Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:5][C:6]1[O:10][C:9]([C:11]([Cl:13])=[O:12])=[N:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[C:17]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:16]=1>>[ClH:13].[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[C:17]([N:29]2[CH2:34][CH2:33][N:32]([C:11]([C:9]3[O:10][C:6]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][N:8]=3)=[O:12])[CH2:31][CH2:30]2)[N:16]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CCCCSc1nnc(C(=O)Cl)o1
Product: CCCCSc1nnc(C(=O)N2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)o1
Product: Cl

Procedure:
The title compound was prepared from 5-n-butylthio-1,3,4-oxadiazole-2-carbonyl chloride and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline following the procedure of Example 1.
Reaction SMILES: C[C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1C=CC=C(C)N=1>>[CH3:17][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)=[N:7][CH:2]=1
Reactant: Cc1cccc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: Cc1cccc(Cl)n1
Product: Cc1ccc(N2C[C@@H]3CCNC[C@@H]32)nc1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 40, substituting 2-chloro-5-methylpyridine for 2-chloro-6-methylpyridine in step A. MS (ESI) mass calcd. for C12H17N3, 203.2; m/z found, 204.1 [M+H]+.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH3+:22])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.CCN(CC)CC.[N:30]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[C:31]=[O:32]>C(Cl)Cl>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:31]([NH:30][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:32])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1
Reactant: COc1ccc(CN=C=O)cc1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OCCCCCC[NH3+])c21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CNC(=O)NCCCCCCOc2cccc3c2C(N)=NS(=O)(=O)N3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 538.3 %

Procedure:
To a suspension of 6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexan-1-aminium chloride (25 μmol, 52 mg) (Example 228) in dry DCM (6 mL) was successively added Et3N (332 μmol, 46 μL) and 1-(isocyanatomethyl)-4-methoxybenzene (183 μmol, 26 μL). The reaction was stirred for 48 hours at room temperature then concentrated in vacuo. The residue was washed with water, dried, then purified on silica gel (20% to 100% EtOAc in hexanes) to give the desired product (64 mg, 81.0% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.296 (m, 2H), 1.371 (m, 4H), 1.791 (pentet, J=8 Hz, 2H), 2.980 (q, J=6 Hz, 2H), 3.695 (s, 3H), 4.086 (d, J=6 Hz, 2H), 4.131 (t, J=6 Hz, 2H), 5.836 (br. t, J=5 Hz, 1H), 6.141 (br. t, J=6 Hz, 1H), 6.585 (d, J=8 Hz, 1H), 6.727 (d, J=8 Hz, 1H), 6.840 (d, J=9 Hz, 2H), 7.137 (d, J=9 Hz, 2H), 7.433 (t, J=8 Hz, 1H), 7.803 (br. s, 1H), 8.321 (br. s, 1H), 10.926 (s, 1H). MS 476 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.Cl.[CH3:22][N:23]1[CH:27]=[N:26][C:25]([CH2:28][NH2:29])=[N:24]1>C(N(CC)CC)C.CN(C=O)C>[CH:17]1([C:3]2[C:2]([NH:29][CH2:28][C:25]3[N:26]=[CH:27][N:23]([CH3:22])[N:24]=3)=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reactant: Cn1cnc(CN)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cnc(CNc2nn3c(-c4ccccc4)nnc3cc2C2CCC2)n1
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (144 mg, 0.52 mmol) and C-(1-methyl-1H-1,2,4-triazol-3-yl)methylamine hydrochloride (300 mg, 2.0 mmol) in triethylamine (1 ml) and dry DMF (1 ml) was stirred and heated at 100° C. in a sealed tube for 20 hours. Upon cooling the volatiles were removed in vacuo, and the residue was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous was further extracted with dichloromethane (x2). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatograhy on silica gel, eluting with 2%→5%→10% methanol-dichloromethane to give, in order of elution:
Reaction SMILES: C(C[C@@H:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:7][CH2:6][CH2:5]1)#N.[OH-:25].[K+].Cl.[CH2:28]([OH:31])[CH2:29]O>>[C:28]([CH2:29][C@@H:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH2:7][CH2:6][CH2:5]1)([OH:31])=[O:25]
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H](CC#N)c3ccccc32)cc1
Reactant: OCCO
Agent: Cl
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](CC(=O)O)c3ccccc32)cc1
Temperature: 172.5 °C
Reaction time: 6 h

