Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[CH:19]1([NH:22][C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[C:26]([CH3:36])[CH:25]=2)[CH2:21][CH2:20]1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH:19]1([NH:22][C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][N:33]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][C@H:8]6[C:7](=[O:16])[NH:6][C:5]=5[CH:4]=4)[CH2:34][CH2:35]3)=[C:26]([CH3:36])[CH:25]=2)[CH2:21][CH2:20]1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: Cc1cc(C(=O)NC2CC2)ccc1N1CCNCC1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CC2)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCN32)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a suspension of (S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (0.1 g, 0.456 mmol), N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (0.179 g, 0.538 mmol), and (cyanomethyl)trimethylphosphonium iodide (0.188 g, 0.775 mmol) in Propiononitrile (Volume: 2.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.556 mL, 3.19 mmol) at 23° C. The reaction was stirred at 90° C. for 8 hr. The reaction mixture was cooled to room temperature, filtered, and rinsed with propiononitrile (3×1 mL). The resulting solid was reconstituted in DMSO (Volume: 3.0 mL) and purified via preparative mass trigger LCMS using a gradient eluant of 25-65% ACN:10 mM NH4HCO3 (aq). The collected fractions were combined and the ACN was removed via rotary evaporation to furnish a suspension. The suspension was filtered, rinsed with H2O (3×10 mL), and the resulting solid was dried in vacuo to provide (S)—N-cyclopropyl-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (0.0624 g, 0.135 mmol, 29.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.59 (m, 2H) 0.60-0.70 (m, 2H) 1.86-2.00 (m, 3H) 2.14-2.20 (m, 1H) 2.25 (s, 3H) 2.47-2.50 (m, 4H) 2.76-2.93 (m, 5H) 3.34-3.44 (m, 3H) 3.55-3.63 (m, 1H) 3.93-4.02 (m, 1H) 6.96-7.04 (m, 2H) 7.56-7.67 (m, 3H) 8.22 (d, J=4.29 Hz, 1H) 10.45 (s, 1H). ESI-MS: m/z 461.4 (M+H)+. mp=226.7-233.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:25])[CH3:26])=[CH:19][CH:18]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 76.2 %

Procedure:
Following general procedure M, 1-(6-bromo-4-((4-((dimethylamino)methyl)phenyl)amino)quinolin-3-yl)propan-1-one (125 mg, 0.30 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (96 mg, 0.33 mmol) to afford the desired product (113 mg, 76%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.01 (s, 1H), 8.09-7.88 (m, 3H), 7.36 (s, 2H), 7.33-7.28 (m, 2H), 7.17-7.08 (m, 2H), 3.47 (s, 2H), 3.08 (q, J=7.1 Hz, 2H), 2.16 (s, 6H), 0.98 (t, J=7.1 Hz, 3H).
Reaction SMILES: CON(C)[C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1.[CH3:32][Mg]Br.[NH4+].[Cl-]>C1COCC1>[CH3:29][N:15]([C@H:12]1[CH2:11][CH2:10][C@H:9]([O:8][CH2:7][CH2:6][CH2:5][C:4](=[O:30])[CH3:32])[CH2:14][CH2:13]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)CCCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)CCCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 260 mg (0.56 mmol) trans-N-Methoxy-N-methyl-4-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyramide in 10 ml THF were added 0.56 ml 3M (1.67 mmol, 3 eq) methylmagnesiumbromide in THF at −78° C. The solution was slowly warmed to RT over night, a saturated aqueous solution of NH4Cl was added and the mixture stirred for 30 min. The phases were separated and the inorganic phase was extracted with EtOAc. The combined organic ones were dried over Na2SO4 and evaporated. Column chromatography on silica gel with EtOAc/hexane 1:1 yielded 143 mg (61%) trans-N-Methyl-N-[4-(4-oxo-pentyloxy)-cyclohexyl]-4-trifluoromethyl-benzenesulfonamide as white solid, MS: 422 (MH+).
Reaction SMILES: CON(C)[C:4](=[O:19])[CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]1[CH:27]=[C:26](I)[C:25]([CH3:29])=[CH:24][N:23]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:4](=[O:19])[CH2:5][CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:25]([CH3:29])=[CH:24][N:23]=1
Reactant: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Reactant: Cc1cnc(F)cc1I
Product: Cc1cnc(F)cc1C(=O)CC(c1ccccc1)c1ccccc1

Procedure:
In analogy to example 55, step 2, the title compound was prepared from N-methoxy-N-methyl-3,3-diphenyl-propionamide and 2-fluoro-4-iodo-5-picoline (CAS RN: [153034-94-7]) as a yellow liquid, MS (ESI+): m/z=320.1 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:16]([C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:6][CH:5]=1.O.[OH-].[Na+].Cl>CO>[CH3:30][C:29]1[C:24]([CH:12]2[CH2:13][CH2:14][CH2:15][CH:16]([C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)[N:11]2[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 108.5 %

