Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7](C)[CH2:8][CH:9]=O.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13]>C(O)(=O)C.N1CCCCC1>[C:12](/[C:14](=[CH:9]\[CH2:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)/[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: CC(CC=O)c1cnccn1
Reactant: COC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)/C(C#N)=C/CCc1cnccn1
Yield: 35.5 %

Procedure:
A solution of 13e (0.191 g, 1.27 mmol) in 0.17 mL glacial acetic acid was treated with NCCH2CO2CH3 (0.115 g, 1.27 mmol, 0.1 mL, 1.0 equiv), then a premixed solution of piperidine (0.0038 g, 0.04318 mmol, 4.4 mL, 3.4 mol %) and 50 mL of acetic acid at room temperature (24 h). The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (15 mL, pH>7) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. SGC chromatotron (SiO2, 1 mm, 25-65% EtOAc/hexanes) afforded 15e (0.098 g, 0.282 g theoretical, 35%). For 15e: 1H NMR (CDCl3, 400 MHz) d 8.52 (dd, 1H, J=1.6, 2.5 Hz, Pyr C5-H), 8.46 (d, 1H, J=1.6 Hz, Pyr C3-H), 8.44 (d, 1H, J=2.5 Hz, Pyr C6-H), 7.59 (dd, 1H, J=7.8, 7.8 Hz, CH=C), 3.82 (s, 3H, OCH3), 3.23 (ddq, 1H, J=6.4, 7.0, 7.2 Hz, PyrCH), 3.07 (ddd, 1H, J=7.2, 7.8, 14.9 Hz, CHH), 2.91 (ddd, 1H, J=6.4, 7.8, 14.6 Hz, CHH), 1.39 (d, 3H, J=7.0 Hz, CH3); IR (neat) nmax 2967, 2360, 2341, 1737, 1626, 1437, 1407, 1282, 1259, 1060, 1017, 850, 761, 668 cm-. See FIG. 19d.
Reaction SMILES: [OH-:1].[Na+].C([CH:5]([CH2:9][C:10](Cl)=[O:11])[C:6](Cl)=[O:7])C.[Cl-].[Na+].[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[O:11]=[C:10]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)[CH2:9][CH2:5][C:6]([OH:7])=[O:1]
Reactant: CCC(CC(=O)Cl)C(=O)Cl
Reactant: [OH-]
Reactant: c1cc(N2CCNCC2)ccn1
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CCC(=O)N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an aqueous solution (10 ml) of 1-(4-pyridyl)-piperazine (1.63 g) were added 2N sodium hydroxide (5.5 ml) and ethylsuccinyl chloride at 0° C. and the solution was stirred for 1 hour at room temperature 1 hour. The reaction solution was saturated with sodium chloride, extracted with ethyl acetate three times and dried over Na2SO4. The solution was removed under reduced pressure and the residue was dissolved in methanol (10 ml). To the solution was added 2N sodium hydroxide (11 ml) and the solution was stirred for 1 hour at room temperature. The pH of the reaction mixture was adjusted to 5 with acetic acid and the solution was concentrated under reduced pressure and the concentrate was recrystallized from ethanol to give the titled compound (1.4 g) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([C:9](I)=[C:10]([CH2:12][O:13][CH3:14])[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]([OH:36])[C:9]3[N:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]4=[N:11][C:10]=3[CH2:12][O:13][CH3:14])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]
Reactant: COCc1nc2c(OC)cccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: COCc1nc2c(OC)cccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 65.5 %

