Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][CH2:7]Cl)[CH3:4].[H-].[Na+].[CH2:11]([C:13]1[C:18]([OH:19])=[N:17][C:16]([CH3:20])=[C:15]2[S:21][CH:22]=[CH:23][C:14]=12)[CH3:12].O>CN(C=O)C>[CH2:11]([C:13]1[C:18]([O:19][CH2:7][CH2:6][CH2:5][N:3]([CH3:4])[CH3:2])=[N:17][C:16]([CH3:20])=[C:15]2[S:21][CH:22]=[CH:23][C:14]=12)[CH3:12]
Reactant: CCc1c(O)nc(C)c2sccc12
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(OCCCN(C)C)nc(C)c2sccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.1 %

Procedure:
3-(N,N-Dimethylamino)propylchloride hydrochloride (5.51 g, 34.9 mmol) and sodium hydride (60% in oil, 1.55 g, 38.8 mmol, prewashed with pentane) in DMF (30 ml) were stirred at room temperature for one hour. This solution was then added to a mixture of 4-ethyl-7-methylthieno[2,3-c]pyridin-5-ol (2.9 g, 15.0 mmol) and sodium hydride (60% in oil, 0.60 g, 15.0 mmol, prewashed in pentane) in DMF (30 ml) which had been allowed to react for two hours. The combination was stirred at room temperature for three days, poured into H2O (500 ml), extracted with CH2Cl2 (3×200 ml) and dried over MgSO4. The solvent was removed in vacuo and the product was purified by flash chromatography on silica gel 60 (120 g) using 8% MeOH in CH2Cl2 as the eluant to give the product (2.3 g, 55% yield) as a yellow oil; IR (neat) 1440, 1580 and 2980 cm-1 ; mass spectrum m/z 279 (MH+); 1H NMR (CDCl3) δ 1.20 (t, J=7 Hz, 3H, CH2CH3), 1.68 to 2.90 (m, 6H, CH2CH2N, CH2CH3), 2.27 (s, 6H, N(CH3)2), 2.63 (s, 3H, 7-CH3), 4.43 (t, J=6 Hz, 1H, OCH2CH2), 7.27 and 7.53 each (d, J=6 Hz, 1H, thiophene-H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[NH:11])OCC)=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:3]=1[C:20]#[N:21].Cl.Cl.N[CH:25]([CH2:30][NH2:31])[C:26]([O:28][CH3:29])=[O:27]>C(O)C>[Br:1][C:2]1[S:6][C:5]([C:7]2[NH:11][CH:25]([C:26]([O:28][CH3:29])=[O:27])[CH2:30][N:31]=2)=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:3]=1[C:20]#[N:21]
Reactant: COC(=O)C(N)CN
Reactant: CCOC(=N)c1sc(Br)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: COC(=O)C1CN=C(c2sc(Br)c(C#N)c2-c2ccc(Cl)cc2Cl)N1
Temperature: 80 °C
Reaction time: 4 h
Yield: 35.6 %

Procedure:
To a solution of ethyl 5-bromo-4-cyano-3-(2,4-dichlorophenyl)thiophene-2-carboximidoate (0.548 g, 1.36 mmol) in ethanol (26 mL) was added methyl 2,3-diaminopropanoate dihydrochloride (0.313 g, 1.64 mmol). The solution was stirred at 80° C. for 4 hours. The solvent was evaporated, and column chromatography was performed to yield the title compound (0.222 g, 36%). LCMS: (FA) ES+ 460. 1H NMR (400 MHz, d4-methanol) 7.70 (s, 1H), 7.55-7.43 (m, 2H), 3.76-3.66 (m, 4H), 1.36-1.26 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:13]=[C:12]([NH2:14])[NH:11][N:10]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH:31]([C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1)=O.C(O)(=O)C.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:13]=[C:12]([NH:14][CH2:31][C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[CH:35][CH:34]=3)[NH:11][N:10]=2)[CH:5]=[C:4]([C:15]([F:18])([F:16])[F:17])[C:3]=1[C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2c(Cl)cc(Nc3n[nH]c(N)n3)cc2C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2c(Cl)cc(Nc3n[nH]c(NCc4ccc(C(=O)OC(C)(C)C)cc4)n3)cc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.2 %