Procedure:
A mixture of (5R)-5-cyanomethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (102 mg), potassium hydroxide (84 mg) and ethylene glycol (2 ml) is heated with stirring at 170-175° C. for 6 hours. The reaction solution is acidified with conc. hydrochloric acid, extracted with ethyl acetate, dried over sodium sulfate, and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol;=9:1) to give (5R)-5-carboxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (108 mg).
Reaction SMILES: Cl[C:2](=[O:25])[C@@H:3]([NH:7][C:8](=[O:24])[O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]([CH3:6])[CH3:5].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[NH:34][C:35]([CH:37]1[C:45]([CH3:47])([CH3:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38]1)=[O:36].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[NH:34][C:35]([CH:37]1[C:45]([CH3:47])([CH3:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]1[C:2](=[O:25])[C@@H:3]([NH:7][C:8](=[O:24])[O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]([CH3:6])[CH3:5])=[O:36]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Cl
Reactant: CC1(C)c2ccccc2NC1C(=O)Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1c2ccccc2C(C)(C)C1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 114.8 %

Procedure:
(S)-(9H-fluoren-9-yl)methyl 1-chloro-3-methyl-1-oxobutan-2-ylcarbamate (0.11 g, 307 μmol, Eq: 3.1) was added to a solution of N-(2,6-difluorophenyl)-3,3-dimethylindoline-2-carboxamide (30 mg, 99.2 μmol, Eq: 1.00) and pyridine (40 μL, 496 μmol, Eq: 5) in DCM (1 mL) and the resulting solution was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with 1 M aqueous HCl (10 mL), 1 M aqueous NaOH (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 30% EtOAc in hexanes) to give (S)-(9H-fluoren-9-yl)methyl 1-(2-(2,6-difluorophenylcarbamoyl)-3,3-dimethylindolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a viscous oil (71 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[C:8](#[N:11])[CH2:9]O.[OH2:12]>>[C:8]([CH2:9][NH:1][CH2:6][CH2:5][O:4][CH2:3][C:2]([OH:7])=[O:12])#[N:11]
Reactant: N#CCO
Reactant: O=C1COCCN1
Reactant: O
Product: N#CCNCCOCC(=O)O
Temperature: 25 °C

