Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[NH:17]2)=[CH:9][CH:8]=1)[CH3:2].[H-].[Na+].I[CH3:45]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:45])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2)cc1)Oc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A slurry of 2-Methyl-3-(4-{2-[2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester (0.544 g, 0.953 mmol) and sodium hydride (0.042 g, 1.05 mmol, 60% dispersion on mineral oil) in DMF (10 mL) is stirred for 1 h, then cooled to 0° C. Iodomethane (0.60 mL, 9.53 mmol, d=2.28) is added, then the reaction mixture is stirred 18 h at ambient temperature and diluted with ethyl acetate. The organic layer is washed, dried, concentrated, and purified by flash chromatography to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, 2H, J=8.0 Hz), 7.37 (d, 2H, J=8.0 Hz), 7.26-7.19 (m, 2H), 7.15 (d, 2H, J=8.9 Hz), 6.97 (t, 1H, J=8.0 Hz), 6.82 (d, 2H, J=8.0 Hz), 6.74 (d, 2H, J=8.9 Hz), 4.46, 4.38 (ABq, 2H, J=15.1 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.97 (t, 2H, J=7.1 Hz), 3.67-3.59 (m, 1H), 3.78 (t, 1H, J=8.9 Hz), 3.26, 3.10 (ABq, 2H, J=14.2 Hz), 2.99 (t, 1H, J=8.9 Hz), 2.85 (s, 3H), 2.28-2.21 (m, 1H), 1.93-1.84 (m, 1H), 1.39 (s, 3H), 1.21 (t, 3H, J=7.1 Hz). MS [EI+]. 585 (M+H)+. Rf=0.35 in 50% acetone in hexanes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.C(O)C.C(O[CH:17]=[C:18]([C:24]([CH3:26])=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>O.Cl>[CH2:22]([O:21][C:19]([C:18]1[CH:17]=[N:9][N:8]([C:5]2[C:4]([Cl:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[C:24]=1[CH3:26])=[O:20])[CH3:23]
Reactant: NNc1ncc(Br)cc1Cl
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnn(-c2ncc(Br)cc2Cl)c1C
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a suspension of (5-bromo-3-chloropyridin-2-yl)hydrazine (14.78 g) in water (15 ml) and concentrated hydrochloric acid (15 ml), was added an ethanol solution (30 ml) of ethyl 2-(ethoxymethylene)acetoacetate (30 ml), prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), and the mixture was stirred at 100° C. for 1.5 hours. The reaction solution was cooled to room temperature, water (100 ml) was added and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. n-Hexane (150 ml) was added, and ethyl acetate was further added little by little at 80° C. to completely dissolve the residue. The solution was cooled to room temperature and the precipitated solid was filtered. The filtrate was concentrated and a similar handling was repeated four times to give 1-(5-bromo-3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (15.93 g) as a pale yellow solid.
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](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[N:43][CH:44]=2)[CH:34]=1)(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](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[N:43][CH:42]=[N:41][CH:40]=2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)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 J17) (347 mg, 1.0 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a red oil (370 mg, 65%).
Reaction SMILES: ClC1N=C(/C=C(/C2C=C(N[S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])C=CC=2)\O)C=CN=1.[NH2:29][C:30]1[C:31]([Cl:40])=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].N1C=CC=CC=1.FC1C=CC=C(F)C=1S(Cl)(=O)=O>C(Cl)Cl>[Cl:40][C:31]1[C:30]([NH:29][S:18]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])(=[O:20])=[O:19])=[CH:39][CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34]
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: COC(=O)c1cccc(N)c1Cl
Agent: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1Cl
Yield: 81.6 %

