Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:5]([C:4]1[CH:3]=[C:2]([CH:12]=[CH:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=1)=[O:6]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C=Cc1cccc(C=O)c1
Temperature: 100 °C

Procedure:
To a stirred mixture of 3-bromobenzaldehyde (20 g), tert butyl acrylate (40 mL), triethylamine (44 mL) and tris(2-methylphenyl)phosphine (3.4 g) in dry dimethylformamide (300 mL) is added palladium (II) acetate in one portion. The resulting dark brown mixture is heated at 100° C. for 18 hours then evaporated in vacuo. The residual semi-solid is partitioned between ethyl acetate (250 mL) and 2 N hydrochloric acid (250 mL). the organic phase is washed three times with water (250 mL), dried over magnesium sulphate and evaporated. The resulting dark brown oil (28.1 g) is purified by flash chromatography on silica eluting initially with a mixture of cyclohexane and dichloromethane (4:1 v/v) then with a mixture of cyclohexane and dichloromethane (1:1 v/v). Fractions homogeneous in the required product are combined and evaporated to give tert-butyl 3-(3-formylphenyl)acrylate as a yellow oil (14.08 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH:36]2[CH2:38][O:39][CH2:40][CH:35]2[CH2:34]1.C(Cl)Cl>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:37][CH:36]5[CH2:38][O:39][CH2:40][CH:35]5[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: ClCCCN1CC2COCC2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2COCC2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.19 g) in DMF (6 mL) was added K2CO3 (0.42 g) and tetrabutylammonium iodide (20 mg). The mixture was stirred at room temperature for 10 min, to this, a solution of 5-(3-chloropropyl)hexahydro-1H-furo[3,4-c]pyrrole (0.13 g) in DMF (2 mL) was added. The reaction mixture was heated at 80° C. for 14 h under N2 and treated with CH2Cl2 (100 mL), then washed with water and brine. The mixture was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound (180 mg, 60.04%), HPLC: 95.78%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 474.0 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.12 (t, J=13.28 Hz, 2H), 2.54 (s, 2H), 2.72 (t, J=13.32 Hz, 2H), 2.83 (d, J=9.00 Hz, 2H), 2.90 (s, 2H), 3.73 (t, J=5.36 Hz, 3H), 3.99 (s, 3H), 4.28 (t, J=13.24 Hz, 2H), 7.15 (t, J=17.60 Hz, 1H), 7.25 (d, J=7.32 Hz, 1H), 7.44 (s, 1H), 7.60-7.64 (m, 1H), 7.93-7.96 (m, 1H), 7.99 (s, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>[C].[Pd].C(O)(=O)C>[NH:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=2)=[CH:6][CH:5]=1)[C:21]([CH3:22])=[O:23]
Reactant: COC(=O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cn1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Cc2ccc(NC(C)=O)cc2)cn1
Reaction time: 1.5 h

Procedure:
3.0 Grams of methyl 5-(4-nitrobenzyl)picolinate were dissolved in 150 ml. of a mixture of acetic acid and acetic anhydride (4:1). The resulting solution was added with 6.0 g of 5% palladium-carbon. Catalytic reduction was carried out at room temperature under atmospheric pressure. After 1.5 hours, the reaction solution was subjected to filtration and the filtrate was concentrated under reduced pressure. The residue was added with n-hexane to form crystals. The crystals were recrystallized from a solvent comprising a mixture of chloroform/n-hexane to obtain 1.5 g of methyl 5-(4-acetaminobenzyl)picolinate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:16]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:16]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Oc2cccc(Cl)c2)CCC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of 3-chlorophenol (7.5 g, 58.0 mmol) in N,N-dimethylformamide (125 mL) was added cesium carbonate (28.3 g, 87 mmol) followed by the addition of ethyl 1-bromocyclobutanecarboxylate (9.8 mL, 58.0 mmol). The reaction mixture was stirred at 55° C. overnight. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (silica, heptane/ethyl acetate, 7:1) afforded ethyl 1-(3-chlorophenoxy)cyclobutanecarboxylate. MS (ESI+) m/z 255 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:33]1[CH:37]=[CH:36][CH2:35][CH2:34]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:34]3[CH2:35][CH2:36][CH2:37][O:33]3)[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC3CCCO3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 39 mg, 0.090 mmol) in CH2Cl2 (2.0 ml) was added 2,3-dihydrofuran (68 μl, 0.90 mmol) and catalytic amount of PPTS. The reaction was stirred at room temperature for 4 h, and was purified directly by PTLC on silica gel (30% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.F[C:25]1[C:30]([CH:31]2[CH2:35][N:34]([CH3:36])[C:33](=[O:37])[CH2:32]2)=[CH:29][CH:28]=[CH:27][N:26]=1>CN1C(=O)CCC1>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:25]2[C:30]([CH:31]3[CH2:35][N:34]([CH3:36])[C:33](=[O:37])[CH2:32]3)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: CN1CC(c2cccnc2F)CC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN1CC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1=O
Temperature: 100 °C
Yield: 73.1 %

