Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:19][C:16]3[CH:17]=[CH:18][N:14]([CH3:13])[N:15]=3)[N:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cn1ccc(N)n1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Product: Cc1ccc2ccnc(Nc3ccn(C)n3)c2n1

Procedure:
The title compound, MS: m/e=240.3 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 1-methyl-1H-pyrazol-3-ylamine.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([N:12]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH3:13])[CH2:9][C@H:8]1[CH2:20][O:21][Si](C(C)(C)C)(C)C)=[O:6])[CH:2]=[CH2:3].Cl.C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([N:12]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH3:13])[CH2:9][C@H:8]1[CH2:20][OH:21])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N(C)[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCC=C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)N(C)[C@H]1C[C@@H](CO)N(C(=O)OCC=C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-(N-allyloxycarbonyl-N-methylamino)-2-t-butyldimethylsilyloxymethylpyrrolidine (3.73 g) in ethyl acetate (100 ml) was added 12N hydrochloric acid (0.82 ml) at ambient temperature. After stirring at ambient temperature for 30 minutes, to the mixture were added sodium hydrogen carbonate (1.90 g) and cold water (100 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (7:3-2:8 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-(N-allyloxycarbonyl-N-methylamino)-2-hydroxymethylpyrrolidine (2.04 g).
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1[CH:17]=[CH2:18]>>[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1/[CH:17]=[CH:18]/[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: C=Cc1ccc(C)cc1C
Reactant: COc1ccc2ccccc2c1I
Product: COc1ccc2ccccc2c1/C=C/c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
Following the general procedure using 1-iodo-2-methoxynaphthalene (142 mg, 0.50 mmol) and 2,4-dimethylstyrene (132 μL, 1.0 mmol), the reaction was stirred for 12 h at rt. Column chromatography on silica gel (eluting with 5% EtOAc/hexanes) afforded the product as a tan semi-solid (137 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:36][CH2:37][CH3:38])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2
Reactant: CCCBr
Product: CCCOc1cc2c(cc1OC)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with propyl bromide
Reaction SMILES: [C:1]([O:9][CH2:10][C@:11]1([F:29])[C@@H:18]2[C@@H:14]([O:15]C(C)(C)[O:17]2)[C@H:13]([N:21]2[CH:26]=[CH:25][C:24](=[O:27])[NH:23][C:22]2=[O:28])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(C)=O>C(O)=O.O>[C:1]([O:9][CH2:10][C@:11]1([F:29])[C@@H:18]([OH:17])[C@@H:14]([OH:15])[C@H:13]([N:21]2[CH:26]=[CH:25][C:24](=[O:27])[NH:23][C:22]2=[O:28])[O:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)O[C@H]2[C@H](n3ccc(=O)[nH]c3=O)O[C@](F)(COC(=O)c3ccccc3)[C@H]2O1
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: O
Product: O=C(OC[C@@]1(F)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
The benzyloxy protected fluoro nucleoside (A2, 3.0 g, 8.25 mmol) was dissolved in formic acid (95%, 30 mL) to which water (3 mL) was added. The mixture was stirred at room temperature and was followed by tlc (silica gel, 100% EtOAc). The reaction was shown to be complete in 3 hours. The reaction mixture was concentrated by rotary evaporation keeping the bath temperature <30° C. The crude product was purified by CombiFlash® column chromatography (Silica gel; 0 to 100% EtOAc:Heptane) providing the desired material in 83% yield (3, 2.8 g).
Reaction SMILES: [C:1]1([C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH:10]([N:12]=[N+]=[N-])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:26]=CC=C[CH:22]=1>CC(C)=O>[CH:21]([NH:12][CH:10]1[CH2:11][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9]1)([CH3:26])[CH3:22]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=NC1C=CC(c2ccccc2)(c2ccccc2)C1
Solvent: CC(C)=O
Product: CC(C)NC1C=CC(c2ccccc2)(c2ccccc2)C1
Reaction time: 0.33 h
Yield: 81.6 %