Procedure:
[step 4] Using 8-methoxy-3-iodo-2-(methoxymethyl)imidazo[1,2-a]pyridine (500 mg, 1.57 mmol) obtained in step 3 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (230 mg, 0.786 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(3-fluoro-8-{hydroxy[8-methoxy-2-(methoxymethyl)imidazo[1,2-a]pyridin-3-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (250 mg, 66%) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(OCC)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: NCCCCO
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CNCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of 4-hydroxybutylamine (9.1 g, 101.8 mmol) in diethyl ether (100 mL), a solution of tert-butyl bromoacetate (7.4 g, 49.3 mmol) in diethyl ether (25 mL) was added dropwise over a period of 2 hours. The reaction mixture was allowed to warm up slowly to room temperature and stirred at the temperature overnight. The product mixture was washed successively with aqueous NaHCO3, water, and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. This intermediate was used in the following reaction without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][C:33]=1[Cl:34])[NH:20][C:21](=[O:30])[C:22]1[C:23](=[CH:25][CH:26]=[C:27]([Cl:29])[CH:28]=1)[OH:24]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:21](=[O:30])[C:22]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=2[O:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(Cl)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)c(Cl)c3)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (116 mg), 3′,4′,5-trichlorosalicylanilide (632 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (14 mg, yield 6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]3[O:21][C:20](=[O:22])[NH:19][CH2:18]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CCOC(C)=O>CS(C)=O.CCOC(C)=O.[Cu]I>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:16][CH:17]3[O:21][C:20](=[O:22])[N:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:18]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Ic1ccccn1
Reactant: O=C1NCC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)O1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1OC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CN1c1ccccn1
Temperature: 130 °C
Yield: 79.4 %

Procedure:
A mixture of 5-((3,6-dibromo-9H-carbazol-9-yl)methyl)oxazolidin-2-one (0.0195 g, 0.0460 mmol), 2-iodopyridine (0.0209 g, 0.102 mmol), CuI (0.0009 g, 0. 00460 mmol), and K2CO3 (0.0058 g, 0.0418 mmol) in 0.5 mL of DMSO was sealed tightly in a vial and heated at 130° C. for 12 hours. The reaction mixture was cooled and diluted with 20 mL EtOAc and washed with water 5×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using CH2Cl2/EtOAc as elute to afford 0.0183 g white solid as product, yield 79.4%.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:20][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1.CCCCCC.C(OCC)(=O)C>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:20][CH2:21][CH:22]3[O:26][CH2:25][CH2:24][O:23]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: BrCCC1OCCO1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc2c(c1)-c1ccccc1C2CCC1OCCO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-(9-Fluorenyl)ethyl-1,3-dioxolane was prepared from a solution of fluorene (30.0 g, 180.5 mmol) in 400 ml of dry THF cooled in a -78° C. bath under argon, to which was added 100 ml of n-butyllithium (2.0M in cyclohexane) over 15 minutes After stirring for 0.5 hours at 78° C. 2-(2-bromoethyl)-1, 3-dioxolane (22.3 ml, 190 mmol) was added dropwise, and the resulting solution stirred at room temperature for 16 hours. Concentration in vacuo yielded an orange residue which was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was then washed with brine, dried with magnesium sulfate, and concentrated in vacuo to afford an orange oil. Flash chromatography on silica, hexane:ethyl acetate 20:1 to 1:1 yielded a yellow oil (36.38 g, 76%).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13]([C:17]3[S:21][C:20]([CH:22]([CH3:24])[CH3:23])=[N:19][CH:18]=3)([OH:16])[CH2:12][CH2:11]2)[CH2:6]1.[O:25]=[C:26]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:27][CH2:28][C:29](O)=[O:30].CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[OH:16][C:13]1([C:17]2[S:21][C:20]([CH:22]([CH3:24])[CH3:23])=[N:19][CH:18]=2)[CH2:12][CH2:11][CH:10]([N:7]2[CH2:8][CH2:9][C@@H:5]([NH:4][C:29](=[O:30])[CH2:28][CH2:27][C:26](=[O:25])[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)[CH2:6]2)[CH2:15][CH2:14]1
Reactant: O=C(O)CCC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)c1ncc(C2(O)CCC(N3CC[C@@H](N)C3)CC2)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)c1ncc(C2(O)CCC(N3CC[C@@H](NC(=O)CCC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a stirred solution of 4-[(3R)-3-aminopyrrolidin-1-yl]-1-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanol 3HCl salt (0.233 g, 0.557 mmol) and 4-oxo-4-[3-(trifluoromethyl)phenyl]butanoic acid (0.15 g, 0.61 mmol) in DMF (5 mL) was added Et3N (0.34 mL, 2.44 mmol) followed by BOP (0.296 g, 0.67 mmol). The mixture was stirred overnight at room temperature. Then the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3 and brine. The organic layer was dried (MgSO4), concentrated and flash chromatographed (EtOAc to 10% MeOH/EtOAc) to give 0.075 g of the title compound. MS (EI) calculated: MS (EI) calcd: (M+H)+=538.2; found: 538.1.
Reaction SMILES: [C:1]([C:3]1([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([F:27])[CH:16]=2)[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42].N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C>[C:1]([C:3]1([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:25][CH2:26]3)=[CH:22][C:18]([C:19]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:21])=[C:17]([F:27])[CH:16]=2)[CH:10]2[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]1[CH2:12]3)[CH2:11]2)#[N:2]
Reactant: CS(N)(=O)=O
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 9.5 %

