Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[CH:19]1([C:22]([NH2:24])=[NH:23])[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[N:23]=[CH:4][C:5]3[CH2:6][C:7](=[O:17])[NH:8][C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[C:11]=3[N:24]=2)[CH2:21][CH2:20]1
Reactant: N=C(N)C1CC1
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Agent: Cl
Product: O=C1Cc2cnc(C3CC3)nc2-c2ccccc2N1
Yield: 62 %

Procedure:
Analogous to Scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and cyclopropanecarboxamidine hydrochloride. Yield: 62%.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[NH:30][CH3:31])[C:18]([NH:20][CH2:21][C:22](=[O:26])[N:23]([CH3:25])[CH3:24])=[O:19].[CH2:32](Cl)CCl>CN(C=O)C>[CH3:24][N:23]([CH3:25])[C:22]([CH2:21][NH:20][C:18]([C:17]1[CH:27]=[CH:28][C:29]2[N:30]([CH3:32])[C:31]([NH:11][C:9]3[S:10][C:6]4[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:13]=[CH:12][C:7]=4[N:8]=3)=[N:14][C:15]=2[CH:16]=1)=[O:19])=[O:26]
Reactant: CNc1ccc(C(=O)NCC(=O)N(C)C)cc1N
Reactant: ClCCCl
Reactant: CC(C)c1ccc2nc(N)sc2c1
Solvent: CN(C)C=O
Product: CC(C)c1ccc2nc(Nc3nc4cc(C(=O)NCC(=O)N(C)C)ccc4n3C)sc2c1
Yield: 3.4 %

Procedure:
2-(6-Isopropyl-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (12 mg) was prepared by following General Procedure D starting from 6-isopropyl-benzothiazol-2-ylamine (150 mg), 3-amino-N-dimethylcarbamoylmethyl-4-methylamino-benzamide (200 mg), thioCDI (200 mg) and EDC (200 mg) in DMF (3 mL). LC/MS: m/z 450.6.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)[CH2:7][CH3:8].II.[I:33](O)(=O)=O>O.C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH2:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([I:33])=[CH:29][CH:30]=3)[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)[CH2:7][CH3:8]
Reactant: [O-][I+2]([O-])O
Reactant: CCCc1ccc(CC[C@H]2CC[C@H](CCc3ccccc3)CC2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1ccc(CC[C@H]2CC[C@H](CCc3ccc(I)cc3)CC2)cc1
Yield: 46.8 %

Procedure:
To a mixed solution comprising 250 ml of acetic acid, 25 ml of carbon tetrachloride, 25 ml of concentrated sulfuric acid, and 50 ml of water were added 26 g of the (2-(trans-4-(2-(4-n-propylphenyl)ethyl)cyclohexyl)ethyl)benzene mentioned above, 10 g of iodine, and 8.4 g of iodic acid, and they were stirred under a reflux for 2 hours. After cooled, they were washed with a saturated aqueous solution of sodium thiosulfate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain a yellow-brown oily product. This product was purified by a column chromatography over an alumina by using heptane as an eluent, and then recrystallized from heptane to obtain 10.3 g of 4-(2-(trans-4-(2-(4-n-propylphenyl)ethyl)cyclohexyl)ethyl)iodobenzene.
Reaction SMILES: CC(C)(C)[C@@H](C(O)=O)N[C:5](OCCCC=C)=[O:6].[C:18]([O:22][CH2:23][C@@H:24]([C:26]([OH:28])=[O:27])[NH2:25])([CH3:21])([CH3:20])[CH3:19].[CH3:29][C:30]([CH3:37])([CH2:33][CH2:34][CH:35]=[CH2:36])[CH2:31][OH:32]>>[C:18]([O:22][CH2:23][C@@H:24]([C:26]([OH:28])=[O:27])[NH:25][C:5]([O:32][CH2:31][C:30]([CH3:37])([CH3:29])[CH2:33][CH2:34][CH:35]=[CH2:36])=[O:6])([CH3:21])([CH3:19])[CH3:20]
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC[C@H](N)C(=O)O
Reactant: C=CCCC(C)(C)CO
Product: C=CCCC(C)(C)COC(=O)N[C@@H](COC(C)(C)C)C(=O)O

Procedure:
O-(tert-Butyl)-N-{[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}-L-serine was prepared according to the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine using O-(tert-butyl)-L-serine and 2,2-dimethylhex-5-en-1-ol. 1H NMR (500 MHz, CDCl3, ppm) δ 5.75-5.86 (m, 1 H), 4.90-5.04 (m, 2 H), 4.02 (m, 1 H), 3.57-3.90 (m, 4 H), 1.98-2.05 (m, 2 H), 1.27-1.36 (m, 2 H), 1.14 (s, 9 H), 1.01 (d, J=6.5 Hz, 1 H), and 6.09 (s, 6 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:13][CH2:14][CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:10][CH2:16][CH2:15][CH:14]=[CH2:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C=CCCBr
Reactant: O=Cc1cc(Br)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCOc1c(F)cc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde from step 4A (2.0 g, 9.13 mmol) in DMF (36.5 ml) was added 4-bromo-1-butene (3.71 ml, 36.5 mmol) and potassium carbonate (1.58 g, 11.4 mmol). The resulting mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (100 mL), washed with water (3×30 mL) and brine (30 mL), dried over magnesium sulfate, and then filtered and concentrated in vacuo. Purification by silica gel column chromatography (0-20% EtOAc/hexanes) gave 5-bromo-2-(but-3-enyloxy)-3-fluorobenzaldehyde (2.38 g, 8.71 mmol, 95% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.22 (d, J=0.9 Hz, 1H), 7.98 (dd, J=11.3, 2.4 Hz, 1H), 7.63 (dd, J=2.4, 1.2 Hz, 1H), 5.89 (ddt, J=17.1, 10.4, 6.7 Hz, 1H), 5.17 (dd, J=17.2, 1.7 Hz, 1H), 5.12-5.07 (m, 1H), 4.29 (t, J=6.4 Hz, 1H), 2.57-2.49 (m, 3H).
Reaction SMILES: C([NH:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([Cl:19])=[CH:12][C:6]=1[CH2:7][O:8]C(=O)C)(=O)C.[OH-].[Na+].Cl>CO.O>[NH2:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([Cl:19])=[CH:12][C:6]=1[CH2:7][OH:8]
Reactant: CC(=O)Nc1c(COC(C)=O)cc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1c(CO)cc(Cl)cc1[N+](=O)[O-]
Yield: 260 %