Procedure:
To a solution of N3-(2-chloro-4′-(isopropylsulfonyl)-6-(trifluoromethyl)biphenyl-4-yl)-1H-1,2,4-triazole-3,5-diamine (135 mg, 294 μmol) in MeOH (3.5 ml) was added tert-butyl 4-formylbenzoate (85 mg, 412 μmol) followed by acetic acid (52.4 mg, 50 μl, 873 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (42.4 mg, 396 μmol) was added and the stirring was continued for 3 days. The reaction mixture was poured into 0.1N HCl solution (20 ml) and the resulting suspension was filtered to collect the solid. The crude material was purified by flash chromatography (silica gel, 24 g, 3% to 5% MeOH in DCM) to afford a white solid as desired product (94 mg, 49% yield). MS +m/z: 650 (M+H)+
Reaction SMILES: [K+].F[C:3]1[CH:8]=[C:7]([C:9]2[C:14]3[CH:15]=[C:16]([C:32]([O-:34])=[O:33])[N:17]([CH2:18][CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=4)[C:13]=3[CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>N1C=CC=CC=1>[OH:36][CH2:35][CH2:37][NH:38][C:3]1[CH:8]=[C:7]([C:9]2[C:14]3[CH:15]=[C:16]([C:32]([OH:34])=[O:33])[N:17]([CH2:18][CH2:19][O:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=4)[C:13]=3[CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=C([O-])c1cc2c(-c3ccnc(F)c3)nccc2n1CCOc1ccc(OC(F)(F)F)cc1
Reactant: NCCO
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1cc2c(-c3ccnc(NCCO)c3)nccc2n1CCOc1ccc(OC(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
4-(2-Fluoropyridin-4-yl)-1-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid potassium salt (25 mg, 0.050 mmole) was taken up in pyridine (0.3 mL) in a screw cap vial. To this was added ethanolamine (0.015 mL, 0.250 mmole). The vial was capped then heated to 120° C. After stirring overnight ethanolamine (0.015 mL, 0.250 mmole) was added and heating continued. After stirring overnight the mixture was cooled to RT and concentrated. The crude material was taken up in DMSO and acidified with TFA. The resulting solution was purified by preparative reversed-phase HPLC (30×100 mm Phenomenex AXIA-Gemini-NX, 5%-95% CH3CN/water containing 0.1% TFA over 18 min at 50 mL/min) to give the title compound (16 mg, 52%) as a yellow solid. 1H NMR (499 MHz, DMSO): δ 8.58 (d, J=5.9 Hz, 1 H); 8.04 (d, J=6.7 Hz, 1 H); 7.95 (d, J=6.0 Hz, 1 H); 7.73 (s, 1 H); 7.66 (s, 1 H); 7.43 (d, J=6.6 Hz, 1 H); 7.23 (d, J=8.6 Hz, 2 H); 6.90 (d, J=8.8 Hz, 2 H); 5.13-5.04 (m, 2H); 4.39-4.35 (m, 2 H); 3.68 (m, 2 H); 3.49 (bs, 2 H). HRMS (ESI) calc (M+H)+=503.1537. found 503.1529.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>S(=O)(=O)(O)O>[C:19]([N:9]1[C:10]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)(=[O:21])[CH3:20]
Reactant: c1ccc(Sc2cc(-c3ccccc3)n[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)n1nc(-c2ccccc2)cc1Sc1ccccc1
Yield: 90 %

Procedure:
At 20° to 25° C, a few drops of concentrated sulfuric acid are added to a solution of 10 parts of 3-phenyl-5-phenylthiopyrazole in 100 parts of acetic anhydride. After 15 hours the solution is concentrated in vacuo and 50 parts of water is added to the residue. There is obtained 10.5 parts (90% of theory) of 1-acetyl-3-phenyl-5-phenylthiopyrazole; m.p.: 83° to 84.5° C (recrystallized from methanol).
Reaction SMILES: Br[CH:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]1([O:10][CH2:11][CH2:12]Cl)C.[CH2:14]([Li])CCC>C1COCC1>[CH3:14][C:7]1[C:2]2[CH2:12][CH2:11][O:10][C:3]=2[CH:4]=[C:5]([CH3:8])[CH:6]=1
Reactant: [Li]CCCC
Reactant: CC1=CC(C)(OCCCl)C(Br)C=C1
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(c1)OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of 1-bromo-2-(2-chloroethoxy)-2,4-dimethylbenzene obtained in Reference Example 217 (8.70 g, 33.0 mmol) in THF (210 mL) was quickly added n-butyllithium (1.6 M hexane solution, 31 mL, 49.5 mmol) under argon atmosphere at 0° C., and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, to which ice was added, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, was filtered, and then was concentrated under reduced pressure to obtain 4.70 g (yield 96%) of the title compound. Oily matter.
Reaction SMILES: C(OC(=O)[N:7]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:8][C@@H:9]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH2:31]([O:30][NH:7][CH2:8][C@@H:9]([C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:20][CH2:21]1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)CN(OCc3ccccc3)C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(=O)[C@H](CNOCc3ccccc3)CC(C)C)CC2)cc1
Yield: 122.2 %

