Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[C:5]([C:15]2[N:16]=[C:17]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]3=[N:19][CH:20]=2)=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:32](=[O:34])[CH3:33])[CH2:10]2)[C:5]([C:15]2[N:16]=[C:17]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:18]3=[N:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(NC2CCCNC2)n1
Product: CC(=O)N1CCCC(Nc2nc(C)ccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-(3-{6-Methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-piperidin-1-yl)-ethanone was prepared from {6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-piperidin-3-yl-amine and acetic anhydride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=1.[O:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[C:12]([C:19]([NH:29][CH2:28][CH:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)=[O:20])=[CH:11][N:10]=1
Reactant: O=C(O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Reactant: NCC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC1CCOCC1)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
To a mixture of rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (150 mg) and N,N-dimethyl formamide (3.0 mL) were added 1-(tetrahydro-2H-pyran-4-yl)methylamine (69 mg), 1-hydroxybenzotriazole (81 mg), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg) in this order at room temperature, and then the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate). The obtained colorless oily substance was solidified using ethanol-water to obtain rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-N-(tetrahydro-2H-pyran-4-ylmethyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (173 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.O=[C:14]1[CH2:18][S:17][CH2:16][CH:15]1[C:19](OC)=[O:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:20]=[C:19]1[N:3]2[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=[CH:12][C:2]2=[N:1][C:14]2[CH2:18][S:17][CH2:16][C:15]1=2
Reactant: COC(=O)C1CSCC1=O
Reactant: CCOC(=O)c1ccc(N)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)c1ccc2nc3c(c(=O)n2c1)CSC3

Procedure:
Ethyl 6-aminonicotinate (2.5 g., 0.015 mol), methyl 4-oxotetrahydrothiophene-3-carboxylate (6.2 g., 0.039 mol) and p-toluenesulfonic acid monohydrate (0.25 g) are thoroughly mixed and heated at 155°-160° C. under nitrogen for 90 minutes. The distillate is collected in a Dean-Stark trap. The residue is cooled, triturated with boiling ethanol and filtered. Recrystallization from methanol gives yellow crystals (1.2 g.), mp 183°-185° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N+:9]([O-])=O)[C:5]([Cl:12])=[C:4]([Cl:13])[N:3]=1.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C@H:27]([CH2:30]N)[C@H:26]([OH:32])[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1CCOCC1>C1COCC1>[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH:9][C:6]2[C:7]([Cl:8])=[C:2]([Cl:1])[N:3]=[C:4]([Cl:13])[C:5]=2[Cl:12])[CH:26]([OH:32])[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)nc(Cl)c1Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2c(Cl)c(Cl)nc(Cl)c2Cl)C(O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,3,5,6-tetrachloro-4-nitropyridine (S. M. Roberts et al., J. Chem. Soc. C, 2844–2848(1968)) (1.7 g, 6.5 mmol) was added to a solution of (cis)-4-aminomethyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (1.71 g, 6.49 mmol) and N-methylmorpholine (0.785 mL, 7.15 mmol) in THF (50 mL) at room temperature. The resulting reaction mixture was stirred for 18 h at room temperature then partitioned between EtOAc and water. The organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and the solvent evaporated to give crude product purified by flash column chromatography (20–80% EtOAc hexane) to give 3-hydroxy-4-[(2,3,5,6-tetrachloro-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester compound. M.S (M+1): 478.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1C[CH2:23][CH:22](I)[C:21]1([CH3:27])[CH3:26].C[OH:29]>[C].[Pd]>[CH3:26][C:21]1([CH3:27])[CH2:22][CH2:23][O:29][CH:20]1[C:11]1[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CO
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2CCC(I)C2(C)C)c1
Agent: [Pd]
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2OCCC2(C)C)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 66.60E (0.388 g, 0.801 mmol) in MeOH (17 mL) (degassed by N2), was added palladium-carbon (0.0853 g, 0.801 mmol). The resulting mixture was stirred at room temperature under H2 for 23 hours. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:19 EtOAc/hexane) and gave 65 mg of 69.43A. MS ESI (pos.) m/e: 376 (M+18)+.
Reaction SMILES: CC1SC(C([O-])=S)=CC=1.[NH2:10][C:11](=[S:22])[C:12]1[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=1[CH3:17].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=O>CC(C)=O>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]1[N:10]=[C:11]([C:12]2[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=2[CH3:17])[S:22][CH:24]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Agent: Cc1ccc(C([O-])=S)s1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccccc3OC)cs2)c(C)s1
Yield: 104.4 %

