Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4]1=[O:21].[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C(N(CC)CC)C.CO>ClC(Cl)C>[O:26]=[C:25]1[C:24]2[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22](=[O:27])[N:2]1[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4]1=[O:21]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc2c(c1)C(N)C(=O)N2c1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(N1C(=O)c3ccccc3C1=O)C(=O)N2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
In one portion of 4.00 g (0.013 mole) of 3-amino-1-(4-fluorophenyl)-2,3-dihydro-5-methoxy-1H-indol-2-one hydrochloride in 80 ml of anhydrous dichloroethane, 2.69 g (0.0182 mole, 1.4 equivalent) of phthalic anhydride was added to a stirred suspension under argon atmosphere. 2 ml (0.0143 mole) of triethylamine was added dropwise to this mixture over 10 minutes. Then, after the whole was stirred at room temperature for 10 minutes, it was further refluxed over an oil bath overnight. Excessive phthalic anhydride was decomposed by adding a mixture of 2 ml of triethylamine and 2 ml of methanol and refluxing the resulting mixture for 20 minutes. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried. The residue obtained by removing ethyl acetate by evaporation was recrystallized from hexane-ethyl acetate to afford 4.50 g of 3-(1,2-dihydro-1,3-dioxoisoindol-2-yl)-1-(4-fluorophenyl)-2,3-dihydro-5-methoxy-1H-indol-2-one as colorless crystals. Melting point: 208.5° to 210.0° C., IR (Nujol) (cm-1): 1730, 1715, 1495, 1400, 1225, 1210, 750, 715, MS (DI, m/e): 402 (M+, base), 227, 184, 76.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]=[C:26]=[O:27]>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:8]([NH:10][C:26]([NH:25][CH3:24])=[O:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Yield: 68.8 %

Procedure:
A solution of 3-cyclopentyl-2-(4-phenoxy-phenyl)-propionamide (143 mg, 0.46 mmol) in toluene (10 mL) was treated with methyl isocyanate (0.04 mL, 0.69 mmol). The reaction mixture was heated under reflux for 24 h. The reaction was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionyl]-3-methyl-urea (116 mg, 69%) as a white solid: EI-HRMS m/e calcd for C22H26N2O3 (M+) 366.1943, found 366.1946.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N:16]([CH3:26])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:19])=[O:18])[CH:15]=1)[NH:12][C:11]([C:27]([O:29]CC)=[O:28])=[CH:10]2.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N:16]([CH3:26])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:18])=[O:19])[CH:15]=1)[NH:12][C:11]([C:27]([OH:29])=[O:28])=[CH:10]2
Reactant: CCOC(=O)c1cc2cc(OCCCOC)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COCCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A mixture of ethyl 5-(3-methoxypropoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (3.50 g), 1N aqueous sodium hydroxide solution (10 mL), ethanol (10 mL) and tetrahydrofuran (10 mL) was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (10 mL) and water were added to the reaction mixture, and the mixture was extracted with a mixed solvent of tetrahydrofuran-ethyl acetate. The organic layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained crystals were washed with hexane to give the title compound (3.26 g, 100%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([OH:19])[CH2:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=CC=CC=2)[CH:10]=1)=[O:8])[CH3:2].[CH3:21][CH2:22]CCCC.CC(O)C>>[CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([OH:19])[CH:6]([C:7](=[O:8])[C:9]1[CH:10]=[CH:11][CH:16]=[CH:17][CH:18]=1)[CH2:21][CH3:22])[CH3:2]