Procedure:
To a solution of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (0.420 g, 1.01 mmol) in MeOH (5 mL) was added water (5 mL) and solid NaOH (0.448 g, 11.21 mmol). The resultant mixture was heated to reflux overnight then cooled to room temperature. The mixture was adjusted to pH ˜5 with 6 N HCl (˜2 mL) and extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated and provided 0.440 g (quantitative yield) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid as a white solid. 1H NMR (CDCl3) δ 1.80-2.05 (m, 6H), 2.42 (s, 6H), 3.83 (br s, 2H), 4.55 (br s, 2H) 6.79 (d, 2H, J=8.1 Hz), 7.02 (dd, 2H, J=7.5, 5.1 Hz), 7.34 (d, 2H, J=7.5 Hz), 7.65 (d, 2H, J=7.8 Hz), 8.42 (d, 2H, J=3.9 Hz); ES-MS m/z 402 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35].C(OCC)C>C(OCC)(=O)C>[ClH:35].[ClH:35].[CH:32]([N:29]1[CH2:28][CH2:27][CH:26]([O:25][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[CH:24]3)[CH2:31][CH2:30]1)([CH3:34])[CH3:33]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (800 mg, 1.7 mmol) in ethyl acetate (25 ml) was treated with hydrogen chloride (5M in ethyl acetate, 12 ml) and the mixture stirred 72 h at room temperature. The resulting suspension was cooled to 0° C. (ice-bath), diethyl ether (2 ml) added and the mixture stirred 1 h. The precipitate was filtered and dried under vacuum to afford the title compound as an off-white solid. MS (m/z): 371.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:24][OH:25])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([NH:21][CH:22]=[O:23])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:24][O:25][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([NH:21][CH:22]=[O:23])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(NC=O)cc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(COc1noc2ccc(NC=O)cc12)COC1CCCCO1

Procedure:
To a suspension of 0.45 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-formylamino-1,2-benzoisoxazole in 9 ml of methylene chloride are added 0.14 g of 3,4-dihydro-2H-pyran and 0.06 g of pyridinium p-toluenesulfonate at 20°-25° C., and they are subjected to reaction at 40° C. for one hour. Water is added to the reaction mixture and the pH is adjusted to 9 with a saturated aqueous sodium hydrogencarbonate solution, after which the organic layer is separated. The separated organic layer is dried over anhydrous magnesium sulfate, and the solvent is then removed by distillation under reduced pressure, to obtain oily 3-[2-tert-butoxycarbonylamino-3-(2,3,4,5-tetrahydropyranyloxy)propoxy]-5-formylamino-1,2-benzoisoxazole.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([NH2:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.CCN(C(C)C)C(C)C.[Br:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>>[Br:28][C:29]1[CH:30]=[C:31]([NH:32][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][C:16]([NH2:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: Nc1cccc(Br)c1
Reactant: NC(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Cc1cccc(Nc2ncnc(Nc3cccc(Br)c3)n2)c1
Temperature: 110 °C

Procedure:
To a mixture of 2-[3-(4-chloro-[1,3,5]triazin-2-ylamino)-phenyl]acetamide (36.6 mg, 0.1388 mmol) in IpOH (1 ml) were added DIEA (27 μl, 0.1527 mmol) and 3-bromoaniline (26.3 mg, 0.1527 mmol). The mix was heated at 100-120° C. for 18 h. The solution was cooled to RT and sonicated. The precipitate was filtered and dried under reduced pressure, giving 2-{3-[4-(3-bromophenylamino)-[1,3,5]triazin-2-ylamino]-phenyl}acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])O)=[O:5])[CH3:2].[Cl:25][C:26]1[C:27]([F:33])=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[C:26]([Cl:25])[C:27]=1[F:33])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])=[O:5])[CH3:2]
Reactant: Nc1cccc(Cl)c1F
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1C
Solvent: O
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cccc(Cl)c1F)c1ccc(Cl)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate C and 3-chloro-2-fluoroaniline. The reaction was stirred at rt for 1.5 h. The reaction mixture was diluted with H2O and extracted. The organic layers were washed with a saturated aqueous NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography (hexane/EtOAc, 90:1→65:35). The residue was then triturated in CH2Cl2 to give the title compound as white foam. tR: 1.45 min (LC-MS 2); ESI-MS: 542.0/544.0/546.0 [M+H]+ (LC-MS 2).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>CC(C)=O.O>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:25])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (28.7 g) in acetone (400 ml) and water (200 ml) is added potassium carbonate (38.8 g), and thereto is added p-nitrobenzoyl chloride (40 g) under ice-cooling and the mixture is stirred at room temperature overnight. To the reaction mixture is added a suitable amount of water. The precipitated crystal is collected by filtration and dried to give 1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline (40.8 g) as white powder, m.p. 86-88° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C:10](=[O:25])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[CH:19][N:20](C)C)=[C:14]([C:23]#[N:24])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].N[C:28]1[CH:42]=[CH:41][C:31]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:33])=[CH:30][CH:29]=1>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C:10](=[O:25])[NH:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][CH:17]=1)[N:18]=[CH:19][N:20]=[C:23]2[NH:24][C:28]1[CH:29]=[CH:30][C:31]([C:32](=[O:33])[NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:41][CH:42]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(C(=O)Nc2ccccc2)cc1
Reactant: CN(C)C=Nc1ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(C(=O)Nc4ccccc4)cc3)c2c1
Yield: 23.9 %