Procedure:
To a solution of 4,4-diphenyl-2-cyclopentenyl azide (0.30 g) in acetone (3 ml) was added triphenylphosphine (0.33 g) at room temperature and refluxed for 21 hours. After being cooled, the solvent was removed under reduced pressure and a solution of sodium borohydride (0.22 g), in methanol (3 ml) was added thereto. After being stirred for 20 minutes, brine and ethyl acetate were added. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-isopropyl-4,4-diphenyl-2-cyclopentenylamine (0.26 g).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([S:28]([C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])(=[O:30])=[O:29])[NH:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23]C(C)(C)C)=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)(C)(C)C.FC(F)(F)C(O)=O>O>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]([S:28]([C:31]([F:35])([F:36])[CH:32]([F:34])[F:33])(=[O:29])=[O:30])[NH:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)Oc1ccc(-c2nc(S(=O)(=O)C(F)(F)C(F)F)[nH]c2-c2ccc(OC(C)(C)C)cc2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1nc(-c2ccc(O)cc2)c(-c2ccc(O)cc2)[nH]1)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4,5-bis(4-t-butoxyphenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole and trifluoroacetic acid is stirred overnight at room temperature. The reaction mixture is poured into water, and work-up affords as product 4,5-bis(4-hydroxyphenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[C:9]([I+]C1C=CC=CC=1)#[CH:10].[C:18]([O-:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>C(Cl)Cl.O>[C:18]([O:26][C:9]#[CH:10])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#C[I+]c1ccccc1
Reactant: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C#COC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
Ethynyl(phenyl)iodonium trifluoromethanesulfonate (3.78 grams, 10 millimoles) dissolved in 10 milliliters of methylene chloride was mixed with sodium benzoate (7.2 grams, 50 millimoles) dissolved in 20 milliliters of water. The reactants were stirred for 5 minutes at 0° C. The organic layer was concentrated by evaporation and chromatographed on silica gel columns to isolate 0.77 grams of ethynyl benzoate (53% yield). The product was identified by spectroscopic means, and had a melting point of 43° C.(dec).
Reaction SMILES: CC1(C)O[C:5](=[CH:7][C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH2:4][O:3]1.[NH:15]([C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1)[NH2:16]>C(O)(C)C>[Cl:23][C:22]1[C:17]([N:15]2[C:8]([OH:13])([C:9]([O:11][CH3:12])=[O:10])[CH2:7][C:5]([CH2:4][OH:3])=[N:16]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C(=O)C=C1COC(C)(C)O1
Reactant: NNc1ncccc1Cl
Solvent: CC(C)O
Product: COC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl
Temperature: 35 °C
Reaction time: 18 h

Procedure:
The mixture of methyl 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate (20 g, 0.1 mol) and 2-hydrazino-3-chloropyridine (14.3 g, 0.1 mol) in 40 ml of isopropanol was stirred for 18 hours at 35° C. The precipitate was filtered off and washed with 15 ml of isopropanol. This gave 24.2 g (85%) of the product as a pale yellow solid with a melting point of 113° C.
Reaction SMILES: C(N(CC)[CH:4]=[C:5]([C:11](=[S:21])[NH:12][C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:24][S:25]([C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31](=[O:34])[CH2:32]Br)(=[O:27])=[O:26]>C(O)(C)C>[F:24][S:25]([C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([C:32]1[S:21][C:11]([NH:12][C:13]([O:15][CH2:16][C:17]([Cl:18])([Cl:19])[Cl:20])=[O:14])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=1)=[O:34])(=[O:27])=[O:26]
Reactant: CCOC(=O)C(=CN(CC)CC)C(=S)NC(=O)OCC(Cl)(Cl)Cl
Reactant: O=C(CBr)c1cccc(S(=O)(=O)F)c1
Solvent: CC(C)O
Product: CCOC(=O)c1cc(C(=O)c2cccc(S(=O)(=O)F)c2)sc1NC(=O)OCC(Cl)(Cl)Cl
Yield: 84.9 %

Procedure:
A mixture of 25 g (0.061 m) of ethyl 3-diethylamino-2-[N-(2,2,2-trichloroethoxycarbonyl)thiocarbamoyl]acrylate, 17.15 g (0.061 m) of m-fluorosulfonylphenacyl bromide, and 125 ml of isopropyl alcohol was heated to reflux for 5 minutes. The reactants dissolved at reflux, and shortly thereafter the product precipitated. The mixture was cooled and the solid collected by filtration. The solid was washed with isopropyl alcohol and then water to give 27.6 g (85 percent) of product, melting point 108° to 110° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].[ClH:23]>O1CCOCC1>[ClH:8].[ClH:23].[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ncc(OC[C@H]2CCCN2)cc1Br

Procedure:
5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from step 69a (150 mg) was stirred with HCl in dioxane (3 mL) at room temperature for 16 hours. The precipitate formed was triturated with Et2O, and the solid was dried under high vacuum to afford the title compound (99.2 mg). mp 230° C. MS (CI/NH3) m/z 291/293 (M+H)+. 1H NMR (D2O, 300 MHz) δ1.89-2.02 (m, 1h), 2.05-2.21 (m, 2H), 2.21-2.35 (m, 1H), 3.42 (t, J=7.2 Hz, 2H), 4/12 (m, 1H)), 4.25 (dd, J=7.8, 10.5 Hz, 1H), 4.47 (dd, J=3.2, 10.5 Hz, 1H), 7.90 (d, J=2.7 Hz, 1H), 8.13 (d, J=2.7 Hz, 1H). Anal. Calcd for C10H12N2OBrCl·2 HCl: C, 36.61; H, 3.99; N, 8.54. Found: C, 36.69; H, 3.91; N, 8.41. [α]25D=-14.80° (c 0.25, MeOH).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:12]([CH:28]=[O:29])=[C:11]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:19][CH2:20][CH2:21]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:12]([C@H:28]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=3)[OH:29])=[C:11]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC2(CCC2)Cc2nc(C3CCOCC3)c(C=O)c(C3=CCOCC3)c21
Reactant: FC(F)(F)c1ccc(Br)nc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC2(CCC2)Cc2nc(C3CCOCC3)c([C@@H](O)c3ccc(C(F)(F)F)cn3)c(C3=CCOCC3)c21