Reactant: CCCCCC
Reactant: CCOC(=O)[C@@H](O)CC(=O)c1ccc2ccccc2c1
Solvent: CC(C)O
Product: CCOC(=O)[C@@H](O)C(CC)C(=O)c1ccccc1

Procedure:
1H NMR syn (CDCl3) δ=0.93 (t, 3H, J=7.5 Hz), 1.19 (t, 3H, J=7.1 Hz), 1.70-2.05 (m, 2H), 3.18 (brs, 1H), 3.83 (dt, 1H, J=5.3, 8.3 Hz), 4.19 (q, 2H, J=7.1 Hz), 4.51 (d, 1H, J=5.3 Hz), 7.42-7.54 (m, 2H), 7.54-7.62 (m, 1H), 7.90-8.02 (m, 2H); anti (CDCl3) δ=1.04 (t, 3H, J=7.6 Hz), 1.15 (t, 3H, J=7.1 Hz), 1.80-1.95 (m, 2H), 3.70 (d, 1H, J=9.5 Hz), 3.83 (dt, 1H, J=4.2, 7.1 Hz), 4.09 (q, 2H, J=7.1 Hz), 4.43 (dd, 1H, J=4.2, 9.5 Hz), 7.46-7.52 (m, 2H), 7.56-7.63 (m, 1H), 7.88-7.95 (m, 2H); 13C NMR syn (CDCl3) δ=12.0, 13.9, 21.3, 51.2, 61.9, 71.1, 128.3, 128.6, 133.2, 137.0, 173.6, 201.5; anti(CDCl3) δ=12.0, 13.9, 22.3, 50.1, 61.4, 71.3, 128.3, 128.7, 133.5, 136.6, 173.4, 203.9; IR (neat) syn 3477, 2972, 2876, 1738, 1675, 1596, 1447, 1372, 1255, 1220, 1118, 1023, 931, 849, 779, 701; anti 3485, 3062, 2966, 2941, 2875, 1738, 1682, 1596, 1579, 1448, 1368, 1268, 1208, 1134, 1100, 1028, 914, 849, 785, 699 cm−1; HRMS (FAB); Exact mass calcd for C14H19O4 [M+H]+, 251.1283. Found 251.1277.; HPLC, Daicel Chiralcel AS, hexane/iPrOH=4/1, flow rate=0.5 mL/min: tR=13.7 min (2S, 3S), tR=15.3 min (2S, 3R), tR=17.6 min (2R, 3R), tR=23.1 min (2R, 3S).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](Cl)(=[O:12])[CH3:11]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([NH:8][C:10](=[O:12])[CH3:11])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(Cl)c(Br)cn1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirred solution of 5-bromo-4-chloropyridin-2-amine (11.6 g, 55.9 mmol) in pyridine (100 mL) at 0° C. was added acetyl chloride (3.98 mL, 55.9 mmol) and the reaction was stirred at rt for 3 hours. The reaction was quenched with cold water. The reaction mixture was concentrated under reduced pressure. The residue was reconstituted in ethyl acetate and water. The organics were extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL) and dried over sodium sulfate. The organics were concentrated under reduced pressure to afford N-(5-bromo-4-chloropyridin-2-yl)acetamide as a white solid (14.6 g, 55.9 mmol, quantitative yield) that was used without further purification in the next step. LCMS (ESI) m/e 249 [(M+H)+, calcd for C7H7BrClN2O 248.9 LC/MS retention time (method B): tR=1.64 min; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.58 (s, 1H), 8.33 (s, 1H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]([NH2:15])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21]>O1CCOCC1>[NH2:15][C:11]1[N:10]=[C:9]([NH:22][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:13]([CH3:14])[N:12]=1
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccccc1
Reactant: CCCCCN
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccccc1
Reaction time: 19 h
Yield: 89.7 %

Procedure:
A mixture of 5-benzyl-4-chloro-6-methylpyrimidine-2-ylamine (500 mg, 2.14 mmol), amylamine (1.24 ml) and dioxane (4 ml) was kept at 95-100° C. for 19 hours. The reaction mixture was concentrated in vacuo, and the residue was extracted with chloroform and a saturated aqueous NaHCO3 solution. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2% MeOH/CHCl3) to give the object compound (546 mg, 89.7%).