Procedure:
1 g of 2-[3-cyano-4-(dimethylamino-methylene amino)-phenylcarbamoyl]-ethyl-carbamic acid t-butylester (see, Journal of Medicinal Chemistry 2004, 44:2719) dissolved in 6 ml of acetic acid was reacted with 650 mg of 4-amino-N-phenyl-benzamide at 60° C. for 3 hours, and the resulting residue was stirred in 100 ml of saturated aqueous sodium bicarbonate solution at room temperature for 30 mins. The reacted solution was extracted with 30 ml of ethylacetate 3 times, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (350 mg, 25%).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[CH:8][C:7]2=[O:17])[CH2:3][CH2:2]1.N1C=CC=CC=1.S(OC)(O[C:28](SC)([S:31][CH3:32])[S:29][CH3:30])(=O)=O>O1CCOCC1>[CH3:30][S:29][C:28]([S:31][CH3:32])=[C:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([NH:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:7]1=[O:17]
Reactant: COS(=O)(=O)OC(SC)(SC)SC
Reactant: O=c1cc(O)c2ccccc2n1NCC1CC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CSC(SC)=C1C(=O)c2ccccc2N(NCC2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To the suspension of 1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (984.4 mg, 4.28 mmol) in 1,4-dioxane (40 mL) was added pyridine (2.8 mL, 34.6 mmol) and tris(methylthio)methyl methyl sulfate (prepared using the procedures in SYNTHESIS, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi) (2.26 g, 8.55 mmol) at room temperature. The suspension was put in a preheated oil bath at 55° C. and stirred for 15 minutes. To the solution was added another portion of tris(methylthio)methyl methyl sulfate (2.26 g, 8.55 mmol) and the mixture was stirred at 55° C. for 15 minutes and cooled to room temperature. The mixture was concentrated in vacuo and the residue was diluted with dichloromethane and loaded on a silica gel column and eluted with dichloromethane, 2% ethyl acetate/dichloromethane and then 5% ethyl acetate/dichloromethane to give 3-[bis(methylthio)methylene]-1-[(cyclopropylmethyl)amino] quinoline-2,4(1H,3H)-dione (852.1 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ 0.15 (m, 2 H) 0.42 (m, 2 H) 0.98 (m, 1 H) 2.61 (s, 6 H) 2.73 (t, J=6.43 Hz, 2 H) 6.05 (t, J=5.88 Hz, 1 H) 7.15 (m, 1 H) 7.64 (m, 1 H) 7.76 (d, J=8.09 Hz, 1 H) 7.98 (m, 1 H).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:5][C:4]([OH:13])=[C:3]([OH:14])[CH:2]=1.S(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[CH3:19][CH2:20][O:10][C:9]([C@@H:8]([NH2:12])[CH2:7][C:6]1[CH:1]=[CH:2][C:3]([OH:14])=[C:4]([OH:13])[CH:5]=1)=[O:11]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H](N)Cc1ccc(O)c(O)c1
Temperature: 5 °C

