(thiophen-3-yl)vinyl]indole (121 mg) in 3 ml of methylene chloride was treated with 120 μl of 2,6-lutidine and cooled to 0° C. Trifluoromethanesulfonic anhydride (100 μl) was added, and after stirring for 30 minutes 5 ml of 40% aqueous methylamine was introduced, and the reaction mixture stirred at 25° C. for 3 hours. After stirring for a further 12 hours at 0° C., the reaction mixture was partitioned between methylene chloride and water, the organic layer dried, and solvent was removed under reduced pressure. Preparative TLC on silica gel (eluting with 10% methanol/methylene chloride) gave 83 mg of 1-[3-(methylamino)propyl)-2-[2-(thiophen-3-yl)vinyl]indole (67%). This product was dissolved in 3 ml of methylene chloride containing 150 μl of pyridine and trifluoracetic anhydride (40 μl) was added. After 30 minutes, the mixture was partitioned between diethylether and aqueous sodium bicarbonate, the organic layer dried, and solvent was removed under reduced pressure. Preparative TLC on silica gel (eluting with 3:1 hexane/EtOAc) gave 80 mg of 1-[3-(N-methyltrifluoromethylacetamido)propyl)-2-[2-(thiophen-3-yl)vinyl]indole (73%).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:15].[K+].OS(O)(=O)=O.N([O-])=O.[Na+]>O>[Br:15][CH:10]([CH2:9][O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([OH:14])=[O:13]
Reactant: [Br-]
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)C(Br)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90.5 %