Procedure:
In a 300 mL beaker was placed 5.78 g (57 mmol) of 3-morpholinone (I), 50% (w/w)sodium hydroxide (5.02 g, 63 mmol), 100 mL of water and a magnetic stir bar. The resulting solution was heated for 30 min at a gentle boil then cooled to room temperature. While the solution was stirring at room temperature, the glycolonitrile (40 percent aqueous, 8.13 g, 57 mmol) was added dropwise. The solution was stirred at room temperature for 1 h. at which time a 13C NMR indicated that the reaction was complete. 13C NMR (D2O): δ50.3, 53.4, 119.4, 179.7, 180.9 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[NH:21][CH2:20][CH2:19][N:9]2[C:10](=[O:18])[C:11]2[N:12]([N:14]=[C:15]([CH3:17])[CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1.[N:22]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:23]=[O:24].O>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[N:21]([C:23]([NH:22][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])[CH2:20][CH2:19][N:9]2[C:10](=[O:18])[C:11]2[N:12]([N:14]=[C:15]([CH3:17])[CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1
Reactant: O=C=NCCc1ccccc1
Reactant: Cc1cc2n(n1)CC1(c3ccc(Cl)cc3)NCCN1C2=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2n(n1)CC1(c3ccc(Cl)cc3)N(C(=O)NCCc3ccccc3)CCN1C2=O
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 10a-(4-chlorophenyl)-7-methyl-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrazolo[1,5-d]pyrazin-5-one (40 mg, 0.13 mmol) in a mixture of pyridine (400 μl) and CH2Cl2 (400 μl) was added (2-isocyanatoethyl)benzene (150 μl) at 0° C. The mixture was let to come back to room temperature. After 1 h the reaction was complete (monitored by LCMS). Water was then added and the mixture extracted with CH2Cl2. The organic fractions were then stirred overnight with PS-trisamine resin to remove the excess of isocyanate. Filtration through a cotton wool plug and concentration in vacuo gave a residue that was purified by flash chromatography (Silica gel, gradient 2:3 acetone/hexane) to give 10a-(4-chlorophenyl)-7-methyl-5-oxo-N-(2-phenylethyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrazolo[1,5-d]pyrazine-1-carboxamide (41) as a white solid (58 mg, yield 99%).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].N[C:9]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=1[C:11](O)=[O:12]>COC(O)C>[CH3:19][O:18][C:15]1[CH:14]=[C:10]2[C:9](=[CH:17][CH:16]=1)[N:7]=[CH:5][NH:6][C:11]2=[O:12]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: N=CN
Agent: COC(C)O
Solvent: CC(=O)O
Product: COc1ccc2nc[nH]c(=O)c2c1
Temperature: 140 °C
Reaction time: 17 h

Procedure:
Formamidine acetate (12.5 g, 119.6 mmol) was added to a stirred solution of 2-amino-5-methoxybenzoic acid (2.0 g, 119.6 mmol) in methoxy ethanol (40 mL) at RT. The reaction mixture was stirred at 140° C. (T oil bath) for ˜17 h. LC/MS showed completion of the reaction. The reaction cooled to RT and concentrated in vacuo. Aq. NaHCO3 solution was added to the concentrate and the precipitated solids were filtered (rinsing with water) to afford 6-methoxyquinazolin-4(3H)-one as off-white solid. MS [M+H]=177.1; Calc'd for C9H8N2O2: 176.2.
Reaction SMILES: [CH:1]1([C:5]2[C:14]([CH:15]=O)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:17])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:22].Br[CH:24]1[C:30](=O)[CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26][CH2:25]1.[OH-].[NH4+:40]>CN(C)C=O>[CH:1]1([C:5]2[CH:6]=[C:7]([CH3:17])[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=2[C:15]2[NH:40][C:24]3[CH2:25][CH2:26][N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:29][C:30]=3[N:22]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(C=O)c(C2CCC2)cc1C
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)CC1
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nc3c([nH]2)CCN(C(=O)OC(C)(C)C)CC3)c(C2CCC2)cc1C
Temperature: 130 °C
Reaction time: 4 h
Yield: 17.6 %

Procedure:
Into a 100-mL round-bottom flask, was placed a mixture of methyl 4-cyclobutyl-5-formyl-2-methylbenzoate (compound 82.5, 300 mg, 1.29 mmol), ammonium acetate (449 mg, 5.83 mmol), tert-butyl 4-bromo-5-oxoazepane-1-carboxylate (compound 82.3, 564 mg, 1.93 mmol) and ammonium hydroxide (25%) (597 μL, 3.87 mmol) in N,N-dimethylformamide (8 mL). The resulting mixture was stirred for 4 h at 130° C., then cooled and quenched with water/ice (10 mL). The aqueous phase was extracted with ethyl acetate (2×30 mL) and the combined organic layers were washed with brine (3×10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/1) as the eluent to yield 0.10 g (18%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]4)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O1CCOCC1>C(Cl)(Cl)Cl>[CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]4)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCc2cc(OCCCc3nnnn3C3CCCCC3)ccc2N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=c1ccc2cc(OCCCc3nnnn3C3CCCCC3)ccc2[nH]1