Procedure:
Methyl 4-4-(2-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: 105 mg (0.424 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-2′-methoxy acetophenone (0.467 mmol; 110 mg) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and the solution concentrated. The crude product was dissolved in 100 mL of CH2Cl2 and washed one time with 50 mL of 1N NaOH. The organic layer was obtained, dried over sodium sulfate, concentrated and purified on a 1 mm silica plate eluting with 20% ethyl acetate/hexane to afford 160 mg (95% yield) of methyl 4-[4-(2-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.S([O-])([O-])(=O)=O.O[NH3+:24].O[NH3+]>>[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:24])=[CH:12][CH:11]=1
Reactant: [NH3+]O
Reactant: CSc1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CSc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
With stirring (20 rpm), a turbine dryer is charged at room temperature with 4000 parts by weight of anhydrous sodium sulfate, 950 parts by weight of 4-(methylthio)benzaldehyde and 538.4 parts by weight of hydroxylammonium sulfate. Following evacuation to 25 mbar, the mixture is heated to 80° C. and stirred at this temperature for 3 hours. It is subsequently heated at 130° C. and held for 30 minutes at the same pressure. A total of about 240 parts by weight of water are removed by distillation altogether. The distillation of the nitrile is initiated and controlled by reduction of the pressure to 5 mbar and subsequent raising of the jacket temperature to 150° C. 708 parts by weight of 4-(methylthio)benzonitrile are obtained with a purity of over 98% (TLC), and also 18 parts by weight of a mixed fraction essentially consisting of 4-(methylthio)benzonitrile and 4-(methylthio)benzaldehyde. The collected 4-(methylthio)benzonitrile has a melting point of 61°-63° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15]1>>[N:14]1([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15][CH:16]=[CH:17][CH2:18][CH2:19]1
Reactant: C1=CCNCC1
Reactant: N#Cc1ccc(F)c2ccccc12
Product: N#Cc1ccc(N2CC=CCC2)c2ccccc12
Yield: 25.5 %