Reaction SMILES: COC1C=CC(C[N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][CH:22]=[CH:23][C:16]=34)[C:12]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[N:11]2)=CC=1>FC(F)(F)C(O)=O.O>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([C:12]2[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][CH:22]=[CH:23][C:16]=34)=[CH:14][NH:10][N:11]=2)=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: COc1ccc(Cn2cc(-c3ccnc4[nH]ccc34)c(-c3ccc([N+](=O)[O-])cc3)n2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(-c2n[nH]cc2-c2ccnc3[nH]ccc23)cc1
Yield: 64 %

Procedure:
A solution of 4-[1-{[4-(methyloxy)phenyl]methyl}-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine (0.22 mmol) in trifluoroacetic acid (0.75 mL) was heated at 740C for 1.5 h. The reaction mixture was diluted with water (4 mL) and extracted with (3×5 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and were concentrated. Purification of the residue by Gilson reverse phase HPLC afforded the title product as a yellow solid (64%). ESMS [M+H]+: 306.4
Reaction SMILES: Cl.[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([C:13]([O:15][C@@H:16]1[CH2:20][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[NH:18][CH2:17]1)=[O:14])[CH2:8]2)=[CH2:3].[CH3:25][C:26]([CH3:43])([CH2:40][CH:41]=[CH2:42])[CH2:27][O:28][C:29]([NH:31][C@H:32]([C:37](O)=[O:38])[C:33]([CH3:36])([CH3:35])[CH3:34])=[O:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[CH3:25][C:26]([CH3:43])([CH2:40][CH:41]=[CH2:42])[CH2:27][O:28][C:29]([NH:31][C@H:32]([C:37]([N:18]1[CH2:17][C@H:16]([O:15][C:13]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH:2]=[CH2:3])[CH2:8]2)=[O:14])[CH2:20][C@H:19]1[C:21]([O:23][CH3:24])=[O:22])=[O:38])[C:33]([CH3:34])([CH3:35])[CH3:36])=[O:30]
Reactant: C=CCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1cccc2c1CN(C(=O)O[C@H]1CN[C@H](C(=O)OC)C1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](OC(=O)N2Cc3cccc(C=C)c3C2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
To a solution of (3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate hydrochloride (2.00 g, 5.67 mmol) and N-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine (1.54 g, 5.67 mmol) in DMF (100 mL) was added EDC (1.41 g, 7.37 mmol), HOBt (1.00 g, 7.37 mmol) and DIPEA (3.16 mL, 22.8 mmol). The reaction mixture was stirred at RT for 18 h and then diluted with ethyl acetate and aqueous NaHCO3. The layers were separated and the organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified on silica gel (gradient elution 5% to 50% ethyl acetate in hexanes) to give methyl N-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate (2.75 g, 85% yield) as a white foam. LRMS (ESI) m/z 570 [(M+H)+; calcd for C31H44N3O7: 570].
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:28])[O:22][C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:28])[O:22][C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)O[C@H]2CCOC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCNC1)O[C@H]1CCOC1
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
TFA (1 mL) was added to a solution of (S)-tetrahydrofuran-3-yl (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate (490 mg, 1.63 mmol) in 5 μL CH2Cl2. After stirring for 30 min, the reaction was quenched with NaOH and extracted twice with EtOAc. The organic extracts were combined, dried over MgSO4, filtered, and concentrated to yield (S)-tetrahydrofuran-3-yl (R)-pyrrolidin-3-ylcarbamate (230 mg) which was used without further purification. LC/MS: m/z 201.3 (M+H)+ at 0.59 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:12]=[C:11]([NH2:13])[S:10][N:9]=1)[C:5]([OH:7])=O.P(Cl)(Cl)(Cl)=O.[NH2:19][CH:20]1[C:31](=[O:32])[N:22]2[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]([CH3:27])[S:26][C@H:21]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:12]=[C:11]([NH2:13])[S:10][N:9]=1)[C:5]([NH:19][CH:20]1[C:31](=[O:32])[N:22]2[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]([CH3:27])[S:26][C@H:21]12)=[O:7]