Procedure:
3.2 Grams of 6-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-3,4-dihydrocarbostyril and 3.4 g of 90% DDQ are added to 100 ml of dioxane and this mixture is refluxed for9.5 hours and then cooled. After the reaction is completed, the solvent is distilled off and the residue obtained is dissolved in chloroform and the organic layer is washed with aqueous saturated NaHCO3 solution, and with water then dried with Na2SO4 and treated with an activatedcharcoal. After the solvent is removed by distillation, the resultant residue is refined by silica gel column chromatography [silica gel: Wakogel C-200; eluent:chloroform:methanol=10:1 (V/V)] and the crude crystals are recrystallized from chloroform to obtain 1.1 g of 6-[3-(1-cyclohexyltetrazol-5-yl)propoxy]carbostyril in the form of colorless needle-like crystals. Melting point: 211°-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[CH3:33][CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:42][CH2:43][CH:34]2[CH3:33])=[O:9])=[CH:10][C:11]([F:14])=[CH:12][N:13]=1
Reactant: CC1CCc2ccccc2N1
Reactant: O=C(O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC1CCc2ccccc2N1C(=O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Temperature: 120 °C
Yield: 22.2 %

Procedure:
A solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinic acid (36.3 mg, 0.12 mmol, 1.0 equiv) in thionyl chloride (492 mg, 300 μL, 4.14 mmol, 34.5 equiv; [CAS RN 7719-09-7]) was heated to 100° C. over night. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (155 mg, 204 μL, 1.20 mmol, 10.0 equiv; [CAS RN 7087-68-5]) and 2-methyl-1,2,3,4-tetrahydro-quinoline (22.1 mg, 0.15 mmol, 1.25 equiv; [CAS RN 1780-19-4]) and the reaction mixture heated by microwave irradiation to 120° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 11.5 mg (22%) of the title compound. MS (ISP): 430.8 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[BrH:8].CCOCC.[Br:14]Br>O>[Br:8][C:2]1[S:1][C:5]([Br:14])=[CH:4][C:3]=1[CH:6]=[O:7]
Reactant: BrBr
Reactant: O=Cc1ccsc1
Reactant: Br
Solvent: O
Solvent: CCOCC
Product: O=Cc1cc(Br)sc1Br
Temperature: 0 °C

Procedure:
Thiophene-3-carboxaldehyde (2.54 g, 22.8 mmol) was mixed with 48% aqueous hydrobromic acid (6.8 mL), and ether (6 mL), then cooled at 0° C. A mixture of bromine (7.36 g, 46.0 mmol) and 48% aqueous hydrobromic acid (6.8 mL) was added dropwise under vigorous stir. The reaction mixture was then heated at 50° C. and reacted for 4 h. After reaction, the mixture was diluted with water (100 mL) and extracted with ether (3×50 mL). The organic layers were combined, washed with 10% sodium thiosulfate solution (2×15 mL) and water (30 mL), and dried (Na2SO4). The solvent was removed under reduced pressure to give dark crude product. The crude product was purified by column chromatography on silica gel (hexane/ethyl acetate=5:1). (4.32 g, 70%). 1H NMR (400 MHz, CDCl3, δ/ppm) 9.80 (s, 1H, CHO), 7.34 (s, 1H);
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O.Cl.[C:37]([C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)(=[NH:39])[NH2:38].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]2[C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:14])=[C:11]([CH2:10][O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:39][C:37]([C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)=[N:38]2)[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccccc1
Reactant: N=C(N)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCCc1ccccc1)C1=C(COCCN2CCCCC2)NC(c2cccs2)=NC1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 15.3 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (2.7 g, 7.77 mmol), 3,4-dichlorobenzaldehyde (1.63 g, 9.32 mmol), 2-amidinothiophene hydrochloride (1.52 g, 9.32 mmol) and sodium hydrogen carbonate (0.79 g, 9.35 mmol) was stirred in N,N-dimethylformamide (20 mL) for 4 days at room temperature and then heated to 60° C. for 3 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (0.73 g) as an oil. Electrospray MS m/z 612/614 [M+H]+.
Reaction SMILES: C(OCCN1CC[N:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])CC1)(=O)CCC.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27]N[CH2:25][CH2:24]1.C(Cl)(Cl)[Cl:30]>>[ClH:30].[N:23]1([CH2:24][CH2:25][CH:16]([CH2:17][CH3:18])[C:15]([NH2:12])=[O:19])[CH2:22][CH2:21][O:20][CH2:27][CH2:28]1
Reactant: OCCN1CCNCC1
Reactant: ClC(Cl)Cl
Reactant: CCCC(=O)OCCN1CCN(C(=O)CCC)CC1
Product: CCC(CCN1CCOCC1)C(N)=O
Product: Cl
Reaction time: 8 h
Yield: 94 %

