Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.Cl.[O:15]([NH2:17])[CH3:16]>>[CH3:16][O:15][N:17]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11]
Reactant: CON
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: Cl
Product: CON=Cc1ccc(F)cc1C(F)(F)F
Yield: 93 %

Procedure:
Reaction of 4-fluoro-2-trifluoromethyl-benzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (93% yield). 1HNMR indicated a 92:8 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 4.00 (3H, s, OCH3), 7.25 (1H, m, aromatic), 7.37 (1H, m, aromatic), 8.08 (1H, m, aromatic), 8.36 (1H, broad s, CH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([CH2:11][NH2:12])[OH:10]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH2:11][CH2:9][OH:10])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NCCO
Product: OCCNc1ccnc(Cl)n1
Yield: 16 %

Procedure:
Prepared in analogy to example 98a), using 2,4-dichloro-pyrimidine and ethanolamine. The title compound was isolated as a colorless solid in a yield of 16%. MS ISP (m/e): 174.3 & 172.1 (100 & 40) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=7.90 (s broad, 1H), 7.84 (d, 1H), 6.48 (d, 1H), 4.77 (t, 1H), 3.52 (qa, 2H), 3.26 (qa broad, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23].Cl>CC(C)=O.CCOCC>[ClH:1].[Cl:9][C:6]1[CH:5]=[C:4]([N:10]2[CH2:11][CH2:12][N:13]([CH2:22][CH3:23])[CH2:14][CH2:15]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: Clc1cc(N2CCNCC2)cc(Cl)c1Cl
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCN1CCN(c2cc(Cl)c(Cl)c(Cl)c2)CC1
Yield: 128.7 %

Procedure:
To a stirred mixture of 1-(3,4,5-trichlorophenyl)piperazine (0.5g) and anhydrous potassium carbonate (0.26 g) in dry acetone (5 ml) was added, slowly, ethyl iodide (0.29g) and the resulting mixture was stirred under reflux for 2 hr. then filtered. Removal of the solvent gave a pale brown solid which was dissolved in ether and treated with ethereal hydrogen chloride to give 1-(3,4,5-trichlorophenyl)-4-ethylpiperazine hydrochloride (0.4g, 67%), m.p. 265°-270° (from ethanol-ether).
Reaction SMILES: [CH:1]1([CH:4]2[CH2:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15]C=O)([OH:8])[CH2:5]2)[CH2:3][CH2:2]1.[OH-].[K+]>CO>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1([OH:8])[CH2:5][CH:4]([CH:1]2[CH2:2][CH2:3]2)[CH2:7]1
Reactant: O=CNc1ccccc1C1(O)CC(C2CC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccccc1C1(O)CC(C2CC2)C1

Procedure:
In a sulfonation flask, a mixture consisting of 2.5 g (0.0108 mol) N-[2-(3-cyclopropyl-1-hydroxy-cyclobutyl)phenyl]-formamide (prepared as described in Example 8), 1.4 g (0.021 mol) potassium hydroxide and 25 ml methanol was stirred at reflux temperature for 4 hours. Then the solvent was distilled off in a water jet vacuum and the residue taken up in 100 ml of ethyl acetate. The organic phase was washed three times with water and after drying with sodium sulphate the solvent was distilled off in a water jet vacuum. The crude material was purified by flash chromatography over silica gel (eluant: hexane/ethylacetate 1:1). Yield: 1.65 g (75% of theory) of 1-(2-aminophenyl)-3-cyclopropylcyclobutanol in the form of a slightly brownish solid (mp.: 58-61° C.).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:5](=[O:8])[NH:6][N:7]=1.C(N(CC)CC)C.[CH:25]([CH:27]=[CH2:28])=[O:26]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:5](=[O:8])[N:6]([CH2:28][CH2:27][CH:25]=[O:26])[N:7]=1
Reactant: C=CC=O
Reactant: O=C(c1ccccc1)n1c(=O)[nH]nc(Br)c1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=CCCn1nc(Br)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.7 %