Reactant: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Reactant: CON=C(C(=O)O)c1nsc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A mixture of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (1.21 g) and phosphorus oxychloride (3.67 g) in methylene chloride (30 ml) was stirred for two hours at ambient temperature, cooled to 0° C. and thereto was added N,N-dimethylformamide (2.4 ml), followed by stirring for an additional 45 minutes at 0° C. A mixture of 7-amino-2-methyl-3-cephem-4-carboxylic acid (3.0 g) and trimethylsilylacetamide (10 g) in methylene chloride (50 ml) was warmed to make a clear solution. The solution was cooled to -15° C. and added to the above obtained solution, followed by stirring for 30 minutes at 0° C. The reaction mixture was poured into a cold aqueous solution of sodium bicarbonate. The aqueous layer was separated and thereto was added ethyl acetate. The resulting mixture was adjusted to pH 2 with 10% hydrochloric acid and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and then evaporated. The residue was triturated with diethyl ether to give a crude product of the title compound (2.2 g). The crude material was dissolved in an aqueous solution of sodium bicarbonate, adjusted to pH 2 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with ice-water and dried to give the title compound (1.6 g), mp. 175° to 180° C. (dec.).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][N:16]4[C:19]([C:22]5[CH:42]=[CH:41][C:25]([CH2:26][NH:27][C:28]([NH:30][C:31]6[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=6)=[O:29])=[CH:24][CH:23]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)CCOC[CH2:2]1.C([O-])([O-])=O.[K+].[K+].N1CCNCC1>CS(C)=O>[CH3:2][NH:1][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]4[CH:23]=[CH:24][C:25]([CH2:26][NH:27][C:28]([NH:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=5)=[O:29])=[CH:41][CH:42]=4)=[CH:20][N:21]=[C:15]3[CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=C(NCc1ccc(-c2cnc3cc(-c4ccc(N5CCOCC5)nc4)ccn23)cc1)Nc1cccc(C(F)(F)F)c1
Agent: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNc1ccc(-c2ccn3c(-c4ccc(CNC(=O)Nc5cccc(C(F)(F)F)c5)cc4)cnc3c2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Dissolve 1-{4-[7-(6-Morpholin-4-yl-pyridin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-benzyl}-3-(3-trifluoromethyl-phenyl)-urea (0.220 g, 0.435 mmol, 1.0 eq.) in DMSO (2 mL). Add K2CO3 (0.120 g, 0.870 mmol, 2.0 eq.). Add piperazine (0.150 g, 1.74 mmol, 4.0 eq.). Stir the reaction mixture at 80° C. overnight under nitrogen. Pour the reaction mixture into 40 mL of ice and filter. Purify the yellow solid by silica gel chromatography using a 0-5% MeOH/DCM gradient to give the title compound 0.170 g (0.33 mmol, 76%) as a slightly yellow solid: MS(ES), m/z 518 (M+1).
Reaction SMILES: [CH3:1][C:2]([OH:12])([CH2:4][CH2:5][C:6]1([CH3:11])OCC[O:7]1)[CH3:3].Cl.[OH-].[Na+]>CC(C)=O>[OH:12][C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][C:6](=[O:7])[CH3:11]
Reactant: CC(C)(O)CCC1(C)OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)CCC(C)(C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
The obtained 2-methyl-4-(2-methyl[1,3]dioxolan-2-yl)butan-2-ol (21.18 g) was dissolved in acetone (165 ml). Thereafter, 1 M hydrochloric acid (6.6 ml) was added to the solution, and the obtained mixture was stirred at a room temperature for 2 hours. The reaction solution was neutralized with an aqueous 1 M sodium hydroxide solution. Thereafter, a saturated saline solution (100 ml) was added thereto, and acetone was then distilled off under a reduced pressure. After extraction with chloroform (200 ml×4), the organic layer was dried over anhydrous sodium sulfate. The solvent was then eliminated under a reduced pressure to obtain 5-hydroxy-5-methylhexan-2-one (14.23 g).