Procedure:
Following a procedure analogous to Intermediate 5, Step A using methyl 3-amino-2-chlorobenzoate (39 g, 211 mmol) in DCM (200 mL) was added pyridine (51 g, 633 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (49.1 g, 232 mmol) the title compound was obtained (62 g, 81.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (dd, J=1.8 Hz, 8.38 Hz, 1H), 7.72-7.79 (br, 1H), 7.56 (dd, J=1.8 Hz, 7.94 Hz, 1H), 7.45-7.53 (m, 1H), 7.28 (dd, J=7.9 Hz, 8.4 Hz, 1H), 6.95-7.01 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](OB(O)O)=[CH:2]1.Br[C:11]1[S:15][C:14]([S:16]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)(=[O:18])=[O:17])=[CH:13][CH:12]=1>>[S:1]1[CH:5]=[CH:4][C:3]([C:11]2[S:15][C:14]([S:16]([N:19]3[CH:23]=[CH:22][CH:21]=[CH:20]3)(=[O:17])=[O:18])=[CH:13][CH:12]=2)=[CH:2]1
Reactant: OB(O)Oc1ccsc1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: O=S(=O)(c1ccc(-c2ccsc2)s1)n1cccc1

Procedure:
N-[5-(3-thienyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 3-thienylboric acid and N-(5-bromothiophene-2-sulfonyl)pyrrole in quantative yield. This was purified by recrystallization using hexane/ethyl acetate as solvent.
Reaction SMILES: [Br-].[CH2:2]1[CH2:29][O:28][C:4]([CH3:27])([CH2:5][CH2:6][CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:3]1.C([O:32][CH:33](OCC)[C:34](=O)[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])C.CCCCCC>O1CCCC1.C(O)(=O)C>[CH2:29]1[CH2:2][O:3][C:4]([CH2:5][CH2:6][CH:7]=[C:34]([CH:33]=[O:32])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])([CH3:27])[O:28]1
Reactant: CCOC(OCC)C(=O)CCC=C(C)C
Reactant: CC1(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)OCCO1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(C)=CCCC(C=O)=CCCC1(C)OCCO1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
In 160 ml of anhydrous tetrahydrofuran was suspended 38.5 g of 4,4-ethylenedioxypentan-1-yltriphenylphosphonium bromide, and to this was added the equimolar amount of a n-butyllithium-hexane solution at -20° C. in a stream of nitrogen. The reaction mixture was stirred for one hour and cooled to -60° C. To this was added 14.5 g of 1,1-diethoxy-6-methyl-5-hepten-2-one, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was, after addition of ice-water, extracted with n-hexane and from the extract was obtained an oil. The oil was suspended in 250 ml of 50% acetic acid and stirred at room temperature for one hour. 2,2-Ethylenedioxy-6-formyl-10-methyl-5,9-undecadiene obtained by the n-hexane extraction, not purified, was reduced in 100 ml of ethanol by using 500 mg of sodium borohydride. The product thus obtained was chromatographed on the silica gel (100 g) column to yield 7.3 g of 2,2-ethylenedioxy-6-hydroxymethyl-10-methyl-5,9-undecadien.
Reaction SMILES: Br.C1COCC1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]O)=[C:10]([CH2:23][OH:24])[CH:9]=1>CC(C)=O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]2[C:11]3[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][C:10]=3[CH2:23][O:24][CH2:21][C:15]=2[CH:16]=1
Reactant: OCc1cc(Br)ccc1-c1ccc(Br)cc1CO
Agent: Br
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)COCc1cc(Br)ccc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
HBr (11 mL, 97 mmol) was added to a THF (10 mL) solution of (4,4′-dibromobiphenyl-2,2′-diyl)dimethanol (for preparation, see: Tetrahedron Letters 2004, 45, 2801; 1.3 g, 3.49 mmol), and the mixture was refluxed for six hours and then allowed to cool to ambient temperature. Most of the organic component was removed with a rotervap, and the residue was extracted with CH2Cl2 (10 mL, 3×). The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo to afford a brown oil, which when dissolved in 5 mL acetone and allowed to stand at ambient condition for 1 h afforded a precipitate. Filtration and drying in vacuo afforded 3,9-dibromo-5,7-dihydrodibenzo[c,e]oxepine as a white solid (0.628 g, 51% yield). 1H NMR (DMSO-d6, δ=2.5, 500 MHz): 4.23-4.29 (m, 4H), 7.53-7.60 (m, 2H), 7.74 (dd, J=7.9, 2.1, 2H) 7.79 (d, J=2.1, 2H).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1>C(OCC)C.C(OCC)C.CCO>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Into a 1000 mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (10.1 g, 420.83 mmol, 2.10 equiv) in diethyl ether (400 mL). To the resulting mixture was then added diethyl carbonate (35.6 g, 301.69 mmol, 1.50 equiv) in 10 min at 0° C., followed by addition of a solution of 1-(4-bromophenyl)ethanone (40 g, 202.02 mmol, 1.00 equiv) in diethyl ether/EtOH (100 mL/1 mL) dropwise with stirring at 0° C. in 20 min. The resulting solution was heated to reflux for 3 hr. The reaction was then quenched by the addition of water/ice. The pH value of the solution was adjusted to about 5-6 with HCl (1 mol/L). The resulting solution was extracted with diethyl ether (3×200 mL), the organic layers combined and dried over anhydrous magnesium sulfate, then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100) to yield ethyl 3-(4-bromophenyl)-3-oxopropanoate as yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].I[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(N)CN>O1CCOCC1.CCOC(C)=O.[Cu]I>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: CC(C)c1ccc(I)cc1
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: NCCN
Product: CCc1cccc(CC)c1-c1cc2ccn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 60 °C
Yield: 48.5 %

