Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40].C(=O)([O-])O.[Na+]>C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:39](=[O:41])[CH3:40])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1
Reactant: CC(=O)Cl
Reactant: COc1nccc2c1c(-c1ccc(C3CCNCC3)cc1)nn2-c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1nccc2c1c(-c1ccc(C3CCN(C(C)=O)CC3)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-3-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (120 mg), triethylamine (0.080 mL) and N,N-dimethylaminopyridine (1.7 mg) in THF (4 mL) was added acetyl chloride (0.080 mL). The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (117 mg).
Reaction SMILES: [C:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.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>[C:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([C:30]3[CH:31]=[CH:32][C:27]([C:19]4[S:18][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20]=4)=[CH:28][CH:29]=3)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(-c2nc3ccccc3s2)cc1
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)n1c2ccccc2c2cc(-c3ccc(-c4nc5ccccc5s4)cc3)ccc21
Yield: 79.5 %

Procedure:
A mixture of 5.8 g of 9-Acetyl-3-bromocarbazole and 5.7 g of (4-benzo[d]thiazol-2-yl) phenylboronic acid were stirred together in 30 ml of toluene. To this was added 0.03 g of tetrakis(triphenylphosphine)palladium, 4.2 g of potassium carbonate and 10 ml of aqueous ethanol were added and refluxed under nitrogen for 6 h. The reaction was quenched with water and the toluene layer was removed and passed through a celite column. The organic layers were combined and then evaporated in a rotary evaporator under vacuum to yield 6.7 g of 9-acetyl-3-[(4-benzo [d]thiazol-2-yl) phenyl]-9H-carbazole as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[N:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.[NH2:25][OH:26]>>[CH3:1][O:2][C:3]1([C:9]2[N:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:25]/[OH:26])/[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: NO
Reactant: COC1(c2csc(Sc3ccc(C(C)=O)cc3)n2)CCOCC1
Agent: Cl
Product: COC1(c2csc(Sc3ccc(/C(C)=N/O)cc3)n2)CCOCC1
Yield: 90 %

Procedure:
Using an analogous procedure to that described in Example 15, 4'-[4-(4-methoxytetrahydropyran-4-yl)thiazol-2-ylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[4-(4-methoxytetrahydropyran-4-yl)thiazol-2-ylthio]acetophenone oxime in 90% yield, m.p. 146° C.;
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:16](=[O:32])[NH:17][C:18]1([CH:22]([OH:31])[C:23](=[O:30])[NH:24][C:25]2[CH:29]=[CH:28][NH:27][N:26]=2)[CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]1([F:15])[CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:39](Cl)([O:41][CH2:42][CH:43]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]2[C:44]1=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40]>O1CCOCC1.O.C(Cl)Cl>[CH:54]1[C:55]2[CH:43]([CH2:42][O:41][C:39]([N:27]3[CH:28]=[CH:29][C:25]([NH:24][C:23](=[O:30])[CH:22]([C:18]4([NH:17][C:16](=[O:32])[CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:33])[CH2:9][C:10]5([F:15])[CH2:14][CH2:13][CH2:12][CH2:11]5)[CH2:21][CH2:20][CH2:19]4)[OH:31])=[N:26]3)=[O:40])[C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:50]=2[CH:51]=[CH:52][CH:53]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(=O)Nc2cc[nH]n2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(=O)Nc2ccn(C(=O)OCC3c4ccccc4-c4ccccc43)n2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
Compound 57-c (22.5 mg, 0.0482 mmol) was dissolved in a mixture of dioxane:water 1:1 (4 mL). NaHCO3 (14.2 mg, 0.168 mmol) was added to the solution followed by addition of Fmoc-Cl (48 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with DCM and extracted. The organic phase was washed with brine, dried over anh. Na2SO4 and concentrated. Purification by flash column chromatography (EtOAc/iso-Hexane, 0:100-40:60) gave the title compound (28 mg, 84%). MS m/z 690.3 (M+H)+.