Reaction SMILES: [CH2:1]([C:8]1([OH:32])[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][Si](C(C)(C)C)(C)C)=[CH:20][CH:19]=2)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[ClH:41]>C1COCC1.CO.O>[ClH:41].[CH2:1]([C:8]1([OH:32])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CN2CCC(O)(Cc3ccccc3)CC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Oc1ccc(NCCN2CCC(O)(Cc3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 5.3 %

Procedure:
A solution of 2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-N-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl)-acetamide (0.97 g, 2.13 mmol) in THF (5 ml) was added dropwise to a room temperature suspension of LiAlH4 (0.162 g, 4.26 mmol) in THF (5 ml). After 20 hours at room temperature, the reaction mixture was refluxed during 3 hours. The reaction mixture was cooled to 0° C., and treated successively with H2O (0.2 ml), 5N NaOH (0.2 ml) and H2O (0.6 ml). After evaporation of THF, the resulting solid was filtered and washed with CH2Cl2. The aqueous phase was extracted with CH2Cl2 (3×10 ml), the combined organic phases were dried over Na2SO4 and concentrated. The residue was dissolved with CH2Cl2 (5ml) and stirred in the presence of tetra-n-butylammonium fluoride/SiO2 (0.5 g, 0.55 mmol, 1.1 mmol/g). After 4 hours at room temperature, the reaction mixture was quenched with 20% NH4Cl (15 ml) and the aqueous phase was extracted with CH2Cl2 (2×5ml). Combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (CH2Cl2 --MeOH 9:1 then 4:1) to give a foam which was dissolved in MeOH and treated with 1N HCl (0.6 ml). The solution was concentrated and the residue was dissolved with ethanol (EtOH). Addition of ether provided 4-Benzyl-1-[2-(4-hydroxy-phenylamino)-ethyl]-piperidin-4-ol hydrochloride (0.045 g, 5.3%) as beige solid, m.p. 130°-140° C. and MS: m/e=327.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]3[C:10]=2[C:5]([C:6](=[O:19])[CH2:7][CH2:8]3)=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Na+]>C(O)C>[OH:19][CH:6]1[C:5]2[C:10]3=[C:11]([CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]3[CH2:8][CH2:7]1)[C:2]([CH3:1])=[CH:3][CH:4]=2
Reactant: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Ethyl 5,6-dihydro-9-methyl-6-oxo-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate (3.00 g, 11.7 mmol) was added to a mixture of tetrahydrofuran (20 ml) and ethanol (80 ml), and the reaction mixture was cooled to 0° C. Then, sodium borohydride (0.44 g, 11.7 mmol) was added and the resulting mixture was stirred at 0° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and then a 5% aqueous sodium hydroxide solution were added to the residue. After being separated, the aqueous layer was further extracted twice with ethyl acetate, and the combined organic layer was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to obtain 2.40 g of ethyl 5,6-dihydro-6-hydroxy-9-methyl-4H-pyrrolo-[3,2,1-ij]-quinoline-2-carboxylate.
Reaction SMILES: C[CH:2]([CH2:16][CH:17]=[CH2:18])[C:3]([CH2:12][CH2:13]CC)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5]>ClCCl>[C:6]1([C:3]2([C:4]#[N:5])[CH2:2][CH2:16][CH:17]=[CH:18][CH2:13][CH2:12]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C=CCC(C)C(C#N)(CCCC)c1ccccc1
Solvent: ClCCl
Product: N#CC1(c2ccccc2)CCC=CCC1

Procedure:
To a solution of methyl 2-butyl-2-phenylhex-5-enenitrile (733 mg, step A) in dichloromethane (65 mL) was added benzylidene-bis(tricyclhexylphosphine) dichlororuthenium (134 mg) and the resulting suspension was heated under reflux for 1 h. The solvent was removed in vacuo to give the title compound. The crude product was used for the reduction to the aldehyde without purification. 1H NMR (400 MHz, CDCl3) δ 1.93 (2H, t, J=12.4 Hz), 2.11 (2H, m), 2.30 (2H, m), 2.57 (2H, t, J=12.0 Hz), 5.91 (2H, m), 7.38 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH:14]1([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][NH:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:22][CH2:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]3[CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1ccc2c(c1)CCNC2C1CCCCC1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2ccccc2C1C1CCCCC1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Cyclohexyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2cnc3[nH]ccc3c2N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
tert-Butyl 4-(5-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazine-1-carboxylate (0.111 g, 0.272 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 2 hours. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give 5-(3-methoxyphenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyri dine (0.083 g, 99% yield) as the dihydrochloride salt.