Procedure:
To a stirring solution of 6-bromo-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (1.46 g, 4.93 mmol) in dry N,N-Dimethylformamide (DMF) (64.9 ml), TRIETHYLAMINE (0.825 ml, 5.92 mmol) was added and the mixture was stirred at room temperature for 15 minutes. Acrolein (0.366 ml, 4.93 mmol) was then added and the mixture was left stirring at room temperature for 3 hours. It was then quenched with NH4Cl saturated solution and diluted with AcOEt. Phases were separated, organic phase was washed with cold water, dried over sodium sulphate, filtered and concentrated under reduced pressure affording 3-[6-bromo-3,5-dioxo-4-(phenylcarbonyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl]propanal (1.8 g, 5.11 mmol). The compound was used for next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:15]#[N:16])[C:11]=1N(C)C)[N:8]=[C:7](CO[Si](C(C)(C)C)(C)C)[CH:6]=[CH:5]2.C(NCC)C.C[Si](C#C)(C)C>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[N:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][C:10]=2[C:15]#[N:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1c(Br)cc2ccc(CO[Si](C)(C)C(C)(C)C)nc2c1C#N
Agent: I[Cu]I
Agent: C#C[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: N#Cc1cccc2cccnc12
Temperature: 110 °C
Yield: 201.8 %

Procedure:
In a sealed tube were introduced the 6-bromo-2-((tert-butyldimethylsilyloxy)methyl)-7-(dimethylamino)quinoline-8-carbonitrile (946 mg, 2.25 mmol, 1.0 eq), PdCl2(PPh3)3 (79 mg, 0.11 mmol, 5% mol), copper iodide (21 mg, 0.11 mmol, 5% mol), and triphenylphosphine (106 mg, 0.39 mmol, 20% mol). Then, DMF (5 mL) was added followed by diethylamine (3.5 mL, 34 mmol, 15 eq) and trimethylsilylacetylene (350 μL, 2.5 mmol, 1.1 eq). The mixture was heated at 110° C. overnight. After cooling down the solvent was evaporated and the crude product was purified by column chromatography (Florisil, Cyclohexane-EtOAc 95:5) to afford 2-((tert-butyldimethylsilyloxy)methyl)-7-(dimethylamino)-6-(trimethylsilyl)ethynyl)quinoline-8-carbonitrile as a white solid (700 mg, 71%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:26]=3[CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]4)=[N:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([N:16]([C:17]3[C:26]4[CH2:25][CH:24]([OH:27])[CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[C:28](=[O:30])[CH3:29])=[N:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cnc(Nc3cccc4c3CC(O)CC4)o2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(c1ncc(-c2ccc(C(C)(C)C)cc2)o1)c1cccc2c1CC(O)CC2
Yield: 44.7 %

Procedure:
The product of Example 3C (76 mg, 0.21 mmol) in 2 mL tetrahydrofuran was stirred with acetic anhydride (0.026 mL, 0.275 mmol) and triethylamine (0.088 mL, 0.63 mmol) at rt for 3 h. The reaction mixture was then diluted with ethyl acetate and washed with water and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 35% ethyl acetate-hexane and then 60% ethyl acetate-hexane to afford the title compound as a tan foam (38 mg, 45%). 1H NMR (DMSO-d6) δ 8.03 (s, 1H), 7.48 (m, 4H), 7.10 (m, 2H), 6.82 (m, 1H), 4.72 (d, J=3.8 Hz, 1H), 3.92 (m, 1H), 2.84-3.02 (m, 3H), 2.73 (s, 3H), 2.44 (m, 1H), 1.86 (m, 1H), 1.61 (m, 1H), 1.27 (s, 9H); MS (ESI+) m/z 405 (M+H)+.
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([OH:12])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.S(=O)(=O)(O)O.[CH3:18]O>>[OH:1][C:2]12[CH2:3][CH2:4][C:5]([C:10]([O:12][CH3:18])=[O:11])([CH2:8][CH2:9]1)[CH2:6][CH2:7]2
Reactant: O=C(O)C12CCC(O)(CC1)CC2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C12CCC(O)(CC1)CC2
Yield: 96 %

Procedure:
To a solution of 4-hydroxybicyclo[2.2.2]octane-1-carboxylic acid (14 g, 82.4 mmol) in methanol (300 mL) was added concentrated sulfuric acid (1 mL). The mixture was refluxed for 10 h and then concentrated. The reside was dissolved in water (100 mL) and the mixture was extracted with ethyl acetate (200 mL×2). The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution (100 mL), brine (100 mL) and dried over sodium sulfate. Concentration gave the title compound (14.5 g, yield 96%). 1H NMR (400 MHz, CDCl3) δ ppm 3.64 (s, 3H), 1.96-1.89 (m, 6H), 1.69-1.64 (m. 6H).
Reaction SMILES: FC(F)(F)S([O:6][C@@H:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=O)=O.O[CH:17]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])=[CH:25][CH:24]=2)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]1>>[CH2:11]([O:10][C:8]([C@H:7]([O:6][CH:17]1[CH:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])=[CH:27][CH:28]=2)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]1)[CH3:13])=[O:9])[CH3:12]
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: CCOC(=O)[C@@H](C)OC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Example 35c, 0.32 ml of ethyl 2(S)-trifluoromethanesulphonyloxypropionate and 0.734 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate are reacted. The title compound is obtained as a colourless oil. Rf=0.19 (1:3 EtOAc-heptane); Rt=5.93.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:21][OH:22])[C:15]([CH2:19][OH:20])=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>C(Cl)Cl.C(Cl)Cl.CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:21]=[O:22])[C:15]([CH:19]=[O:20])=[CH:16][C:17]=1[Cl:18]
Reactant: OCc1cc(Cl)c(Cl)cc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cc(Cl)c(Cl)cc1C=O
Temperature: -78 °C
Reaction time: 0.07 h
Yield: 78 %