Procedure:
Levodopa (50 g.) was added in portions to a cooled (2-8° C.) solution of 30 ml. thionyl chloride in 250 ml. absolute ethanol. The resulting mixture was heated to 40° C. for 16 hours and then the volatiles were removed in vacuo. The residue was dissolved in 50 ml. of water and diluted with a solution of 20 g. of sodium bicarbonate, 26 g. of sodium sulfate and 50 mg. of ascorbic acid in 400 ml. of water. The pH of the resulting solution was carefully adjusted to pH 7 with 10% aqueous sodium hydroxide and it was extracted with deaerated free ethyl acetate containing 0.01% BHT.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[CH:34]=[CH:33][C:11]([O:12][C:13]2[C:27]([CH:28]3[CH2:32][CH2:31][CH2:30][NH:29]3)=[CH:26][C:16]3[NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[N:19][C:15]=3[CH:14]=2)=[CH:10][CH:9]=1>[Zn].C1C=CC=CC=1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[C:27]([CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:2]([O:4][CH2:5][CH3:6])=[O:3])=[CH:26][C:16]3[NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[N:19][C:15]=3[CH:14]=2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)Cl
Reactant: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.2 mg of zinc powder and 0.006 ml of ethyl chloroformate were added in order to a benzene (1 ml) solution of 20 mg of 5-(4-fluoro-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 168, and the reaction liquid was stirred overnight at room temperature. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][NH:4][C:5]([C:7]1[NH:16][C:10]2=[CH:11][N:12]=[C:13]([Cl:15])[CH:14]=[C:9]2[CH:8]=1)=[O:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.C([O-])(O)=O.[Na+].O>[O:1]=[C:2]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][NH:4][C:5]([C:7]1[NH:16][C:10]2=[CH:11][N:12]=[C:13]([Cl:15])[CH:14]=[C:9]2[CH:8]=1)=[O:6]
Reactant: O=C(NCC(O)c1cccnc1)c1cc2cc(Cl)ncc2[nH]1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: O
Product: O=C(CNC(=O)c1cc2cc(Cl)ncc2[nH]1)c1cccnc1
Reaction time: 0.5 h

Procedure:
To a solution of racemic 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide (EXAMPLE 261, 80 mg, 0.253 mmol) in dry THF (20 mL) was added Dess-Martin periodinane (307 mg, 0.724 mmol). After stirring for 4 h at rt alkaline sodium thiosulfate solution was added (5.4 g Na2SO3 dissolved in 20 mL saturated NaHCO3 solution) and the emulsion was vigorously stirred for additional 30 min before further diluted with water (˜150 mL). Extraction with THF (4×50 mL), washing of the combined extracts with saturated sodium hydrogen carbonate (50 mL) and brine (50 mL) gave a solution which was concentrated after drying (MgSO4). Purification of the residue by flash chromatography on silica gel (eluent: DCM/methanol: 90/10) gave the title compound as off-white solid. m/z (ES+)=315.19 [M+H]+; RT=2.65 min.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=O)[CH3:13].Cl.[NH2:27][OH:28].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:27][OH:28])[CH3:13]
Reactant: NO
Reactant: CC(=O)COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 509.8 %

Procedure:
To a mixture of 1.67 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone and 30 ml of pyridine was added 8.60 g of hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which afforded 8.81 g (yield, 99%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime, nD25.0 1.5460.
Reaction SMILES: O[CH:2]1[C:8]2=[N:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:21])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:21][CH:2]1[C:8]2=[N:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc2c(nc1C)C(O)CCCC2
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2c(nc1C)C(Cl)CCCC2
Temperature: 25 °C
Reaction time: 21 h
Yield: 79.8 %

Procedure:
Ethyl 9-hydroxy-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (3.92 g, 15.7mmol) was dissolved in chloroform (12.0 ml) to which was subsequently added dropwise thionyl chloride (4.4 ml) at −11° C. This was stirred at room temperature for 21 hours, and the reaction solution was poured into ice water, adjusted to pH 8 with 2 N sodium hydroxide aqueous solution and then extracted with chloroform. The thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:2) to obtain the title compound (3.35 g, 79.8%) as pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[C:28]=2[CH:39]=1>S(Cl)(Cl)=O>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][N:29]1[C:28]2[CH:39]=[C:24]([NH:23][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:3]4[CH:4]=[CH:5][C:6]([C:8]5[N:12]=[C:11]([CH3:13])[O:10][N:9]=5)=[CH:7][C:2]=4[CH3:1])=[CH:15][CH:16]=3)=[O:21])[CH:25]=[CH:26][C:27]=2[O:32][CH2:31][C:30]1=[O:33]
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: CN(C)CCN1C(=O)COc2ccc(N)cc21
Solvent: O=S(Cl)Cl
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc5c(c4)N(CCN(C)C)C(=O)CO5)cc3)c(C)c2)no1
Yield: 75.4 %

Procedure:
2'-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0553268A1) (0.188 g, 0.64 mmol) was converted to the acyl chloride by stirring at reflux under Ar in thionyl chloride (10 ml) for 45 min, cooling, and then evaporating to dryness. This was reacted with 6-amino-4(2-dimethylaminoethyl)-1,4-benzoxazin-3(4H)-one (D8) (0.150 g, 0.64 mmol) following the procedure of Example 1. This gave the title compound (0.247 g, 75%) as a white foam, which was converted to the oxalate, a white solid.