Reaction SMILES: S([C:5]1C=CC(C)=CC=1)(O)(=O)=O.[C:12]1([C:18]2([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[Si](Cl)(C)C>CO>[CH3:5][O:25][C:24]([C:18]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1)=[O:26]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCNCC1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 4-phenyl-piperidine-4-carboxylic acid tosylate (4.6 g, 20 mmol) in MeOH (25 mL) is added TMSCl (10 mL) and the reaction mixture is stirred at 50° C. for 15 h. The reaction mixture is cooled and evaporated. The residue is taken up in MeOH (5 mL), poured into sat. Na2CO3 (100 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([B:17]3[O:21]C(C)(C)C(C)[O:18]3)=[C:13]([CH:16]=2)[CH:14]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].Cl.C([O-])(O)=O.[Na+]>CCO.O>[N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[B:17]([OH:18])[O:21][CH2:14][C:13]=3[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC1OB(c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2C=O)OC1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a suspension of 5-(4-nitro-phenoxy)-2-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (721 mg, 1.9 mmol, 1.0 eq.) in EtOH (15 mL) at 0° C. was added NaBH4 (73.8 mg, 1.9 mmol, 1.0 eq.) in small portions. The mixture was stirred at 0° C. for 20 minutes and allowed to warm to room temperature in another 1 h. After cooling to 0° C., the clear solution was carefully treated with H2O (1 mL), followed by slow addition of HCl (5 mL, 3N). The resulting yellow suspension was allowed to ward to room temperature gradually and stirred for 2 h. The mixture was then treated with sat. NaHCO3 drop wise until PH reaching 7. The precipitate was collected by filtration, washed with H2O to give 5-(4-nitro-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol as a white powder. LCMS (m/z) 294 (M+23); 1H NMR (DMSO-d6) δ: 7.26 (d, J=8.6 Hz, 1H), 6.93 (d, J=3.0 Hz, 1H), 6.56 (dd, J=8.5, 3.0 Hz, 1H), 4.37 (s, 2H). Amount obtained, 510 mg, 96.4% yield.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:18])[NH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:19]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[NH:7][C:6](=[O:18])[C:5]([CH:2]([NH:1][C:24]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:25])[CH2:3][CH3:4])=[N:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCC(N)c1nnc(-c2ccc(Br)cc2)[nH]c1=O
Product: CCC(NC(=O)C1CCCC1)c1nnc(-c2ccc(Br)cc2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 3.35 g (10.8 mmol) 6-(1-aminopropyl)-3-(4-bromophenyl)-1,2,4-triazin-5(4H)-one, 2.16 g (16.3 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[CH3:25][CH:26]([CH3:37])[CH2:27][CH:28](C1C=NC=CC=1)[CH2:29][NH2:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH:30][CH2:29][CH2:28][CH2:27][C:26](=[CH2:25])[CH3:37])=[O:9])=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cn(-c2ncccn2)nc1Cl
Reactant: CC(C)CC(CN)c1cccnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CCCNC(=O)c1cn(-c2ncccn2)nc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (75 mg, 0.33 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.11 mL, 0.66 mmol), 4-methyl-2-pyridin-3-yl-pentan-1-amine (59 mg, 0.33 mmol), and BOP (177 mg, 0.40 mmol). The resulting mixture is stirred at RT for 20 h. Water (3 mL) is added, and the mixture is extracted with EtOAc (5 mL). The EtOAc layer is dried (Na2SO4), filtered, and evaporated in vacuo. The residue is purified by preparative chromatography (2% MeOH/CH2Cl2) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (1H, s), 8.89 (2H, d, J 4.8), 8.39 (3H, m), 7.67 (1H, d, J 7.6), 7.55 (1H, t, J 4.4), 7.32 (1H, m), 3.43 (1H, m), 3.32 (1H, m), 2.99 (1H, bs), 1.58 (1H, m), 1.50 (1H, m), 1.25 (1H, m), 0.81 (6H, d, J 6). MS (M+1)=385.09; RT=1.25 min.
Reaction SMILES: [N:1]12[CH2:10][N:5]3[CH2:6][P:7]([CH2:9][N:3]([CH2:4]3)[S:2]1(=[O:12])=[O:11])[CH2:8]2.C([O:17]O)(C)(C)C>>[N:1]12[CH2:10][N:5]3[CH2:6][P:7](=[O:17])([CH2:9][N:3]([CH2:4]3)[S:2]1(=[O:12])=[O:11])[CH2:8]2
Reactant: CC(C)(C)OO
Reactant: O=S1(=O)N2CN3CN1CP(C3)C2
Product: O=P12CN3CN(C1)S(=O)(=O)N(C3)C2
Yield: 93.3 %

Procedure:
2-Thia-1,3,5-triaza-7-phosphaadamantane 2,2-dioxide (0.5g, 0.0024 mole) and t-butyl hydroperoxide (70% solution, 0.3 g, 0.0024 mole) were stirred in a 25 ml acetone-25 ethanol solution for 1 hour at room temperature. The solution was filtered to yield 0.5 g of crude 2-thia-1,3,5-triaza-7-phosphaadamantane 2,2,7-trioxide (92% yield) [MP 245°-6° (propanol)].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Li+].[Cl-].[I:11]I>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[I:11]
Reactant: II