Procedure:
A mixture of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (700 mg, 2.8 mmol), 1-iodo-4-isopropyl-benzene (2.0 g, 8.1 mmol), CuI (1.0 g, 5.3 mmol), cesium carbonate (1.8 g, 5.5 mmol) and ethylenediamine (336 mg, 5.6 mmol) in dioxane (10 mL) is heated at 60° C. overnight. The reaction mixture is cooled, diluted with EtOAc, and filtered through Celite. The filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (Hexane/EtOAc, 4:1) to afford 500 mg of 2.7 g of 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine as a solid. 1H NMR: (CDCl3) 8.97 (s, 1H), 7.41-7.52 (m, 6H), 7.28 (t, 1H), 7.15 (d, 2H), 6.68 (d, 1H), 3.03 (m, 1H), 2.36 (m, 4H), 1.34 (d, 6H), 1.01 (t, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.S(Cl)([Cl:24])=O>ClCCl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([Cl:24])=[O:21])=[CH:14][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Yield: 99.2 %

Procedure:
A slurry of [4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-phenyl]-acetic acid (19, Chart B) (24.0 g, 85.4 mmol) in dichloromethane (300 ml) was treated with thionyl chloride (12.4 ml, 170 mmol). After heating at reflux temperature for 3.5 hours, the solvent and excess reagent were removed by evaporation to yield sufficiently pure product (25.4 g, 99%).
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.C([O:36][C:37]([C:39]1(Br)[CH2:42][CH2:41][CH2:40]1)=[O:38])C>>[CH:1]1([N:7]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]2)[C:8](=[O:9])[NH:10][C:11]2[S:12][C:13]([S:16][C:39]3([C:37]([OH:36])=[O:38])[CH2:40][CH2:41][CH2:42]3)=[CH:14][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC3(C(=O)O)CCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and ethyl-1-bromocyclobutane carboxylate.
Reaction SMILES: C(O)(=O)CCCCC#C.OC(C1(CCC)COC1)C(F)(F)F.[CH2:23]([C:29]12[O:36][CH2:35][C:32]([CH2:37][CH2:38][CH3:39])([CH2:33][O:34]1)[CH:31]([C:40]([F:43])([F:42])[F:41])[O:30]2)[CH2:24][CH2:25][CH2:26][C:27]#C>>[CH2:23]([C:29]12[O:36][CH2:35][C:32]([CH2:37][CH2:38][CH3:39])([CH2:33][O:34]1)[CH:31]([C:40]([F:41])([F:42])[F:43])[O:30]2)[CH2:24][CH2:25][C:26]#[CH:27]
Reactant: C#CCCCCC12OCC(CCC)(CO1)C(C(F)(F)F)O2
Agent: C#CCCCCC(=O)O
Agent: CCCC1(C(O)C(F)(F)F)COC1
Product: C#CCCCC12OCC(CCC)(CO1)C(C(F)(F)F)O2