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-(3,6-dihydro-2H-pyran-4-yl)-2′-(tetrahydro-2H-pyran-4-yl)-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 2-bromo-5-(trifluoromethyl)pyridine.
Reaction SMILES: O[CH2:2][C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].C1CCN2C(=NCCC2)CC1>ClCCl.CN(C)C=O.O>[N:11]1[CH:10]=[CH:9][N:8]2[C:3]([CH2:2][N:18]3[C:19](=[O:21])[CH2:20][S:16][C:17]3=[O:22])=[CH:4][CH:5]=[CH:6][C:7]=12
Reactant: O=C1CSC(=O)N1
Reactant: OCc1cccc2nccn12
Solvent: O=S(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1CSC(=O)N1Cc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1.19 g (8.0 mmol) of 5-hydroxymethylimidazo[1,2-a]pyridine in 10 ml of dichloromethane, 4.05 ml (56 mmol) of thionyl chloride was added, followed by stirring at room temperature for 1 hour, after which the solvent was distilled off. To a solution of this residue and 0.94 g (8.0 mmol) of thiazolidine-2,4-dione in 15 ml of N,N-dimethylformamide, 2.40 ml (16.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by stirring at 80° C. for 16 hours. After the reaction mixture was cooled, water was added; the mixture was extracted with ethyl acetate and dried, after which the solvent was distilled off. The residue was purified by recrystallization (solvent, chloroform/ethyl acetate/diethyl ether) to yield 247 mg (12.5%, light brown powder) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[C:28]([F:29])=[CH:27][C:13]2[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3I)[CH3:19])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].[O:41]=[C:42]1[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:43]1>C1COCC1.CS(C)=O>[CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[C:28]([F:29])=[CH:27][C:13]2[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:42]3([OH:41])[CH2:43][N:44]([C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[CH2:45]3)[CH3:19])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4I)c3cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4C4(O)CN(C(=O)OC(C)(C)C)C4)c3cc2F)c(OC)c1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
In an oven-dried 25 mL RB flask, added (R)—N-(2,4-dimethoxybenzyl)-5-fluoro-3-(1-(2-iodophenyl)ethyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (32-1, 400 mg, 0.574 mmol) to THF (2154 μl) and cooled to −40° C. Was a suspension. Added isopropylmagnesium chloride-lithium chloride complex (1325 μl, 1.723 mmol) dropwise, stirred at −40° C. for 20 min—became a dark orange solution. Following this duration, added tert-butyl 3-oxoazetidine-1-carboxylate (32-2, 295 mg, 1.723 mmol) in THF (718 μl) dropwise via syringe. Solution turned yellow in color. After 60 min at −40° C., partitioned between 10 mL saturated NH4Cl+15 mL EtOAc, separated layers. Back-extracted aqueous with 2×10 mL EtOAc. Dried combined organics over Na2SO4, filtered, concentrated to give a yellow oil. Dissolved in 2 mL DMSO, purified by reverse-phase HPLC (C18 column, 10-90% (0.1% TFA/CH3CN:0.1% TFA/H2O) to give 32-3 as a white solid.
Reaction SMILES: [OH-].[Na+].O.C1(O[C:11](=O)[N:12]([CH2:14][CH2:15][C@H:16]([O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)C)C=CC=CC=1>CS(C)=O>[CH3:11][NH:12][CH2:14][CH2:15][C@H:16]([O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=12)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(CC[C@H](Oc1cccc2ccccc12)c1cccs1)C(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Temperature: 115 °C
Yield: 92 %