Procedure:
The title compound (7 mg, 26% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 1,2,3,6-tetrahydropyridine (39 mg, 0.468 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:26](Br)[CH:27]=[CH2:28].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:28]([C@H:10]1[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:12]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:11]1=[O:25])[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one (1481 mg, 3957 μmol; Example 35, Step A) and allyl bromide (360 μl, 4155 μmol) in THF (16 mL, 0.25 M) was added dropwise lithium bis(trimethylsilyl)amide (1M solution in THF, 4352 μl, 4352 μmol) at −78° C. After being stirred at −78° C. for 3 h, the reaction was quenched (sat. aqueous NH4Cl), extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 20 to 30% EtOAc/Hex, gradient elution) provided the title compound as a mixture of stereoisomers.
Reaction SMILES: C([Li])CCC.CCCCCC.[Br:12][C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][C:19](Br)=[CH:20][CH:21]=3)[C:16]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:15]=2[CH:14]=1.Cl[Si:44]([CH3:47])([CH3:46])[CH3:45]>C1COCC1>[Br:12][C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][C:19]([Si:44]([CH3:47])([CH3:46])[CH3:45])=[CH:20][CH:21]=3)[C:16]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:15]=2[CH:14]=1
Reactant: C[Si](C)(C)Cl
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc([Si](C)(C)C)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium in hexane (6.0 mL, 1.6 M, 9.6 mmol) was added to a solution of 2,7-dibromo-9,9-di-n-octylfluorene (7) (5.00 g, 9.13 mmol) in dry THF (50 mL) in a schlenk flask at −78° C. and the mixture was stirred for 20 minutes. Then chlorotrimethylsilane (1.5 mL, 1.29 g, 1.3 equiv) was added and the reaction was allowed to slowly warm to room temperature. The mixture was stirred overnight and the reaction was quenched with saturated brine. The product was extracted into diethyl ether, and the extract was washed with brine and dried over MgSO4. The crude product was chromatographed on silica using hexane as eluent to give 2-bromo-7-trimethylsilyl-9,9-di-n-octylfluorene as a colourless oil, (3.50 g, 71%). n-Butyllithium in hexane (4.4 mL, 1.6 M, mmol) was added to a solution of 2-bromo-7-trimethylsilyl-9,9-di-n-octylfluorene (3.47 g, 6.41 mmol) in dry THF (75 mL) in a schlenk flask at −78° C., and the mixture was stirred for 20 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.44 mL, 1.31 g, 7.04 mmol) was added and the reaction was stirred for 24 h after warming to room temperature. The reaction was then quenched with brine, and the product was extracted into diethyl ether. The extract was washed with brine and dried over MgSO4. The crude product was chromatographed on silica using 0–3% ethylacetate in hexane as eluent, to give 8 as a colourless solid (2.67 g, 71%). 1H NMR (CD2Cl2): δ 7.73 (m, 4H) 7.51 (m, 2H) 1.99 (t, 4H, J=8.2 Hz) 1.36–0.54 (m, 42H) 0.31 (s, 9H)ppm. 13C NMR: δ 151.60, 151.34, 149.76, 145.29, 142.69, 141.07, 134.71, 133.01, 130.08, 129.03, 120.50, 120.25, 84.93, 56.22, 41.26, 33.01, 32.84, 31.11, 30.37, 25.98, 24.95, 23.85, 15.08, 0.01. FDMS m/z 588.90.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F:16][C:17]1[CH:31]=[C:30]2[C:20]([NH:21][CH:22]=[C:23]2[CH2:24][CH:25]([C:27]([OH:29])=[O:28])[NH2:26])=[CH:19][CH:18]=1>>[C:27]([CH:25]([NH:26][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:24][C:23]1[C:30]2[C:20](=[CH:19][CH:18]=[C:17]([F:16])[CH:31]=2)[NH:21][CH:22]=1)([OH:29])=[O:28]
Reactant: NC(Cc1c[nH]c2ccc(F)cc12)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1c[nH]c2ccc(F)cc12)C(=O)O
Yield: 90 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 5-fluoro-DL-tryptophan to provide the title compound in 90% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=O)=[N:12][CH:13]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:12][CH:13]=1
Reactant: O=C(c1ccc(Br)cn1)N1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCCCC2)nc1
Temperature: 25 °C

Procedure:
Lithium aluminium hydride in 1M THF (1.858 mL, 1.858 mmol) was cooled to 0° C. 5-bromo-2-(1-piperidinylcarbonyl)pyridine (for a preparation see Intermediate 25) (250 mg, 0.929 mmol) was dissolved in THF (7 mL) and added dropwise to the LiAlH4 under nitrogen and stirred. After addition to the reductant, the solution was warmed to room temperature. After 1 hour the reactions were filtered, washed with EtOAc (3×10 mL) and evaporated to dryness to give a brown/yellow solid (159 mg). This was purified on a 25+S Biotage silica column, eluting with DCM:2M MeOH/NH3 (1:0 to 97:3). Product-containing fractions were evaporated to dryness to give a dark yellow solid (61 mg).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][C:6]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]2[CH:23]=[N:24][C:25]3N[CH2:27][CH2:28][CH2:29][C:30]=3[CH:31]=2)[CH:21]=1)([CH3:15])[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8]>>[CH3:5][C:6]([C:16]1[CH:21]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25](=[N:24][CH:23]=2)[N:1]([C:2]([NH2:4])=[O:3])[CH2:27][CH2:28][CH2:29]3)[CH:19]=[N:18][CH:17]=1)([CH3:15])[C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8]
Reactant: CC(C)(C(=O)N1CCOCC1)c1cncc(-c2cnc3c(c2)CCCN3)c1
Reactant: NC(N)=O
Product: CC(C)(C(=O)N1CCOCC1)c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1