Procedure:
To a mixture of cesium carbonate (0.625 g, 1.92 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.445 g, 1.84 mmol), and 4-(2-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one (0.111 g, 0.572 mmol) was added NMP (2 mL). The reaction mixture was degassed and heated to 100° C. for 30 min, heated to 120° C. for 3.5 h, and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (3×), and the combined organic extracts were washed with 1 M NaOH (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (20% to 80% EtOAc (10% MeOH) in hexanes) gave 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-one (0.174 g, 0.418 mmol, 73% yield) as a white solid and a 1:1 mixture of enantiomers. MS (ESI, pos. ion) m/z: 417.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: CN(C(N[C@H](C(O)=O)C(C)C)=[O:13])CC1N=C(C(C)C)SC=1.[NH2:22][C@@H:23]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:24][C@H:25](O)[C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C1COCC1>[NH2:22][C@H:23]([C@@H:24]([OH:13])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 126.3 %

Procedure:
A solution of 70 mg (0.223 mmol) of N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine, 79 mg (0.186 mmol) of (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane, 30 mg (0.223 mmol) of 1-hydroxybenzotriazole hydrate, and 51 mg (0.266 mmol) of N-ethyl-N'-dimethylaminopropyl carbodiimide in 2 ml of THF was stirred at ambient temperature for 16 h. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 97:3 CH2Cl2 :CH3OH to provide 100 mg (74%) of the desired compound (Rf 0.4, 95:5 CH2Cl2 :CH3OH) as a solid. 1H NMR (d6 -DMSO) δ0.73 (d, J=7 Hz, 6H), 1.30 (d, J=7 Hz, 6H), 1.45 (m, 2H), 1.87 (m, 1H), 2.5-2.7 (m, 4H), 2.87 (s, 3H), 3.23 (heptet, J=7 Hz, 1H), 3.57 (m, 1H), 3.81 (m, 1H), 3.93 (m, 1H), 4.15 (m, 1H), 4.44 (AA', 2H), 4.62 (d, J=6 Hz, 1H), 5.13 (AA', 2H), 6.01 (d, J=9 Hz, 1H), 6.89 (d, J=9 Hz, 1H), 7.1-7.2 (m, 11H), 7.68 (d, J=9 Hz, 1H), 7.85 (s, 1H), 9.05 (s, 1H). Mass spectrum: (M+H)+ =721. Anal. Calcd for C37H48N6O5S2.0.5H2O: C, 60.88; H, 6.77; N, 11.51. Found: C, 60.68; H, 6.53; N, 11.36.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH:11][C:12]3[C:13](=[O:23])[N:14]([CH2:19][C:20]([OH:22])=O)[C:15]([Cl:18])=[CH:16][N:17]=3)[CH2:9][O:8][CH2:7]2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[N:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[Cl:37].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl.CO>CN(C=O)C.Cl>[CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH:11][C:12]3[C:13](=[O:23])[N:14]([CH2:19][C:20]([NH:26][CH2:27][C:28]4[CH:29]=[C:30]5[C:34](=[N:35][CH:36]=4)[NH:33][CH:32]=[C:31]5[Cl:37])=[O:22])[C:15]([Cl:18])=[CH:16][N:17]=3)[CH2:9][O:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: O=C(O)Cn1c(Cl)cnc(N[C@@H]2COC[C@H]2OCC2CC2)c1=O
Reactant: NCc1cnc2[nH]cc(Cl)c2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1c(Cl)cnc(N[C@@H]2COC[C@H]2OCC2CC2)c1=O)NCc1cnc2[nH]cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(trans-3-cyclopropylmethoxytetrahydrofuran-4-ylamino)-6-chloro-1-carboxymethylpyrazinone from step 7 above (50 mg, 0.15 mmol) in DMF (1.0 mL) was added 5-aminomethyl-3-chloro-7-azaindole bis-hydrochloride salt (41 mg, 0.16 mmol) and HOBT (24 mg, 0.16 mmol). The solution was brought to pH 7 by the addition of DIEA (approximately 0.1 mL). EDC (70 mg, 0.24 mmol) was added and the solution was stirred at ambient temperature for 18 h. The reaction was concentrated in vacuo and partitioned between water and EtOAc. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 9:1 CH2Cl2:MeOH as eluant. The free base of the title compound was dissolved in MeOH containing 3 equivalents of aqueous HCl and the solution was evaporated in vacuo to give the HCl salt of the title compound as an amorphous solid (45 mg, TLC Rf=0.46, 92:8:0.4 CH2Cl2:MeOH:NH4OH; HPLC RT=8.6 min, method A; M+1 peak at m/z=508, electrospray mass spec).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH2:14][NH:13][CH2:12][CH2:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cccc2c1CN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1cccc2c1CNCC2
Reaction time: 0.5 h