Procedure:
To a dry 500 mL three-necked flask equipped with a thermometer and a dropping funnel, was added a solution of dry CH2Cl2 (60 mL) and oxalyl chloride (2.7 mL, 34.35 mmol) under Ar. The stirred solution was cooled to −78° C. and a solution of DMSO (4.24 mL, 59.67 mmol) in CH2Cl2 (10 mL) was added dropwise. The solution was stirred for 3-5 min. and 4,5-dichlorobenzene-1,2-dimethanol (2.0 g, 9.71 mmol) dissolved in CH2Cl2-DMSO mixture (25 mL) was added dropwise. The reaction was allowed to continue for 0.5 h and then triethylamine (24 mL, 0.18 mol) was slowly added at −78° C. the reaction mixture was allowed to stir for 10 min. and then slowly warmed to RT. Ice-cold water (50 mL) was added to the reaction mixture and the aqueous layer extracted with CH2Cl2 (2×50 mL) and then dried over CaCl2. Removal of solvent gave the yellow solids of 4,5-dichlorobenzene-1,2-dicarbaldehyde in 78% yield (1.53 g). 1H NMR (500 MHz, CDCl3): δ 10.46 (s, 2H), 8.05 (s, 2H). 13C NMR (125.68 MHz, CDCl3): δ 189.92, 139.07, 135.32, 133.08.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([N:15]([CH3:23])[CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[N:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.C(OC(=O)[NH:30][CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1)(C)(C)C.Cl>CS(C)=O>[NH2:30][CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH:38][C:5]2[CH:4]=[C:3]([C:9]3[N:14]=[C:13]([N:15]([CH3:23])[CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH:12]=[N:11][CH:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:34][CH2:33]1
Reactant: CN(CC1CCOCC1)c1cncc(-c2cc(F)ncc2Cl)n1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CS(C)=O
Product: CN(CC1CCOCC1)c1cncc(-c2cc(N[C@H]3CC[C@H](CN)CC3)ncc2Cl)n1
Temperature: 102.5 °C
Reaction time: 18 h

Procedure:
A mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (15 mg, 0.045 mmol), DMSO (0.4 ml), and tert-butyl(trans-4-aminocyclohexyl)methylcarbamate (92 mg, 0.401 mmol) was stirred at 100-105° C. for 18 hours, and the reaction progress was followed by LCMS. To the crude intermediate was added 6 M aq.HCl (120 μl, 0.720 mmol) and heated at 80° C. for 40 minutes, and the reaction progress was followed by LCMS. The reaction mixture was let cool, added 0.5 ml of DMSO, filtered and purified by prep LC. After lypohilization, 15.6 mg of the title compound, as a TFA salt was obtained. LCMS (m/z): 445.2 (MH+), retention time=0.59 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.12-1.47 (m, 6H) 1.59 (d, J=12.60 Hz, 2H) 1.67 (ddd, J=7.18, 3.81, 3.66 Hz, 1H) 1.92 (d, J=12.31 Hz, 2H) 2.01-2.11 (m, 1H) 2.16 (d, J=11.43 Hz, 2H) 2.83 (d, J=7.03 Hz, 2H) 3.17 (s, 3H) 3.33-3.45 (m, 2H) 3.56 (d, J=7.33 Hz, 2H) 3.60-3.72 (m, 1H) 3.93 (dd, J=11.14, 2.93 Hz, 2H) 6.92 (s, 1H) 8.02 (d, J=2.64 Hz, 2H) 8.11 (s, 1H).
Reaction SMILES: Cl.[N:2]([O-:4])=O.[Na+].[CH2:6]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[NH:9][CH2:8][CH2:7]1>O>[N:2]([N:9]1[CH2:8][CH2:7][CH2:6][CH2:11][CH:10]1[C:12]([OH:14])=[O:13])=[O:4]
Reactant: O=N[O-]
Reactant: O=C(O)C1CCCCN1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCCCC1C(=O)O
Reaction time: 1 h