Procedure:
Synthesis of 2-(4-Butanoylpiperazinyl)ethyl butanoate (BEB) 3 Butyryl chloride (11.83 g, 0.11 mol) was added dropwise to a cooled solution of 4.84 g (0.04 mol) of 1-(2-hydroxyethyl)-piperazine in 20 ml of chloroform. Cooling was maintained for 2 h, and a white precipitate formed. Chloroform (15 ml) was added and the mixture was stirred overnight, washed with 210 ml of cold 0.6 N sodium hydroxide solution, then washed twice with 50 ml of cold water. The organic fraction was dried over anhydrous sodium sulfate, filtered and, concentrated in vacuo to yield 9.39 g (94%) of a clear yellow liquid. This was distilled: bp 144-146° C., (0.5 mm Hg) to give 6.08 g (65%) of MEB. 1H NMR (CDCl3) δ 0.897 (t, 3H, J=7.4, CH3), 0.901 (t, 3H, J=7.4, CH3), 1.59 (m, 2H, CH3CH2), 1.61 (m, 2H, CH3CH2), 2.24 (t, 2H, J=7.4, CH2CO), 2.25 (t, 2H, J=7.4, CH2CO), 2.42-2.43 (app t, 2H, J=5.2, axial CI ester end of ring), 2.43-2.44 (app t, 2H, J=5.2, equatorial CH ester end of ring), 2.59 (t, 2H, J=5.8, N—CH2—CH2—O), 3.41 (app t, 2H, axial CH amide end of ring), 3.57 (app t, 2H, equatorial CH amide end of ring), 4.16 (t, 2H, N—CH2—CH2—O); MS m/z 270 (M+), 255, 242, 227, 199, 182, 169 (Base Peak).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:20]([OH:21])=[C:19]([C:22]([OH:24])=[O:23])[C:18]3[C:9](=[C:10]4[C:15](=[CH:16][CH:17]=3)[CH2:14][CH2:13][NH:12][CH2:11]4)[N:8]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(N(CC)CC)C.[O:38]([C:40]#[N:41])[K].N1C=CC=CC=1>>[C:40]([N:12]1[CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[C:18]3[C:9]=2[N:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][CH:25]=2)[C:20]([OH:21])=[C:19]3[C:22]([OH:24])=[O:23])[CH2:14][CH2:13]1)(=[O:38])[NH2:41]
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c3c(ccc12)CCNC3
Reactant: N#CO[K]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: NC(=O)N1CCc2ccc3c(C(=O)O)c(O)c(Cc4ccc(Cl)cc4)nc3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
A mixture of 2-(4-Chloro-benzyl)-3-hydroxy-7,8,9,10-tetrahydro-(1,9]phenanthroline-4-carboxylic acid (0.213 g, 0.53 mmol), acetic acid (0.6 mL, 5.3 mmol), triethylamine (0.146 mL, 1.06 mmol), KOCN (43 mg, 0.53 mmol), and pyridine (0.84 mL, 5.3 mmol) was stirred at 25° C. overnight. The solid was removed by filtration. HPLC of the mother liquor gave pure product (49.1 mg, 22%) as a beige solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.25 (m, 2H), 3.68 (m, 2H), 4.34 (s, 2H), 4.63 (s, 2H), 7.22-7.45 (m, 5H), 8.47 (d, J=9.09 Hz, 1H).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:10]([O:12][CH2:13][CH:14]([OH:19])[CH2:15][O:16][CH2:17][CH3:18])[CH3:11].[C:20](Cl)(Cl)=[O:21]>C1(C)C=CC=CC=1>[C:5]([O:4][C:3]([NH:2][O:1][C:20]([O:19][CH:14]([CH2:15][O:16][CH2:17][CH3:18])[CH2:13][O:12][CH2:10][CH3:11])=[O:21])=[O:9])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)NO
Reactant: O=C(Cl)Cl
Reactant: CCOCC(O)COCC
Solvent: Cc1ccccc1
Product: CCOCC(COCC)OC(=O)ONC(=O)OC(C)(C)C