Reactant: Clc1ccc(Cl)nn1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1cc(I)c(Cl)nn1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
3,6-Dichloropyridazine (3) (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 30 min according to TP 2. I2 (381 mg, 1.5 mmol) dissolved in dry THF (2 mL) was then dropwise added and the resulting mixture was stirred for 0.5 h. The reaction mixture was quenched with a sat. aq. Na2S2O3 solution (10 mL) and with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:2) furnished compound 5a (231 mg, 84%) as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[NH:6][C:5]2=O.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:32])=O.[OH-].[Na+]>C1C=CC=CC=1.ClCCl>[Cl:32][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[N:6]=1
Reactant: COc1ccccc1-c1nc2ccc(F)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A suspension of 6-fluoro-2-(2-methoxyphenyl)-3H-quinazolin-4-one (14.0 g, 52 mmol), N,N-dimethylaniline (6.6 mL, 52 mmol), and phosphorus oxychloride (4.8 mL, 52 mmol) in benzene (100 mL) was heated at reflux until a clear, dark solution was obtained (1 hour). The reaction mixture was cooled to room temperature, and the volume was reduced under reduced pressure. The black, oily residue was poured into 300 g of ice. Dichloromethane (600 mL) was added with vigorous stirring, and the temperature was kept below 5° C. at all times. The pH was monitored, and aqueous 1 N sodium hydroxide was added until the pH was 10-11. The mixture was stirred for one hour at a temperature below 5° C., and the pH was kept between 10-11 by addition of 1 N aqueous sodium hydroxide. The layers were separated, and the organic layer was washed with ice-cold 1 N aqueous sodium hydroxide (2×200 mL). Heptanes (300 mL) were added to the organic layer. This mixture was filtered through a short plug of silica gel and eluted with dichloromethane/heptanes (2:1). All fractions containing product were combined and evaporated to dryness. The residue was triturated with heptanes to yield 4-chloro-6-fluoro-2-(2-methoxyphenyl)-quinazoline (11.5 g, 76%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:26]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:27]=[O:28])[CH2:10][O:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](Cl)Cl>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)C)(C)C>[CH2:1]([O:8][C@H:9]([C@@H:26]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@@H:27]([OH:28])[CH3:37])[CH2:10][O:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: COC(=O)[C@H](COC[C@H](OCc1ccccc1)[C@H](C=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)O[Ti](C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](COC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](C)O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of (S)-methyl 3-((2S,3R)-2,3-bis(benzyloxy)-4-oxobutoxy)-2-((tert-butoxycarbonyl)amino)propanoate (7.55 g, 15.05 mmol) in DCM (30 ml) and THF (30 ml) at −78° C. was added triisopropoxy(methyl)titanium, 1.0 M in THF (31.6 ml, 31.6 mmol) and the reaction was stirred at −78° C. for 2 h, warmed to −20° C., and stored at −20° C. overnight. The reaction was warmed to 0° C., stirred for 4 h between 0° C. and −10° C., and then quenched at this temperature with saturated aqueous NH4Cl. The reaction mixture was extracted with EtOAc, and the combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash chromatography (SiO2, hexanes/EtOAc) to yield the title compound as a colorless oil (4.59 g, 59%, diastereomer selectivity=6:1): 1H NMR (400 MHz, CDCl3) δ 7.45-7.14 (m, 11H), 5.45 (d, J=8.8 Hz, 1H), 4.67 (d, J=11.6 Hz, 1H), 4.61-4.51 (m, 3H), 4.50-4.41 (m, 1H), 3.90 (dd, J=9.4, 3.0 Hz, 1H), 3.84-3.78 (m, 1H), 3.74-3.61 (m, 6H), 3.31 (dd, J=6.8, 4.0 Hz, 1H), 2.85 (d, J=4.5 Hz, 1H), 1.45 (s, 9H), 1.20 (d, J=6.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.04, 155.45, 137.99, 137.76, 128.51, 128.44, 128.12, 128.00, 127.97, 127.87, 81.43, 80.05, 77.91, 73.55, 72.88, 71.60, 70.91, 67.53, 54.00, 52.47, 28.34, 19.89; ESIMS m/z 540.6 ([M+Na]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=3)=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccccc1
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1-benzyl-1H-indole-2-Carboxylate and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in step 2 of Example 1. The product was obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:27])[C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:27][CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccccc1)c1cccs1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1cccs1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-thiophen-2-yl-methylamine (CA [5693-42-5]).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.C(N(CC)CC)C.[CH3:16][CH2:17][CH2:18][C:19](Cl)=[O:20].OP([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:19]([NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1)(=[O:20])[CH2:18][CH2:17][CH3:16]