Procedure:
To a solution of 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid (0.17 g, 0.45 mmol) in anhydrous tetrahydrofuran (5 mL) was added 1,1′-carbonyldiimidazole (0.15 g, 0.89 mmol). The reaction solution was heated to reflux under a nitrogen atmosphere for 15 minutes and cooled to ambient temperature. To this reaction solution methanesulfonamide (0.10 g, 1.05 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL, 1.40 mmol) was added. The mixture was stirred at ambient temperature for 2.5 hours, then diluted with ethyl acetate (10 mL), washed with 1 M hydrochloric acid (2×10 mL) and brine (2×10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a colorless powder (0.019 g, 10%): 1H NMR (300 MHz, DMSO-d6) δ 11.94 (br s, 1H), 7.16-7.12 (m, 2H), 4.46 (s, 2H), 3.31 (s, 3H), 2.16-1.79 (m, 11H), 1.70-1.61 (m, 4H), 0.90-0.84 (m, 2H), 0.69-0.64 (m, 2H); MS (ES−) m/z 445.2 (M−1).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([NH:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([NH:36][CH3:37])=[O:35])=[CH:38][CH:39]=3)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Reactant: CNC(=O)c1ccc(CN)cc1
Product: CNC(=O)c1ccc(CNC(=O)Cn2ncc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc32)cc1

Procedure:
Example 127 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 117) and 4-(aminomethyl)-N-methylbenzamide to give the title compound (0.005 g).
Reaction SMILES: [Na+].[Cl-].[O:3]([CH2:10][C:11]([OH:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:17]([O:19][CH:20]([CH2:22][CH3:23])[CH3:21])=[O:18]>C(OCC)C>[C:17](=[O:18])([O:19][CH:20]([CH3:21])[CH2:22][CH3:23])[O:12][C:11](=[O:13])[CH2:10][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)COc1ccccc1
Reactant: CCC(C)OC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCC(C)OC(=O)OC(=O)COc1ccccc1
Temperature: 7.5 °C
Yield: 81 %

Procedure:
To a well-stirred reaction vessel equipped with a thermometer and a pH electrode were added 100 ml of diethyl ether, 40 ml of a 25 wt % aqueous NaCl solution, and 0.4 g of Arquad CB50. After cooling the reaction mixture to 5-10° C., 0.066 mole of phenoxy acetic acid was added. The pH was adjusted to a value between 6 and 7 using a 25 wt % aqueous NaOH solution. Then, 0.066 mole of sec-butyl chloroformate was dosed within 5 min at 5-10° C. During this time and a post-reaction time of 40 min at 5-10° C. the pH was kept at 6-7. The reaction mixture was allowed to separate. After removal of the diethyl ether, 15 g of phenoxyacetyl 1-methyl-1-propyl carbonate having a content of 90% were obtained in a yield of 81%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([O:20]C)=O)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.O.[NH2:23][NH2:24]>CCO>[NH2:1][C:2]1[C:3]([C:18]([NH:23][NH2:24])=[O:20])=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: NN
Reactant: CCC(=O)N1CCC(c2cnc(N)c(C(=O)OC)n2)CC1
Solvent: O
Solvent: CCO
Product: CCC(=O)N1CCC(c2cnc(N)c(C(=O)NN)n2)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 94.5 %