Procedure:
Racemic O-(phenylmethyl)serine (5 g, 25.6 mmol) and potassium bromide (10.7 g, 89.6 mmol) were dissolved in ice-cooled H2SO4 (2.5N) and treated with an solution of sodium nitrite (2.65 g) in water (30 ml) over 50 minutes (keeping the reaction temperature <4° C.). The reaction was then stirred at 0° C. for 45 minutes and then at rt for 1 h, extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and evaporated to give the product as a yellow oil (6 g, 90%).
Reaction SMILES: C(O[CH2:9][C:10]1[C:11]([O:24]C)=[N:12][CH:13]=[CH:14][C:15]=1[C@@:16]([OH:23])([CH2:21][CH3:22])[CH2:17][C:18]([O-:20])=[O:19])C1C=CC=CC=1.C([O-])=O.[NH4+].C1(N=C=NC2CCCCC2)CCCCC1.[I-].[Na+].C[Si](Cl)(C)C.[OH-].[NH4+]>ClCCl.Cl.CO.O1CCCC1.O.C(#N)C>[CH2:21]([C@:16]1([OH:23])[C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:24])[C:10]=2[CH2:9][O:19][C:18](=[O:20])[CH2:17]1)[CH3:22]
Reactant: CC[C@@](O)(CC(=O)[O-])c1ccnc(OC)c1COCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@]1(O)CC(=O)OCc2c1cc[nH]c2=O
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
The residue obtained in Stage 1a is agitated for 16 hours at 20° C. in a mixture of dichloromethane (270 ml) and 1N hydrochloric acid (270 ml). After decanting, the organic phase is concentrated, and the residue is taken up in methanol (87 ml) to be used in the following phase. This solution is poured under nitrogen onto Palladium at 10% on damp carbon at 50% (27.7 g; 13 mmol). The reaction medium is agitated for 5 min, then poured into a solution of ammonium formate (11.5 g; 183 mmol) in methanol (135 ml). The reaction medium is agitated for 30 min whilst allowing the temperature to rise, then it is heated at 40° C. for 30 min. The medium is then filtered on a bed of Clarcel and concentrated. Toluene (40 ml) is poured in followed by evaporation, and this operation is repeated in order to eliminate the traces of methanol. The residue, taken up in tetrahydrofuran (45 ml), is treated with a solution of dicyclohexylcarbodiimide (7.18 g; 34.5 mmol) in tetrahydrofuran (20 ml). The reaction medium is heated at 50° C. for 1 hour, then taken to 20° C., and the dicyclohexylurea is filtered. The filtrate is concentrated to dryness and the residue, taken up in acetonitrile (46 ml), is treated with sodium iodide (6.0 g; 40.5 mmol) and trimethylsilyl chloride (5.13 ml; 40.5 mmol). The reaction medium is maintained under agitation at ambient temperature for 5 hours, then acetonitrile (28 ml) and water (5.6 ml) are added. The precipitate obtained is recovered by filtration, then taken up in water (10 ml), and the mixture obtained is neutralized using a solution of ammonium hydroxide. The precipitate is recovered by filtration then taken up in acetone (40 ml) to which water (150 ml) is added. The crystals formed are recovered by filtration and dried to produce 3 g of (+)-EHHOPD with an enantiomeric proportion of 99.4/0.6.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC.[N:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C=O)C>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:43]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:44])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N1CCCCC1)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of the compound (100 mg) obtained in Example 1 and Et3N (70 mg). in DMF (5.0 ml), piperidine-1-carbonyl chloride (44 mg) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 3% potassium hydrogensulfate solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound as pale yellow oil (0.11 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1.[C:22]([OH:34])(=[O:33])[CH2:23][C:24]([CH2:29][C:30]([OH:32])=[O:31])([C:26]([OH:28])=[O:27])[OH:25].C(=O)([O-])[O-].[K+:39].[K+].O.C(=O)(O)[O-].[Na+:46]>>[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1.[C:22]([O-:34])(=[O:33])[CH2:23][C:24]([CH2:29][C:30]([O-:32])=[O:31])([C:26]([O-:28])=[O:27])[OH:25].[Na+:46].[Na+:46].[Na+:46].[C:22]([O-:34])(=[O:33])[CH2:23][C:24]([CH2:29][C:30]([O-:32])=[O:31])([C:26]([O-:28])=[O:27])[OH:25].[K+:39].[K+:39].[K+:39]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Effervescent Tablets and Granules were prepared using standards techniques known to persons skilled in the art. For Example: From one 20 mg duloxetine capsule, granules were emptied into mortar and pestle to prepare fine powder. A homogeneous mixture of effervescent duloxetine powder was obtained by diluting the above powdered duloxetine with about 958 mg sodium bicarbonate USP, about 832 mg citric acid USP and about 312 mg potassium carbonate USP. This powder reacted with the 60 ml water to create effervescence resulting in a bubbling solution of duloxetine with sodium citrate and potassium citrate as principal antacids
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].CC[N:15](C(C)C)C(C)C.C1C2C3C(=O)N(O)C(=O)C3C1C=C2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:15])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc(Cl)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(Cl)n1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
6-Chloropyridine-2-carboxylic acid (1.20 g, 7.62 mmol) and ammonium chloride (0.81 g, 15.2 mmol) were dissolved in DMF (20 mL) and DIPEA (5.31 mL, 30.5 mmol), HONB (2.05 g, 11.4 mmol) and HBTU (4.33 g, 11.4 mmol) were added. The reaction mixture was stirred for 1 h and the solvents were removed in vacuo. The residue was partitioned between DCM (50 mL) and 1 M aq HCl (50 mL) and the aq fraction was extracted with DCM (2×25 mL). The combined organic fractions were washed with sat aq NaHCO3 (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from MeOH/water to give the title compound (1.12 g, 94%) as a white solid. LCMS (ES+): 157.4 [MH]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:25]([S:29](Cl)(=[O:31])=[O:30])[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([S:29]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1)(=[O:31])=[O:30])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCS(=O)(=O)Cl
Reactant: NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
In 50 ml of dimethylformamide were dissolved 1.14 g of 2-amino-5-[pyridazin-3(2H)-on-6-yl]indane and 0.8 g of triethyl amine, and 1.25 g of n-butanesulfonyl chloride was added thereto. The mixture was stirred at 50° C for 30 minutes and then stirred at room temperature overnight. The solvent was removed, water was added to the residue, and crystals precipitated were collected by filtration. The resulting crystals were recrystallized from methanol to obtain 1.27 g of 2-n-butylsulfonylamino-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].[CH3:15][N:16]1[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[C:17]1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC.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.O>[F:14][C:3]1[C:2]([C:17]2[N:16]([CH3:15])[C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH3:13])([CH3:12])[C:6](=[O:11])[NH:7]2
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CC1(C)C(=O)Nc2ccc(Br)c(F)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cn1c(C#N)ccc1-c1ccc2c(c1F)C(C)(C)C(=O)N2
Reaction time: 0.25 h
Yield: 4.4 %

Procedure:
5-bromo-4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.25 g, 4.86 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.4 g) was dissolved in ethylene glycol dimethyl ether (40 mL) and stirred 15 minutes. N-methyl-5-cyanopyrroleboronic acid (2.0 g, 13.33 mmol) and potassium carbonate (3.48, 25 mmol) were added followed by water (20 mL) and the mixture heated under reflux (24 hours). The mixture was then poured into water, neutralized with dilute hydrochloric acid, and extracted with ethylacetate. The solvent was dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography; SiO2, Hexane/THF 9/1 then 7/3 gave 5-(4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (0.060 g, 5%):
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23]O)[CH2:18][CH2:17]2)=[CH:8][CH:7]=1>C(Cl)Cl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][Cl:3])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1
Reactant: OCCC1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(C(CCCN2CCC(CCCl)CC2)c2ccc(F)cc2)cc1

Procedure:
115 g of thionyl chloride were added dropwise to 23 g (61.6 mmol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2-hydroxyethyl)piperidine in 100 ml of methylene chloride, while cooling with ice, and the mixture was then heated under reflux for 5.5 hours. The solvent and excess reagent were stripped off in vacuo, the residue (the hydrochloride of the product) was crystallized by addition of 450 ml of ether and the crystals were filtered off with suction, washed several times with ether and dried in vacuo.