Procedure:
The titled product is synthesized according to the procedure of Urea Formation Method II using 2-methyl-1-morpholin-4-yl-2-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-propan-1-one.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=2[O:2]1.[I:12]I>C(Cl)(Cl)Cl>[I:12][C:8]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[O:2][CH2:1][O:11][C:10]=2[CH:9]=1
Reactant: II
Reactant: OCc1ccc2c(c1)OCO2
Solvent: ClC(Cl)Cl
Product: OCc1cc2c(cc1I)OCO2
Temperature: -5 °C
Yield: 53.9 %

Procedure:
To a solution of 3,4-(methylenedioxy)benzyl alcohol (1.8 g, 12 mmol) and CF3COOAg (3.434 g, 15.5 mmol) in dry CHCl3 (55 mL) at −5° C. was added I2 (3.9 g, 15.5 mmol) in portion. The resulting yellow mixture was maintain at −5° C. for 5 min, then filtered. The filtrate was washed with 20% Na2S2O3, dried and evaporated. The crude was purified by column chromatography on silica gel (petroleum ether) to obtain (6-iodobenzo[d][1,3]dioxol-5-yl)methanol (1.8 g, 56%) as a white solid. LCMS: 279[M+1]+; 1H NMR (DMSO-d6) δ 4.31 (d, 2H, J=4.2 Hz), 5.40 (t, 1H, J=4.2 Hz), 6.03 (s, 2H), 7.03 (s, 1H), 7.34 (s, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[OH-].[Na+].[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl)([O-:13])=[O:12]>ClCCl.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([O:1][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)[CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CN1CCC(O)CC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN1CCC(OCc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Hydroxy-1-methylpiperidine (11.5 g, 0.1 mol) is dissolved in 250 mL dichloromethane. A solution of 100 g NaOH in 100 mL of water is added followed by 17.2 g (0.1 mol) 3-nitro-benzylchloride and a catalytic amount of benzyl-triethylammonium chloride. The mixture is stirred very efficiently during 2 h at rt and then poured into 300 mL of ice-cold water. The organic layer is separated and the organic phase extracted once more with dichloromethane. The organic phase is extracted with 1N HCl (2×200 mL) and the aqueous extracts adjusted to pH 9-10 by the addition of solid sodium carbonate. The basic solution is extracted with ethyl acetate (2×200 mL) and the organic phase washed with brine, dried over potassium carbonate and evaporated. 1-Methyl-4-(3-nitro-benzyloxy)-piperidine is obtained as brown viscous oil. HPLC: 1.35 (System XS); [M+H]+ 251.0.
Reaction SMILES: [NH2:1]CC(O)=O.[CH2:6]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][CH:13]=1)[CH3:7].N([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[CH3:19][O:18][C:16](=[O:17])[CH2:15][N:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:6][CH3:7])[CH:9]=1)[NH2:1]
Reactant: NCC(=O)O
Reactant: CCc1cccc(NCC(=O)OC)c1
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cccc(N(N)CC(=O)OC)c1
Reaction time: 2 h
Yield: 14 %