Procedure:
In an analogous manner the following compound was prepared from hept-6-ynoic acid and 3-(1-hydroxy-2,2,2-trifluoroethyl)-3-n-propyloxetane: 1-(Hex-5-ynyl)-4-propyl-3-trifluoromethyl-2,6,7-trioxabicyclo[2.2.2]octane.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:4][N:3]=1.[NH2:16][NH2:17]>>[NH:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:4][N:3]=1)[NH2:17]
Reactant: NN
Reactant: COc1cccc(-c2ccc(Cl)nc2)c1
Product: COc1cccc(-c2ccc(NN)nc2)c1

Procedure:
In the manner described in Example 31, a mixture of 2-chloro-5-(3-methoxyphenyl)pyridine and hydrazine yields the product of the Example.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([S:21][CH2:22][C:23]([OH:25])=O)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:29][NH:30][CH3:31].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([S:21][CH2:22][C:23]([N:30]([CH3:31])[CH3:29])=[O:25])[N:11]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: O=C(O)CSc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CSc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the carboxylic acid from Step 1 (0.18 g, 0.46 mmol), dimethylamine hydrochloride (56 mg, 0.69 mmol), 1-hydroxy-7-azabenzotriazole (62 mg, 0.46 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg, 0.55 mmol), and diisopropylethylamine (0.2 mL, 0.46 mmol) in DMF (2.3 mL) was stirred at room temperature overnight. The product mixture was treated with 1 M aq HCl at 0° C. The resulting yellow solid was filtered, washed with diethyl ether. The solid was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provide the title compound as yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])([O-])=O>C1C=CC=CC=1>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:11](=[O:20])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]1=[O:19]
Reactant: O=C1c2ccccc2C(=O)N1c1ccccc1[N+](=O)[O-]
Solvent: c1ccccc1
Product: Nc1ccccc1N1C(=O)c2ccccc2C1=O
Reaction time: 0.75 h
Yield: 28.3 %

Procedure:
To a suspension of the 2-(2-nitrophenyl)isoindole-1,3-dione (1.0 g, 3.50 mmol) in benzene, pre-sparged with nitrogen gas, was added 10% palladium on activated carbon (1.0 g). The reaction mixture was placed under an atmosphere of hydrogen gas and was vigorously stirred. After 45 minutes, the reaction mixture was filtered over celite and the filter pad was washed with benzene. Concentration in vacuo gave 236 mg (40%) of 2-(2-aminophenyl)-isoindole-1,3-dione as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 8.85 (m, 4H), 7.10 (m, 1H), 6.98 (m, 1H), 6.75 (m, 1H), 6.55 (m, 1H).
Reaction SMILES: [Mg].CI.C[O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]([O:17]C)[C:7]=1[C@H:19]1[C@H:24]([C:25]([CH3:27])=[CH2:26])[CH2:23][CH2:22][C:21](=[CH2:28])[CH:20]1[OH:29]>CCOCC>[OH:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]([OH:17])[C:7]=1[C@H:19]1[C@H:24]([C:25]([CH3:27])=[CH2:26])[CH2:23][CH2:22][C:21](=[CH2:28])[CH:20]1[OH:29]
Reactant: C=C1CC[C@@H](C(=C)C)[C@H](c2c(OC)cc(CCCCC)cc2OC)C1O
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: C=C1CC[C@@H](C(=C)C)[C@H](c2c(O)cc(CCCCC)cc2O)C1O
Temperature: 210 °C
Yield: 40 %