Procedure:
In a 10 dram vial, added 7-1 (292.5 mg, 0.958 mmol) to DCM (3831 μl) and TFA (958 μl). After 30 min at RT, concentrated to give a clear, colorless oil. Carried crude material forward to subsequent step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:9]=[CH:10][CH:11]=1)[CH3:2].[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:30]([CH:27]2[CH2:29][CH2:28]2)=[O:31])[CH2:24][CH3:25])[CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)OCC)c1
Reactant: O=C(Cl)C1CC1
Product: CCOC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: C(O[C:4](=[O:33])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH:6]=1)C.[C:34]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:4](=[O:33])[C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=3)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH:6]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: NCCCCCCCCc1ccccc1
Product: COc1ccc(-c2cc(C(=O)NCCCCCCCCc3ccccc3)cc(-c3cccc(C(F)(F)F)c3)c2OCCO)cc1

Procedure:
The product was prepared as a viscous yellow oil (0.165 g, 61%) from 3-(4-methoxyphenyl)-5-(3-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester and 8-phenyloctylamine using a procedure similar to step 2 of example 1; 1H NMR (300 MHz, DMSO-d6) δ1.21-1.34 (m, 8H), 1.45-1.58 (m, 4H), 2.50 (t, J=7.5 Hz, 2H), 3.10 (q, J=6 Hz, 2H), 3.20-3.30 (m, 4H), 3.80 (s, 3H), 4.38 (t, J=6 Hz, 1H), 7.01-7.05 (m, 2H), 7.10-7.25 (m, 5H),7.60 (d, J=9 Hz, 2H), 7.68-7.78 (m, 2H), 7.84-7.88 (m, 2H), 7.90-7.95 (m, 2H), 8.54 (t, J=5 Hz, 1H); mass spectrum [(+)ESI], m/z 620 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[CH:4][CH:3]=1.P(OCC)(OCC)(OCC)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:14][C:4]=2[CH:3]=1
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Solvent: CCOP(=O)(OCC)OCC
Product: Cc1ccc2c(c1)[nH]c1ccccc12
Temperature: 160 °C
Reaction time: 6 h
Yield: 58.8 %

Procedure:
3 g of 2-(4-methylphenyl)nitrobenzene and 20 m of triethyl phosphate were heated and stirred at 160° C. for 6 hours. After triethyl phosphate was distilled off under reduced pressure, 10 ml of methanol was added, followed by filtration. The resulting solid was vacuum-dried to obtain 1.5 g of 2-methylcarbazole.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2>C1C=CC=CC=1.[Ag]>[OH:1][CH2:2][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[C:2](=[O:1])[CH:11]=1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ag]
Solvent: c1ccccc1
Product: O=C1C=C(OCCCCCCO)c2ccccc2C1=O
Yield: 100.8 %

Procedure:
A mixture of 6-bromohexanol-1 (4.5 g, 24.85 mmol) and the silver salt of 2-hydroxy-1,4-naphthoquinone (6.46 g, 23.01 mmol) in benzene (24 mL) was stirred for 48 h at 60° C. The reaction mixture was worked up as described for 502 and crystallized from hexane to afford a yellow solid (3.18 g, 50%). mp 96-98° C., 1H NMR (CDCl3) 8.12 (d, J=7.5 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.70 (t, J=7.5 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 5.95 (s, 1H), 4.15 (t, J=6.3 Hz, 2H), 3.69 (t, J=6.2 Hz, 2H), 1.92-1.97 (m, 2H), 1.3-1.8 (m, 7H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[C:19]([F:26])=[CH:18][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]1=[O:17].F[C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]([F:38])([F:37])[F:36])=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[C:19]([F:26])=[CH:18][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:28]3[C:33]([F:34])=[CH:32][C:31]([C:35]([F:38])([F:36])[F:37])=[CH:30][N:29]=3)[CH2:13][CH2:12]2)[C:6]1=[O:17]
Reactant: CS(=O)(=O)c1cc(F)c(O[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Reactant: Fc1cc(C(F)(F)F)cnc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cc(F)c(O[C@H]2CCCN(C3CCN(c4ncc(C(F)(F)F)cc4F)CC3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.5 %