Procedure:
Conc. HCl (1.96 mL) and NaNO2 (2.2 g) were added to the H2O (21 mL) solution of DL-pipecolic acid (3.04 g) under a nitrogen atmosphere at 0° C. and stirred for 1 h. The solution was extracted with CH2Cl2 and organic layer was washed with brine. The mixture was dried over Na2SO4 and concentrated under reduced pressure to afford crude (2RS)-1-nitrosopiperidine-2-carboxylic acid as pale yellow crystals.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10](C(OCC)=O)=[CH:9][N:8]=[C:7]2[CH:16]=[N:17][NH:18][C:6]=12)[CH:2]=[CH2:3].[OH-].[Na+]>C(O)C>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:16]=[N:17][NH:18][C:6]=12)[CH:2]=[CH2:3]
Reactant: C=CCNc1c(C(=O)OCC)cnc2cn[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCNc1ccnc2cn[nH]c12

Procedure:
Ethyl 7-Allylamino-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (D10) (1.0 g 0.004 mole) was converted to the corresponding acid by heating under reflux with a 2% sodium hydroxide solution in ethanol (50 ml). The ethanol was removed under reduced pressure, and the residue diluted with water (10 ml) and acidified to pH5 with dilute hydrochloric acid. The resulting acid was filtered and dried, m.p. 230°-232° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:13]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: O=C1CCc2cc(Br)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(-n3ccnc3)ccc2N1
Temperature: 90 °C

Procedure:
A mixture of 1.0 g of 6-bromo-3,4-dihydrocarbostyril, 300 mg of imidazole, 40 mg of cuprous iodide and 600 mg of potassium carbonate in 4 ml of N,N-dimethylformamide was heated at 90° C. for 48 hours. The reaction mixture was poured into water and extracted with a mixture of 10% methanol in methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent removed under reduced pressure and the residue chromatographed on silica gel, eluting with 3% methanol in methylene chloride, giving 6-(imidazol-1-yl)-3,4-dihydrocarbostyril, m.p. 205°-208° C.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:53]=[CH:52][C:51]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][C:62]3[C:71]4[C:66](=[CH:67][C:68]([O:74][CH3:75])=[C:69]([O:72][CH3:73])[CH:70]=4)[N:65]=[CH:64][CH:63]=3)=[CH:57][CH:56]=2)=[CH:50][CH:49]=1.[NH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:73][O:72][C:69]1[CH:70]=[C:71]2[C:66](=[CH:67][C:68]=1[O:74][CH3:75])[N:65]=[CH:64][CH:63]=[C:62]2[O:61][C:58]1[CH:59]=[CH:60][C:55]([NH:54][C:51]2[CH:52]=[CH:53][C:48]([N:76]3[CH2:81][CH2:80][O:79][CH2:78][CH2:77]3)=[CH:49][CH:50]=2)=[CH:56][CH:57]=1
Reactant: COc1cc2nccc(Oc3ccc(Nc4ccc(Br)cc4)cc3)c2cc1OC
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(Nc4ccc(N5CCOCC5)cc4)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
Palladium acetate (18 mg) and (+)-BINAP (70 mg) were dissolved in toluene (1.5 ml), and the solution was stirred at room temperature for 5 min. (4-Bromophenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]amine (100 mg), morpholine (0.15 ml), and cesium carbonate (200 mg) were added in that order to the reaction solution, and the mixture was stirred at 80° C. overnight. The insolubles were removed by filtration, and the solvent was then removed by evaporation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel using chloroform/acetone to give the title compound (10 mg, yield 9%).
Reaction SMILES: C([NH:4][C:5]1[C:28]([Cl:29])=[CH:27][C:8]([C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14]2)=[O:10])=[C:7]([O:30][CH2:31][CH3:32])[CH:6]=1)(=O)C.[OH-].[Na+]>Cl>[NH2:4][C:5]1[C:28]([Cl:29])=[CH:27][C:8]([C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:14]2)=[O:10])=[C:7]([O:30][CH2:31][CH3:32])[CH:6]=1
Reactant: CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Reaction time: 1 h
Yield: 77 %

Procedure:
A mixture of 4-acetylamino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (2.0 g) and 10% hydrochloric acid (40 ml) is refluxed with stirring for 1 hour and cooled. The reaction mixture is neutralized with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is dried over magnesium sulfate and evaporated. The residue is recrystallized from ethanol to give the title compound (1.4 g), mp 151°-153° C.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)(O)=[O:4].C(Cl)(=O)C([Cl:21])=O>O1CCCC1>[Cl:21][C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCCCC1=CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cl)CCCCCCC1=CCCC1=O
Temperature: 0 °C