Procedure:
Methyl 3-amino-6-(1-propanoyl-4-piperidyl)pyrazine-2-carboxylate (110 mg, 0.38 mmol) was suspended in EtOH (2 mL) and hydrazine hydrate (94 mg, 92 μL, 1.9 mmol) was added and the reaction mixture was heated at 70° C. for 1.5 h, followed by 16 h heating at 35° C. forming a thick yellow solid. The solid was isolated by filtration, washed with water (20 mL) and ethanol (40 mL). The solid was dried under high vacuum to yield 3-amino-6-(1-propionylpiperidin-4-yl)pyrazine-2-carbohydrazide (105 mg, 95%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.12 (s, 1H), 7.27 (bs, 2H), 4.57-4.43 (m, 3H), 3.94 (d, J=13.6 Hz, 1H), 3.33 (bs, 2H), 3.13-2.97 (m, 1H), 2.90-2.76 (m, 1H), 2.58 (t, J=11.7 Hz, 1H), 2.34 (q, J=7.4 Hz, 2H), 1.83-1.70 (m, 3H), 1.69-1.55 (m, 1H), 1.01 (t, J=7.4 Hz, 3H). LC/MS m/z 293.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[S:17][C:11]=2[N:10]=[C:9]1[CH3:22].ClCCl.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([S:18]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)(=[O:20])=[O:19])[S:17][C:11]=2[N:10]=[C:9]1[CH3:22]
Reactant: CN1CCNCC1
Reactant: Cc1nc2sc(S(=O)(=O)Cl)cc2c(=O)n1-c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2sc(S(=O)(=O)N3CCN(C)CC3)cc2c(=O)n1-c1ccccc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101 %

Procedure:
To 5.0 g of 3,4-dihydro-3-(2-chlorophenyl)-6-chlorosulfonyl-2-methyl-4-oxothieno[2,3-d]pyrimidine were added 80 ml of dichloromethane, 4.5 ml of triethylamine and 1.4 g of N-methylpiperazine, and the mixture was stirred at room temperature for 20 minutes. After the reaction mixture was washed with water, isopropyl alcohol saturated with hydrochloric acid gas was added to the concentrated residue to convert it into hydrochloride, which was recrystallized from methanol to afford 3.2 g of the title compound, m.p. 295°-297° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][N:13]2[C:22](=[O:23])[C:21]3[CH:24]=[CH:25][CH:26]=[C:19]4[C:20]=3[C:15](=[C:16]3[CH:30]=[CH:29][CH:28]=[CH:27][C:17]3=[CH:18]4)[C:14]2=[O:31])(=O)=O)=CC=1.[CH2:33]([NH2:37])[CH2:34][CH2:35][NH2:36].[C:38](=[O:41])([O-])[O-].[Na+].[Na+]>C(#N)C>[O:31]=[C:14]1[C:15]2[C:20]3[C:19](=[CH:26][CH:25]=[CH:24][C:21]=3[C:22](=[O:23])[N:13]1[CH2:12][CH2:11][NH:36][CH2:35][CH2:34][CH2:33][NH:37][CH2:11][CH2:12][N:13]1[C:22](=[O:23])[C:21]3[CH:24]=[CH:25][CH:26]=[C:19]4[C:20]=3[C:15](=[C:16]3[CH:30]=[CH:29][CH:28]=[CH:27][C:17]3=[CH:18]4)[C:38]1=[O:41])[CH:18]=[C:17]1[CH:27]=[CH:28][CH:29]=[CH:30][C:16]1=2
Reactant: O=C([O-])[O-]
Reactant: NCCCN
Reactant: Cc1ccc(S(=O)(=O)OCCN2C(=O)c3cccc4cc5ccccc5c(c34)C2=O)cc1
Agent: [Na+]
Solvent: CC#N
Product: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCNCCCNCCN1C(=O)c2cccc3cc4ccccc4c(c23)C1=O
Yield: 19.3 %