Procedure:
Sodium hydroxide (19 g) and water (25 mL) were added to a solution of (S)-N-Methyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-carbamic acid phenyl ester (64.8 g) dissolved in DMSO (250 mL). The mixture was heated at 115° C. for 6 hours, cooled to ambient temperature, and water (200 mL) was added. The mixture was then extracted with toluene (2×200 mL) and the organic layers were combined. The organic layers were then washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The resulting residue was then dissolved in methanol (500 mL), combined with activated carbon (2 g), and heated at reflux for 1 hour. After cooling, the mixture was filtered through Celite® (20 g), the filter cake was washed with methanol (50 mL), and the solution was concentrated to yield duloxetine base as an oil (37.07 g, Yield: 92% yield, Chiral HPLC: 90% ee).
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH2:14][O:15][C:16]3[CH:31]=[CH:30][C:19]4[O:20][CH2:21][C:22]5[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=5[CH:24](O)[C:18]=4[CH:17]=3)=[N:11]2)=[CH:6][CH:5]=1.[SH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[C:36]([CH2:35][CH2:34][S:33][CH:24]1[C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[CH2:21][O:20][C:19]2[CH:30]=[CH:31][C:16]([O:15][CH2:14][C:10]3[CH:9]=[CH:8][C:7]4[C:12](=[CH:13][C:4]([O:3][CH:2]([F:32])[F:1])=[CH:5][CH:6]=4)[N:11]=3)=[CH:17][C:18]1=2)([OH:38])=[O:37]
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(OC(F)F)cc4n3)cc21
Reactant: O=C(O)CCS
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(OC(F)F)cc4n3)cc21

Procedure:
2-(7-Difluoromethoxyquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[O:44][N:43]=[C:42]([CH3:45])[CH:41]=2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[O:44][N:43]=[C:42]([CH3:45])[CH:41]=2)[CH:35]=1)=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J35) (360 mg, 1.04 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (312 mg, 1.04 mmol) according to the general procedure M. Obtained as a light red foam (270 mg, 45%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[N:11](CC2C=CC=CC=2)[C@@H:10]([C:19]([O:21]CC2C=CC=CC=2)=[O:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([C@H:8]1[CH2:9][C@@H:10]([C:19]([OH:21])=[O:20])[NH:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](C(=O)OCc2ccccc2)N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)O)N1
Yield: 94 %

Procedure:
267 mg (0.7 mmol) of stereochemically pure transor cis-N-benzylazetidine-2,4-dicarboxylic acid benzyl t-butyl ester, 50mg of 10% Pd/C, and 20 ml of methanol are hydrogenated under 3 atm of hydrogen in a Parr shaker for 4 hours. The catalyst is filtered off and thoroughly washed, and the solution evaporated to dryness and dried in vacuo to afford as off-white solids the trans- or cis-azetidine-2,4-dicarboxylic acid mono-t-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:5][CH:4]=1.[CH:27](O)=O.C=O>CO>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6]([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:5][CH:4]=1
Reactant: O=CO
Reactant: COc1ccc(N2CCNCC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Agent: C=O
Solvent: CO
Product: COc1ccc(N2CCN(C)CC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 34 %

Procedure:
To a solution of 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-piperazin-1-yl-benzothiazol-2-yl)-amide (100 mg, 0.26 mmol) in methanol (8 ml) were added formic acid (100 μl, 2.6 mmol) and formaldehyde (23 μl, 0.31 mmol) and the mixture refluxed for 18 h. Workup and purification as described for 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-piperazin-1-yl-benzothiazol-2-yl)-amide afforded the product as light yellow powder (34%), MS: m/e=403(M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:3]=12.C(N(CC)CC)C>[Pd].C(O)(=O)C>[CH2:17]([N:13]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=[C:3]2[C:15]([CH3:16])=[N:14]1)[CH3:18]
Reactant: CCOC(=O)c1cnc2c(c(C)nn2CC)c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2c(c1)c(C)nn2CC

Procedure:
To 80.3 g. of 4-chloro-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (0.3 mol.) [prepared according to Journal of Heterocyclic Chemistry 9, 235-253 (1972)] dissolved in 270 ml. glacial acetic acid, are added 33.4 g. of triethylamine (0.33 mol.) and 7.5 g. of palladium on charcoal (10%). The mixture is hydrogenated at room temperature and a pressure of 2.5 atm. After about 19 hours the theoretical amount of hydrogen is absorbed. Then the catalyst is filtered off and the filtrate evaporated. The residue is treated with 200 ml. of water and extracted with ether. The combined ether extracts are dried and the ether distilled off. The oily 1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester is distilled in vacuo; b.p.0.3 144°-146°, which after a short time begins to crystallize, yield: 64.5 g. (92%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[N:7][CH:8]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[NH2:17].O.[OH-].[Cs+]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:13][C:14]1[CH:15]=[C:16]([NH:17][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:8][N:7]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: C=Cc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(N)cc1C
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1C
Temperature: 120 °C
Yield: 62.8 %

Procedure:
A mixture of 200 mg (0.92 mmol) 5-trifluoromethyl-2-vinyl-pyridine (CAS: 204569-89-1), 570 mg (4.62 mmol) 3,4-dimethylaniline and 33 mg (0.18 mmol) cesium hydroxide monohydrate in 2 mL NMP was heated in a 120° C. oil-bath for 22 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed 3 times with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.17 g (63%) of the title compound as a light yellow oil. MS (m/e): 295.2 [M+H]+.