Procedure:
2-{[({[(tert-Butoxy)carbonyl]amino}oxy)carbonyl]oxy}-1,3-diethoxypropane is prepared from tert-butyl N-hydroxycarbamate and 1,3-diethoxypropan-2-ol using 20% solution of phosgene in toluene according to Scheme 10. (10.37 g, 85%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.73 (1H, s), 5.03 (1H, quin, 5.2 Hz), 3.64 (4H, dd, 5.1, 2.7 Hz), 3.48-3.57 (4H, m), 1.50 (9H, s), 1.19 (6H, t, 7.0 Hz).
Reaction SMILES: [C-]#N.[K+].CC(C)(O)[C:6]#[N:7].[Cl:10][C:11]1[CH:12]=[C:13](/[C:18](/[C:37]([F:40])([F:39])[F:38])=[CH:19]\[C:20]([C:22]2[CH:35]=[CH:34][C:25]([C:26]([NH:28][C:29]3([CH3:33])[CH2:32][S:31][CH2:30]3)=[O:27])=[C:24]([CH3:36])[CH:23]=2)=[O:21])[CH:14]=[C:15]([Cl:17])[CH:16]=1.O>C1(C)C=CC=CC=1>[C:6]([C@@:18]([C:13]1[CH:14]=[C:15]([Cl:17])[CH:16]=[C:11]([Cl:10])[CH:12]=1)([C:37]([F:40])([F:39])[F:38])[CH2:19][C:20]([C:22]1[CH:35]=[CH:34][C:25]([C:26]([NH:28][C:29]2([CH3:33])[CH2:32][S:31][CH2:30]2)=[O:27])=[C:24]([CH3:36])[CH:23]=1)=[O:21])#[N:7]
Reactant: CC(C)(O)C#N
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1(C)CSC1
Agent: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C(=O)C[C@](C#N)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1(C)CSC1
Temperature: 90 °C
Reaction time: 144 h
Yield: 23.7 %

Procedure:
Potassium cyanide (0.0090 g, 0.139 mmol) and acetone cyanohydrin (0.034 ml, 0.372 mmol) were added to a solution of 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamide (0.0600 g, 0.123 mmol) in toluene (3.0 ml). To this vigorously stirred suspension was added 2,3,4,5,6-pentafluorophenyl-methyl quininium chloride (0.0180 g, 0.031 mmol). The reaction mixture was stirred at 90° C. for 6 days. After this time water was added and the reaction mixture was extracted with dichloromethane (3×). The crude product was purified by flash chromatography (0% to 25% ethyl acetate in cyclohexane) to afford 4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamide (0.015 g, 24%) as a light yellow solid. Chiral HPLC analysis (Chiralpack IB, Heptane:2-propanol=70:30, 1 ml/min, retention time 5.91 minutes (major enantiomer), 5.31 minutes (minor enantiomer) indicated that the reaction proceeded with 69% enantioselectivity.