Reactant: Cc1cc(N)n(C)n1
Reactant: CCCC(=O)Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(C)nn1C
Reaction time: 1 h
Yield: 114.2 %

Procedure:
A stirred solution under nitrogen of 5-amino-1,3-dimethylpyrazole (7.09 g, 63.8 mmol) and triethylamine (10 mL) in sieve-dried methylene chloride (100 mL) was chilled in an ice-bath and n-butyryl chloride (7.3 mL, 70.3 mmol) was added dropwise. After 1 hour, the reaction mixture was shaken with 50 mL of 1M K2HPO4 solution and the aqueous phase was further extracted with CH2Cl2 (2×70 mL). The organic phase was dried over MgSO4, filtered and then evaporated to dryness to give 13.2 g of an orange-yellow oil. This was purified by chromatography on SiO2 (300 g), developing with EtOAc/hexane (45:55) to give the Step A compound (10.53 g; 91%) as an oil. 1H NMR (200 MHz, CDCl3), δ 6.00 (s, 1H), 3.65 (s, 3H), 2.37 (t, 2H, J=9 Hz), 2.22 (s, 3H), 1.62-1.90 (m, 2H), 1.01 (t, 3H, J=9 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:12])[CH:3]=[N:2]1.[CH3:13][O:14][CH2:15]Cl>CN(C=O)C>[CH3:13][O:14][CH2:15][N:1]1[CH:5]=[C:4]([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:12])[CH:3]=[N:2]1
Reactant: O[C@H]1CCCC[C@@H]1c1cn[nH]c1
Reactant: COCCl
Solvent: CN(C)C=O
Product: COCn1cc([C@H]2CCCC[C@@H]2O)cn1
Yield: 72.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 169c by using the (1S,2R)-2-(1H-pyrazol-4-yl)cyclohexanol (144 mg, 0.866 mmol) prepared in Example 171a, chloromethyl methyl ether (0.069 mL, 0.908 mmol) and DMF (4.0 mL), to yield the title compound (132.2 mg, 73%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[C:19]([CH3:20])=[C:18]([Cl:21])[CH:17]=[C:16]([CH2:22][CH3:23])[N+:15]=1[O-:24]>C1COCC1>[Cl:21][C:18]1[CH:17]=[C:16]([CH2:22][CH3:23])[N+:15]([O-:24])=[C:14]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:19]=1[CH3:20]
Reactant: CCc1cc(Cl)c(C)c(Cl)[n+]1[O-]
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(Cl)c(C)c(Oc2c(C)cc(C)cc2C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,4,6-trimethylphenol in dry THF was added NaH and stirred at room temperature for 20 minutes. A solution of 2,4-dichloro-6-ethyl-3-methyl-pyridine 1-oxide was added and the resulting mixture was heated at reflux for 1.5 hour. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give the title compound which was used directly for the next step reaction.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH3:15])[CH2:9]1)C1C=CC=CC=1.[ClH:24]>CO.O1CCOCC1.[OH-].[Pd+2].[OH-]>[ClH:24].[ClH:24].[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C@H:14]([NH:13][C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH3:15])[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc([C@@H](C)N[C@H]2CCN(Cc3ccccc3)C2)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cccc([C@@H](C)N[C@H]2CCNC2)c1
Reaction time: 72 h

Procedure:
To a solution of 3.67 g of (S)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine dissolved in 100 ml of methanol were added 830 mg of palladium hydroxide and 8.85 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 3 days. Palladium hydroxide was removed, and the solvent was evaporated. To the residue was added methanol, and the resulting precipitates were collected by filtration, washed with methanol and dried to obtain 1.14 g of (S)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.001).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.[ClH:27]>O1CCOCC1>[ClH:27].[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][N:6]2[CH2:5][CH2:4][C:3]([OH:26])=[O:2])=[CH:14][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Reaction time: 4 h
Yield: 60 %

Procedure:
3-[(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidin-1-yl]-propionic acid methyl ester (32.6 mg, 0.092 mmol) was added to a solution of HCl (conc.) in Dioxane (1:3, 2 mL). The reaction was run a 60° C. for 4 h. The Mixture was concentrated to dryness and dried in a vacuum over at 50° C. The residue was triturated with diethyl ether and dried to provide the title product (19 mg, 0.056 mmol, 60% yield); LCMS: m/z 339.44 (free amine), found 340 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 1.77 1.837 (m, 1H), 1.93-1.96 (m, 1H), 1.99-2.04 (m, 1H), 2.20-2.25 (m, 1H), 2.80-2.85 (m, 1H), 3.16-3.18 (m, 1H), 3.31-3.41 (m, 1H), 3.56-3.88 (m, 6H), 4.25-4.32 (m, 2H), 6.90-6.92 (d, J=8.4, 2H), 7.16-7.21 (m, 5H), 7.26-7.29 (m, 2H), 10.34 (s, 1H).