Procedure:
To the glycine (Intermediate 38; 35 g; 0.181 mol) in acetic acid (50 ml) at -5° C. was added, dropwise, a solution of sodium nitrite (13.75 g; 0.199 mol) in H2O (10 ml). The temperature of the reaction mixture was not allowed to rise above 0°. After stirring for a further 2 h, zinc dust (26.02 g, 0.398 mol) was added portionwise, once again so as not to allow the temperature of the reaction mixture to rise above 0°. After 5 h, a further quantity of zinc dust (13.01 g, 0.199 mol) was added and the mixture was stirred overnight. The excess zinc dust was removed by filtration through celite. The reaction mixture was then quenched with sodium bicarbonate solution. Extraction into ethyl acetate followed by washing with water, brine and finally drying (over Na2SO4) gave the crude title compound (ca. 35 g). This crude material was chromatographed using Ethyl acetate: Petroleum ether (1:3) to yield Intermediate 39 (5.21 g; 14%) as an oil.
Reaction SMILES: C([N:9]1[C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13][N:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1>N>[C:24]1([N:12]2[CH2:13][CH2:14][N:15]3[C:16](=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=43)[NH:9][CH2:10][CH2:11]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(c1ccccc1)N1CCN(c2ccccc2)CCn2c1nc1ccccc12
Agent: N
Product: c1ccc(N2CCNc3nc4ccccc4n3CC2)cc1

Procedure:
A mixture of 1-benzoyl-1,2,3,4,5,6-hexahydro-4-phenyl[1,3,6]-triazocino[1,2-a]benzimidazole (10.00 g) from Example 2 and methanolic ammonia (1150 ml), presaturated at 0°, was stirred magnetically and heated in a sealed bomb at 100° for 4 days. The resulting cooled solution was filtered and the filtrate was evaporated to a syrup which crystallized. The residue was dissolved in dichloromethane-methanol and the solution was evaporated to a syrup. Crystallization from methanol gave crude titled product; wt. 5.24 g (72%), mp=158°-159°. The mother liquor was evaporated to a crystalline residue which was subjected to an oil pump vacuum. A solution of the residue in a minimum volume of warm dichloromethane was applied to a column (56×3.2 cm) of dry column grade neutral alumina prepacked in toluene. Elution was with toluene (400 ml), toluene-dichloromethane (4:1, 500 ml) followed by dichloromethane. The product was eluted with dichloromethane. The fractionation was monitored by t.l.c. on Alox-25 uv254 plates with dichloromethane-methanol (19:1) as developer. Fractions which contained only product were evaporated to a syrup which crystallized. Recrystallization with decolorization from methanol gave product; wt. 0.93 g (13%), mp=158°-160°. This material, combined with material obtained above, was recrystallized with decolorization from methanol to give pure titled product; wt. 5.46 g, mp=159°-160°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:23][CH:22]=1>CN(C)C=O>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:26][CH:25]=1
Reactant: Clc1ccc(-c2ccc(CBr)cc2)c(Cl)c1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4ccc(Cl)cc4Cl)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4′-bromomethyl-2,4-dichlorobiphenyl in N,N-dimethylformamide. Column chromatography provided an off-white solid. 1H NMR: δ 8.01 (v br s, 1H), 7.93 (dm, J=9.0 Hz, 2H), 7.47 (d, J=2.0 Hz, 1H), 7.22-7.35 (m, 6H), 7.07 (dm, J=9.0 Hz, 2H), 3.98 (a of ab, J=13.7 Hz, 1H), 3.93 (s, 3H), 3.40 (b of ab, J=13.7 Hz, 1H). MS (m/e): 519.9 (M−H)−. Anal: Calc for C23H17Cl2NO5S2.0.75 C4H10O: 54.03% C, 4.27% H, 2.42% N; Found: 53.63% C, 4.33% H, 2.23% N. MP: 104-107° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>ClCCl>[C:10]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=1[Br:1])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(O)c1Br
Solvent: ClCCl
Product: CC(=O)Oc1cccc(O)c1Br

Procedure:
To a solution of 2-bromo-1,3-benzenediol (3.028 g, 16.02 mmol) in dichloromethane (70 ml), TEA (3.35 ml, 24.03 mmol) and acetic anhydride (1.512 ml, 16.02 mmol) were added under stirring. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with a saturated solution of ammonium chloride (100 ml), and extracted with ethyl acetate (3 times 70 ml). The combined organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound as a black oil which was used directly used in the next step. (3.028 g)