Procedure:
A solution of tert-butyl(benzyloxy)((2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-4-methylpentyl)carbamate (134 mg; 0.25 mmol; 1.0 eq.) and HCl 4M in dioxan (0.938 mL, 15 eq.) in DCM (1 mL) was stirred overnight at room temperature. The solvents were evaporated to give the title product as a yellow oil (130 mg, 100%). HPLC, Rt: 2.9 min (purity: 95.9%). M+(LC-MS (ESI)): 426.4.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH:17]=O)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CO.[CH3:21][NH2:22]>>[Br:1][C:2]1[CH:16]=[C:15]([CH2:17][NH:22][CH3:21])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1Br
Reactant: CN
Solvent: CO
Product: CNCc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
t-Butyl 2-(2-bromo-4-formylphenoxy)acetate (1) (10.11 g, 32.1 mmol, 1 eq) was dissolved in a 2 M solution of methylamine in methanol (30 mL, 60 mmol, 1.9 eq) and stirred at room temperature for 4 h. The solvent and excess methylamine were removed in vacuo and the resultant imine was dissolved in anhydrous methanol (200 mL). Sodium Borohydride (2.4 g) was added slowly under argon and the mixture was stirred for 2 h. Saturated NaHCO3 (100 mL) was added and allowed to stir for 15 minutes at which point the methanol was removed in vacuo. The resultant aqueous mixture was extracted with DCM (2×50 mL) and the combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated in vacuo to yield 6.2 g (58%) of t-butyl 2-(2-bromo-4-((methylamino)methyl)phenoxy)acetate (2). 1HNMR (CDCl3, 300 MHz): δ 7.50 (d, 1H), 7.15 (m, 1H), 6.72 (d, 1H), 4.55 (s, 2H), 3.65 (s, 2H), 2.41 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]([CH3:14])([CH3:13])[C:11]2[CH:10]=[C:9]([C:15]([NH2:17])=[O:16])[CH:8]=[CH:7][C:6]=2[CH2:5][C@H:4]1[O:18][CH3:19].C(N(CC)CC)C.[CH2:27]([O:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:33])[CH2:31][CH2:32][NH:2][C@H:3]1[C@H:4]([O:18][CH3:19])[CH2:5][C:6]2[C:11](=[CH:10][C:9]([C:15](=[O:16])[NH2:17])=[CH:8][CH:7]=2)[C:12]1([CH3:14])[CH3:13])[CH3:28]
Reactant: C=CC(=O)OCC
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1N
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN[C@H]1[C@H](OC)Cc2ccc(C(N)=O)cc2C1(C)C
Temperature: 70 °C
Reaction time: 23 h

Procedure:
A mixture of trans-7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide hydrochloride (0.25 g, 0.88 mmol) anhydrous ethanol (0.90 mL), triethylamine (0.14 mL, 1.32 mmol) and acrylic acid ethyl ester (0.14 mL, 1.0 mmol) were heated at 70° C. After 23 h, additional acrylic acid ethyl ester (0.04 mL, 0.3 mmol) was added and heating was continued. Five hours after the addition, the reaction was cooled to room temperature, combined with another run (0.36 mmol scale) and concentrated under vacuum. The title compound (0.61 g) was used without further purification. (m/z): [M+H]+ calcd for C19H28N2O4 349.21; found 349.0.
Reaction SMILES: [C:1]1([S:7]([N@@:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]1([S:7]([N:10]2[CH2:12][C@H:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:38]2=[O:39])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3C[N@]3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 2, ((R)-1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone was reacted with sodium iodide and phenylisocyanate to give the title compound as a colorless solid. MS: 519.0 ([M+H]+)
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([CH:24]1[CH2:27][CH2:26][CH2:25]1)=[O:23])=[O:19])C1C=CC=CC=1>CO.[Pd]>[CH:24]1([C:22]([NH:21][NH:20][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[OH:8])=[O:19])=[O:23])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CCC1
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)C1CCC1
Reaction time: 3 h
Yield: 116.8 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N′-(cyclobutylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 200 (0.34 g, 0.91 mmol) and Pd/C (0.12 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite and concentrated to provide 201 (0.30 g, quant. yield) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:15])[C:12]([OH:14])=[O:13].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:15])[C:12]([O:14][CH3:21])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Yield: 94.9 %