Procedure:
To a solution of (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-[1,4′-bipiperidin]-2-one (Preparation G; 30 mg, 0.077 mmol) in DMF was added 2,3-difluoro-5-(trifluoromethyl)pyridine (42 mg, 0.23 mmol) and DIEA (30 μL, 0.23 mmol) and the reaction was stirred at ambient temperature for 18 hours. The reaction was diluted with EtOAc and washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc/DCM 4:1) to give (S)-3-(2,5-difluoro-4-(methyl-sulfonyl)phenoxy)-1′-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-[1,4′-bipiperidin]-2-one as a white solid (20 mg, 0.035 mmol, 46% yield). Mass spectrum (apci) m/z=552.2 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[CH2:9]([NH:1][CH2:2][CH2:3][C:4]1[NH:8][CH:7]=[N:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCCc2cnc[nH]2)cc1
Reaction time: 3 h
Yield: 82.8 %

Procedure:
A solution of histamine (free base) (1.00 g, 9.0 mmol) and benzaldehyde (0.91 mL, 9.0 mmol) in MeOH (25 mL) was stirred at rt for 30 min. To this solution was slowly added NaBH4 (0.21 g, 5.4 mmol). The reaction was let stir for 3 h, quenched with a minimal amount of H2O and concentrated. The residue was dissolved in EtOH and filtered through Celite©. The solvent was concentrated to give the title product (1.50 g, 83%). MS (ESI): mass calculated for C12H15N3, 201.1. m/z found 202.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]([CH3:15])([CH3:14])[N+:12]([O-])=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10]2)=[CH:5][CH:4]=1.C(O)C>[Zn].C(O)=O>[CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:10][C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:12][C:13]2([CH3:14])[CH3:15])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(C2CC(c3ccccc3)=[N+]([O-])C2(C)C)cc1
Agent: [Zn]
Solvent: O=CO
Solvent: CCO
Product: CN(C)c1ccc([C@H]2C[C@H](c3ccccc3)NC2(C)C)cc1

Procedure:
47 G. of 4-(p-dimethylaminophenyl)-5,5-dimethyl-2-phenyl-1-pyrroline 1-oxide are dissolved in a mixture of 400 ml. of ethanol and 400 ml. of formic acid and treated portionwise while stirring with 80 g. of zinc powder. The temperature is held at 43° C. during this addition. Subsequently, the mixture is stirred for a further 2 hours, the zinc sludge is then filtered off and the filtrate evaporated under reduced pressure. The residue is taken up in water, neutralized with 3-N sodium hydroxide and extracted with ether. The ether phase is then dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out first with pure benzene and then with benzene/acetone mixtures with increasing acetone content (up to 50% acetone). There is thus obtained trans-3-(p-dimethylaminophenyl)-2,2-dimethyl-5-phenyl-pyrrolidine which melts at 108°-109° C. after crystallization from n-hexane.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][CH:15]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:29])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:26]3[CH2:27][CH2:28][N:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[CH3:29])[CH2:24][CH2:25]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: O=CCCCC1CC(c2ccccc2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(CCCCC2CC(c3ccccc3)=NO2)CC1
Yield: 62.1 %

Procedure:
4-(3-Phenyl-4,5-dihydroisoxazol-5-yl)butanal (27.1 mg, 0.124 mmol), 1-(o-tolyl) piperazine (20.0 mg, 0.113 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (72.1 mg, 0.340 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 26.5 mg (67.3%) of the target compound was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[O:4].[OH-].[Na+].CO.Cl>O>[F:24][C:23]([F:25])([F:26])[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:5]=2[C:3]([OH:4])=[O:2])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Yield: 79.8 %

Procedure:
To 1.59 g of 1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carboxylic acid methyl ester were added 10 ml of 2 M aqueous sodium hydroxide and 10 ml of methanol. After 3 h at reflux the mixture was poured unto water, treated with 2 M hydrochloric acid, and three times extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated in vacuo. The resulting residue was purified by crystallization from pentane to yield 1.22 g of 1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carboxylic acid.