Procedure:
A Grignard reagent was prepared with magnesium (84 mg, 3.5 mmol) and CH3I (0.2 ml, 3.5 mmol) in dry ether (1 ml, distilled over sodium) under N2 atmosphere. (6a) (360 mg, 1 mmol) in ether (0.5 ml) was added to the stirred solution and the ether was distilled. The residue was heated under N2 atmosphere till 210° C. for 45 min. Then the flask was cooled till room temperature and the reaction was quenched with ice water. The aqueous solution was extracted several times with ether. The combined organic extracts were dried on MgSO4 and filtered. Removal of the solvents under reduced pressure afforded a residue that was chromatographed on silica gel (25% Ether/P.E.) to give 132 mg of the pure (11a) (yield 40%).
Reaction SMILES: O.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=O)[CH2:4]1.O1CCC[CH2:12]1.B(F)(F)F.CCOCC>C=O.C(O)=O>[OH:2][C@H:3]1[CH2:7][N:6]([CH3:12])[C@H:5]([CH2:8][OH:10])[CH2:4]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: C1CCOC1
Agent: C=O
Agent: FB(F)F
Solvent: O=CO
Solvent: CCOCC
Solvent: O
Product: CN1C[C@H](O)C[C@H]1CO
Temperature: 0 °C
Yield: 54.5 %

Procedure:
A 2-L three-necked, round-bottomed flask was equipped with a mechanical stirrer, heating mantel, 250-mL graduated additional funnel, and an 8-in., air-cooled vigreux column topped with a water-cooled distillation head and a 1-L receiving flask. The assembly was flushed with nitrogen and charged with trans-4-hydroxy-L-proline (100 g, 0.76 mol) and tetrahydrofuran (THF, 1.2 L), and boron trifluoride etherate (123.9 g, 0.88 mol). The mixture was heated at a rate sufficient to cause the THF to reflux gently and borane-methyl sulfide complex (360 mL, 3.6 mol) was added dropwise over 2 hrs. The solution was then refluxed for 24 hrs. The methyl sulfide, collected at stillhead was discarded, and the reaction mixture was cooled to 0° C. and quenched by the slow addition of methanol (300 mL). The reaction mixture was concentrated by distillation at reduced pressure and the residue was dissolved in 6N sodium hydroxide (1 L) and refluxed for 6 hrs. After cooling to room temperature, the insoluble material was removed by filtration and the filtrate was concentrared at reduced pressure. In order to remove the insoluble materials, the residue was dissolved in 2-propanol (1 L), filtered and concentrated. The operation was repeated three times, affording an oil, which was dissolved in 35% formaldehyde solution (200 mL) and formic acid (600 mL). The reaction mixture was refluxed for 24 hrs and concentrated at reduced pressure. The residue was dissolved in methanol (800 mL) and treated with potassium carbonate (100 g) and refluxed for 6 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and dissolved in methylene chloride (600 mL) and filtered again. The filtrate was concentrated and Kugelrohr distilled (200°-220° C./1 mmHg) to give (2S, 4R)-4-hydroxy-1-methyl-2-pyrrolidinemethanol (54.48 g, 54.5%) as a viscous oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.C(Br)C1C=CC=CC=1.[OH-].[Na+].S([O-])(O)(=O)=O.[Na+]>C(O)C.O>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: BrCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1

Procedure:
N-tert-butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid ethyl ester (prepared as in Gilligan et al J. Med. Chem. 1994, 364-370 using benzyl bromide as the alkylating agent) (11.0 g; 32 mmol) was refluxed for 7 h. in a mixture of ethanol (190 ml) and aqueous sodium hydroxide (18% 190 ml). The volume was reduced to a third in vacuo and pH was adjusted to 3 with sodium hydrogen sulfate. Water (300 ml) was added and the mixture was extracted with ethylacetate (2×250 ml). The combined organic phases were evaporated to afford 8.6 g of N-tert-butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@H:13]([OH:26])[CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH2:7]1.O.NN>C(O)C>[NH2:15][CH2:14][C@@H:13]([OH:26])[CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
(S)-2-[3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl]-1H-isoindole-1,3(2H)-dione (4 g) in ethanol (100 ml) was treated with 20 ml of hydrazine monohydrate and the resulting mixture was refluxed for 3 h. The reaction was cooled and filtered. The filtrate was evaporated and the product was chromatographed (ethyl acetate) to give the title compound as a yellow oil which solidified on standing (2.5 g).