Procedure:
To a solution of 12.4 g of 2-(2,6-dichloroanilino)-phenylglyoxylic acid in 80 ml of anhydrous acetone were added 6.05 g of anhydrous potassium carbonate and then 7.5 ml of dimethyl sulfate at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was filtered and washed with anhydrous acetone. The filtrate was concentrated under 10 mmHg without heating. The residue was recrystallized from ethanol to give 12.3 g of methyl 2-(2,6-dichloroanilino)phenylglyoxylate as yellow prisms. m.p. 124.5-125.5° C. Yield: 95% of theoretical amount
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][CH:12]=[C:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]3)[N:14]=2)[CH:5]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[O:38]([CH2:45][C:46](Cl)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][CH:12]=[C:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:46](=[O:47])[CH2:45][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:14]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(-c2nc([C@H]3CCCCN3)cs2)c1
Reactant: O=C(Cl)COc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-c2nc([C@H]3CCCCN3C(=O)COc3ccccc3)cs2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-((R)-4-piperidin-2-yl-thiazol-2-yl)-benzoic acid methyl ester (0.048 g, 0.16 mmol) in dry dichloromethane (2 mL) under argon was treated with triethylamine (0.064 g, 0.09 ml.), dimethylaminopyridine (0.002 g, 0.020 mmol) and phenoxyacetyl chloride (0.027 g, 0.16 mmol). The mixture was stirred at room temperature for 4 h. The mixture was washed with water and saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The residual oil was purified by preparative HPLC: Column: YMC-Pack Pro C18 RS, 20×50 mm, S-5 um, 8 nm, No200504707(W); Gradient: 0-0.4 min: 30% acetonitrile in (water+0.1% HCO2H), 0.4-2.4 min: increse of acetonitrile fraction from 30% to 95%, 2.4-4.7 min: 95% acetonitrile, 4.7-4.8 min: decrease of acetonitrile fraction from 95% to 30%; Program end at 4.87 min; Flow: 30 ml/min. 3-{4-[(R)-1-(2-Phenoxy-acetyl)-piperidin-2-yl]-thiazol-2-yl}-benzoic acid methyl ester was obtained after lyophilization as a light yellow oil (0.033 g, 48%), MS (ISP): 437.3 (M+H)+..
Reaction SMILES: C([NH:8][CH2:9][CH2:10][NH2:11])C1C=CC=CC=1.[CH2:12]([N:14]1[C:26]2[CH:25]=[CH:24][C:23]([C:27]([OH:29])=O)=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13]>>[NH2:8][CH2:9][CH2:10][NH:11][C:27]([C:23]1[CH:24]=[CH:25][C:26]2[N:14]([CH2:12][CH3:13])[C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:29]
Reactant: NCCNCc1ccccc1
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Product: CCn1c2ccccc2c2cc(C(=O)NCCN)ccc21
Yield: 92 %

Procedure:
N1-Benzyl-ethane-1,2-diamine (6.0 g, 25.1 mmol) was coupled with 9-Ethyl-9H-carbazole-3-carboxylic acid as described in example 81 to afford, after chromatographic purification (silica; 3% MeOH/CH2Cl2) 9-Ethyl-9H-carbazole-3-carboxylic acid (2-benzylamino-ethyl)-amide (4.5 g, 48%) (MS m/z @ 372 (m+1). This material was subjected to catalytic hydrogenation ((10%Pd—C/H2 @ 50 psi) in EtOH/AcOH to afford 9-Ethyl-9H-carbazole-3-carboxylic acid (2-amino-ethyl)-amide (3.16 g, 92%) as a white solid MS m/z @ 282 (m+1). This material was reductively aminated using sodium triacetoxyborohydride and thiazole-2-carbaldehyde similarly to conditions described for example 75 to afford the title compound (350 mg, 65%). MS m/z @ 379 (m+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH:14]([CH2:15][CH2:16]4)[CH:13]2[CH2:12][N:11](C)[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH:14]([CH2:15][CH2:16]4)[CH:13]2[CH2:12][N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1CC2C3CCC(C3)C2(c2ccc(Cl)c(Cl)c2)C1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2C3CCC(C3)C2(c2ccc(Cl)c(Cl)c2)C1