Procedure:
A mixture of 2.2 g (5 mmol) of 2-[2-(p-toluenesulfonyloxy)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione, 0.4 g (2.5 mmol) of 1,3-propanediamine in 200 ml of acetonitrile is refluxed in the presence of 0.6 g (5.6 mmol) of sodium carbonate for 24 hours. The reaction mixture is concentrated in vacuo. The residue is treated with water (100 ml) and extracted with dichloromethane. The organic layers are combined, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed, eluting with dichloromethane, methanol, acetic acid (80:15:5). The appropriate fractions are combined, concentrated in vacuo and crystallized from toluene to give 0.3 g (20%) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-propanediamine. M.p. 191° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CCC2(CC1)OCCO2
Reaction time: 18 h
Yield: 101.4 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ylmethanol (8.60 g, 49.9 mmol) and imidazole (8.50 g, 125 mmol) in DMF (50 mL) was added tert-butyldimethylsilyl chloride (9.03 g, 59.9 mmol), and the mixture stirred at room temp. for 18 hours. The mixture was concentrated in vacuo and the residue redissolved in ethyl acetate (20 mL), washed with water followed by brine, then dried (Na2SO4), and concentrated in vacuo to provide the title compound (14.5 g, 50.6 mmol, 101% yield) as a clear oil: LCMS: m/z 287 (M+H); 1H NMR (500 MHz, CDCl3) δ ppm 0.01 (6H, s), 0.86 (9H, s),1.14-1.26 (2H, m), 1.45-1.54 (3H, m), 1.67-1.82 (4H, m), 3.40 (2H, d, J=6.7 Hz), 3.91 (4H, s); 13C NMR (126 MHz, CDCl3) δ ppm-5.25, 18.5, 26.1, 26.9, 34.3, 39.2, 64.3, 68.0, 109.3.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C@H:3]([NH2:5])[CH3:4].C(N(CC)CC)C.[Cl:15][C:16]1[C:21]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])=[C:20](Cl)[N:19]2[N:32]=[CH:33][N:34]=[C:18]2[N:17]=1>ClCCl>[Cl:15][C:16]1[C:21]([C:22]2[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=2[F:28])=[C:20]([NH:5][C@@H:3]([C:2]([CH3:7])([CH3:6])[CH3:1])[CH3:4])[N:19]2[N:32]=[CH:33][N:34]=[C:18]2[N:17]=1
Reactant: C[C@@H](N)C(C)(C)C
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2Cl)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(C)(C)C
Yield: 76 %

Procedure:
With stirring, a mixture of 1.4 mmol of (R)-3,3-dimethylbut-2-ylamine, 1.4 mmol of triethylamine and 10 ml of dichloromethane was introduced into a mixture of 1.4 mmol of 5,7-dichloro-6-(2,4,6-trifluorophenyl)-1,2,4-triazolo[1,5-a]-pyrimidine in 30 ml of dichloromethane. The reaction mixture was then stirred at room temperature for 16 hours and finally washed with 1 N hydrochloric acid and water. The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography. This gave the title compound in the form of colorless crystals in a yield of 76% (m.p.: 169-171° C.).
Reaction SMILES: OC1C=C2C(=CC=1)C(=O)N(C1C=C(OC)C=CC=1CCC1C=CC(OC)=CC=1)C2=O.Cl.ClCCN1CCCCC1.[CH3:41][O:42][C:43]1[CH:44]=[CH:45][C:46]([CH2:69][CH2:70][C:71]2[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=2)=[C:47]([N:49]2[C:57](=O)[C:56]3[C:51](=[CH:52][CH:53]=[C:54]([O:59][CH2:60][CH2:61][N:62]4[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]4)[CH:55]=3)[C:50]2=O)[CH:48]=1>>[CH3:41][O:42][C:43]1[CH:44]=[CH:45][C:46]([CH2:69][CH2:70][C:71]2[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=2)=[C:47]([N:49]2[CH2:57][C:56]3[C:51](=[CH:52][CH:53]=[C:54]([O:59][CH2:60][CH2:61][N:62]4[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]4)[CH:55]=3)[CH2:50]2)[CH:48]=1
Reactant: COc1ccc(CCc2ccc(OC)cc2N2C(=O)c3ccc(OCCN4CCCCC4)cc3C2=O)cc1
Agent: COc1ccc(CCc2ccc(OC)cc2N2C(=O)c3ccc(O)cc3C2=O)cc1
Agent: Cl
Agent: ClCCN1CCCCC1
Product: COc1ccc(CCc2ccc(OC)cc2N2Cc3ccc(OCCN4CCCCC4)cc3C2)cc1
Yield: 86.3 %

Procedure:
Synthesized from 5-hydroxy-2-{5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenyl} isoindole-1,3-dione and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Example 383 described below, 2-{5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenyl}-5-(2-piperidin-1-ylethoxy)isoindole-1,3-dione (772 mg) was used according to an analogous synthetic method to Example 337 to provide the title compound (630 mg).