Procedure:
To a suspension of 1.94 g. (0.08 mol) of sodium hydride in 100 ml. of tetrahydrofuran is added with stirring under argon dropwise a solution of 17 g. (0.08 mol) of 2-(6-carboxyhexyl)-cyclopent-2-en-1-one in 160 ml. of tetrahydrofuran. After the addition is complete, the mixture is stirred for 1 hour 15 minutes. The mixture is cooled to 0° C. and 13 ml. of oxalyl chloride is added. The mixture is stirred at 0° C. for 30 minutes and at room temperature for 30 minutes. The solution is diluted with 500 ml. of ether and filtered through Celite. The solvent is removed from the filtrate and the residue is extracted with hot hexane twice. The hexane is removed to give 16.0 g. of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[NH2:13][C:14]([NH2:16])=[S:15].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:16][C:14]1[S:15][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:13]=1
Reactant: NC(N)=S
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2csc(N)n2)cc1
Temperature: 25 °C

Procedure:
Slurry 4-cyanophenacyl bromide (40 g, 179 mmol), thiourea (13.6 g, 181 mmol) and sodium bicarbonate (15.3 g, 181 mmol) in absolute ethanol (560 mL). Stir the mixture at reflux for 20 h under a nitrogen atmosphere. Cool the slurry to room temperature, filter, wash the solids with ethanol (100 mL), water (3×75 mL) and hexane (3×75 mL). Collect the yellow solid, add water (200 mL) and stir the slurry for 30 min at room temperate. Filter and wash the solid with hexane (excess). Slurry the solid in EtOAc (50 mL) and concentrate in vacuo twice to remove residual water. Collect the desired intermediate as a light yellow solid (36 g, 99%). MS (ES+) m/z: 202.1 (M+H)+.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[N:16]3[C:12](=[N:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)[S:11][CH:10]2[CH2:21][C:22]([OH:24])=[O:23])=[CH:5][CH:4]=1.CS(O)(=O)=O.C(OCC)(=O)C.C(O)(=O)C.C([O-])(=O)C.C(O)(=O)C>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:16]3[C:12](=[N:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)[S:11][C:10]=2[CH2:21][C:22]([OH:24])=[O:23])=[CH:5][CH:4]=1
Reactant: O=C(O)CC1Sc2nc3ccccc3n2C1(O)c1ccc(Cl)cc1
Agent: Br
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)Cc1sc2nc3ccccc3n2c1-c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A mixture of 100 g of 3-(p-Chlorophenyl)-2,3,-dihydro-3-hydroxythiazolo[3,2-a]benzimidazol-2-acetic acid, hydrobromide and 200 ml of methanesulfonic acid was stirred overnight in a 500 ml round bottom flask. Thin layer chromatography on silica plates (solvent ethyl acetate/acetic acid) indicated rapid formation of an intermediate. After 20 hours at room temperature thin layer chromatography (silica plates, ethyl) acetate/acetic acid) showed the presence of a single component. The mixture was poured into water and the resulting crystals removed by filtration. The crystalline product was suspended in 5 volumes of hot water for 1/2 hour, filtered and the procedure repeated. After a final aqueous wash the material was dried in vacuo to yield the title compound (75 g, 91%) m.p. 242°-3° C.
Reaction SMILES: [ClH:1].CNC.CCN(C(C)C)C(C)C.C(OC([NH:21][C@@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:23]([OH:25])=O)=O)(C)(C)C.CN(C(O[N:41]1[N:49]=[N:48][C:43]2C=CC=C[C:42]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[ClH:1].[NH2:21][C@@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:23]([N:49]([NH:41][CH3:42])[NH:48][CH3:43])=[O:25]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNN(NC)C(=O)[C@@H](N)Cc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of dimethylamine hydrochloride (0.153 g, 1.87 mmol) in DMF (8 mL) was added DIPEA (2 mL, 6.55 mmol), (S)-2-tert-butoxycarbonylamino-3-pyridin-2-ylpropionic acid (0.50 g, 1.87 mmol, Acros) and TBTU (0.60 g, 1.87 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was dissolved in methanol (15 mL). To this was added 4M hydrochloric acid in dioxane (20 mL) and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (100 mL) and ethyl acetate (2×100 mL). The aqueous layer was evaporated to dryness to give a solid, which was recrystallised from ethanol to give the title compound as a pale brown solid. m/z (ES+)=194.