Procedure:
By the method of Example 26, (-)-3a-(3,4-dichlorophenyl)octahydro-2-methyl-4,7-methano-1H-isoindole is reacted with ethyl chloroformate in toluene to give the corresponding 3a-(3,4-dichlorophenyl)octahydro-4,7-methano-2H-isoindole-2-carboxylic acid, ethyl ester. This urethane is hydrolyzed with hydrochloric acid and the solution is evaporated to give (-)-3a-(3,4-dichlorophenyl)octahydro-4,7-methano-1H-isoindole hydrochloride as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1>CCOCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:3]([OH:4])[C:2]([CH3:6])([CH3:5])[CH3:1])=[CH:10][CH:9]=1
Reactant: CC(C)(C)C=O
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: CC(C)(C)C(O)c1ccc(Cl)cc1

Procedure:
Grignard reaction of trimethylacetaldehyde (240.0 mg; 2.8 mmol) with 4-chlorophenylmagnesium bromide in anhydrous ether afforded 0.58 grams of 1-(4-chlorophenyl)-2,2-dimethylpropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH2:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C1CCNCC1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].N.S(Cl)(Cl)(=O)=O>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH:17][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: N
Solvent: C1CCNCC1
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)c1ccc(S(=O)(=O)NCC(=O)NCC2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine (14.8 mg, 0.05 mmol) in CHC3 (2 mL) was treated with (piperidinomethyl)polystyrene resin (28 mg, 2.8 mmol/g), 4-isopropylbenzenesulfonyl chloride (1.5 equiv.) and stirred at 25° C. for 16 h. (Aminomethyl)polystyrene was added to scavenge the residual sulfonyl chloride and the reaction mixture was stirred at 25° C. for 16 h. Filtration and concentration afforded 1-(4-chlorobenzyl)-4-[{(4-isopropylphenylsulfonyl)glycyl}aminomethyl]piperidine (compound No. 869) (22.1 mg, 92%): The purity was determined, by RPLC/MS (86%); ESI/MS m/e 478 (M++H, C24H32ClN3O3S).
Reaction SMILES: [F:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([C@H:9]([CH2:30][CH3:31])[CH2:10][C@@:11]([C:26]([F:29])([F:28])[F:27])([OH:25])[CH:12]=NC2C=CC=C3C=2C=NC(C)=N3)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br.C([O-])(O)=[O:39].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([CH:9]([CH2:30][CH3:31])[CH2:10][C:11]([OH:25])([C:26]([F:27])([F:29])[F:28])[CH:12]=[O:39])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F)c1ccc(F)c(F)c1OC
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC(O)(C=O)C(F)(F)F)c1ccc(F)c(F)c1OC
Temperature: -30 °C

Procedure:
300 mg (0.92 mmol) of (2R,4R)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 146 mg (0.92 mmol) of 5-amino-2-methylquinazoline are dissolved in 20 ml of toluene, and the solution is admixed with 0.29 ml (0.92 mmol) of titanium tert-butoxide and 0.1 ml of acetic acid. The reaction mixture is heated at 100° C. for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 349 mg of (2R,4R)-4-(3,4-difluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol as a crude product. The crude imine is dissolved in 35 ml of CH2Cl2 and the solution is cooled to −30° C. 6 ml (6 mmol) of a 1 M BBr3 solution in dichloromethane are added slowly dropwise over 5 minutes and the reaction solution is allowed to warm to room temperature over 16 hours. It is poured onto a mixture of saturated NaHCO3 solution and ice. Extraction is carried out repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/isopropanol 0-10%) and subsequent HPLC separation on a chiral stationary phase afford 70 mg of product (analytical HPLC: Rt=8.36 min (Chiralcel OD 5μ, 250×4.6 mm, hexane/ethanol 5%, 1 ml/min flow rate) as the (−)-enantiomer.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][NH2:31])=[O:29])=[CH:24][CH:23]=2)=[O:19])=[CH:16][CH:15]=1>C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][N:31]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:29])=[CH:24][CH:23]=2)=[O:19])=[CH:32][CH:33]=1
Reactant: NNC(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)cc1
Temperature: 100 °C
Yield: 92 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-chloro-N-[4-(hydrazinocarbonyl)benzyl]benzamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 126 mg of the title compound (92%) as a yellow solid in 89.18% purity by HPLC (Rt: 4.48, gradient of 8 min, MaxPlot detection between 230 and 400 nm).