Procedure:
Acetic acid 2-acetylamino-5-chloro-3-nitro-benzyl ester (0.454 g, 0.45 mmol) and sodium hydroxide (0.436 g, 11 mmol) were dissolved in methanol-water (1:3, 40 ml) and the resulting solution heated at reflux for 5 h. After cooling the mixture was taken to pH 6 by the addition of conc. HCl. The precipitate formed was collected by filtration to give (2-amino-5-chloro-3-nitro-phenyl)-methanol as a dark orange solid (0.237 g, 73%). (LC/MS: Rt 2.63, [M−H]− 200.96).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6](=[O:7])[C:5]2[C:8]([CH3:17])=[C:9]([CH3:16])[C:10]([NH:13][CH:14]=[O:15])=[C:11]([CH3:12])[C:4]=2[O:3]1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1COCC1>[CH2:19]([C:6]1([OH:7])[C:5]2[C:8]([CH3:17])=[C:9]([CH3:16])[C:10]([NH:13][CH:14]=[O:15])=[C:11]([CH3:12])[C:4]=2[O:3][C:2]1([CH3:18])[CH3:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1NC=O)OC(C)(C)C2=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)c2c(c(C)c1NC=O)OC(C)(C)C2(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2,2,4,5,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-6-yl)formamide obtained in Reference Example 73 (600 mg, 2.43 mmol) in THF (5 mL) was added dropwise to a solution of benzylmagnesium chloride (a 2.0 M THF solution, 10.0 mL, 20.0 mmol) in THF (20 mL) under argon atmosphere, and the mixture was stirred at room temperature for 2 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain (3-benzyl-3-hydroxy-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-yl)formamide. To a mixture of said compound with trifluoroacetic acid (5 mL) was added triethylsilane (0.5 mL, 3.2 mmol) with ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and to the residue was added a saturated sodium hydrogen carbonate solution to alkalify the aqueous layer, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a solution of the obtained residue in methanol (20 mL) was added concentrated hydrochloric acid (10 ml), and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure and the residue was neutralized with a 12 N aqueous sodium hydroxide solution. After extracting with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 440 mg (yield 62%) of the title compound. Melting point: 75-76° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][NH2:15].[S:17]1(=[O:28])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][NH:20][CH2:19][CH2:18]1>>[O:28]=[S:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][N:20]([C:2]2[N:3]=[C:4]([NH:15][CH2:14][CH2:13][CH2:12][NH2:16])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:19][CH2:18]1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: O=S1CCNCc2ccccc21
Reactant: NCCCN
Product: NCCCNc1nc(N2CCS(=O)c3ccccc3C2)nc2ccsc12

Procedure:
The title compound was prepared in analogy to Example 1-1 in Scheme 1 by using 2,4-dichlorothieno[3,2-d]pyrimidine and propane-1,3-diamine, followed by reaction with 2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide. MS obsd. (ESI+) [(M+H)+] 388, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.73-7.78 (m, 2H), 7.71 (d, J=8.3 Hz, 1H), 7.43-7.52 (m, 2H), 7.11 (d, J=5.3 Hz, 1H), 5.24 (d, J=15.2 Hz, 2H), 3.68-3.74 (m, 2H), 3.50 (br. s., 2H), 3.46 (br. s., 2H), 2.93 (t, J=7.6 Hz, 2H), 1.93-2.03 (m, 2H)
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[C:17](Cl)(=[O:19])[CH3:18]>>[C:17]([N:6]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:16])(=[O:19])[CH3:18]
Reactant: CN(C)CCCNc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Cl
Product: CC(=O)N(CCCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(3-dimethylamino-propylamino)-nitrobenzene and acetylchloride
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:21]2[C:26](/[CH:27]=[N:28]/[S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:21]2[C:26]([CH2:27][NH:28][S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)/N=C/c1cccnc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)S(=O)NCc1cccnc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Yield: 74 %

Procedure:
To a solution of N-[(1E)-(2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}pyridin-3-yl)methylene]-2-methylpropane-2-sulfinamide (170 mg, 0.34 mmol) in MeOH (1.2 ml) and CH2Cl2 (2.5 ml) was added NaBH4 (78 mg, 2.06 mmol). The reaction was left for 10 minutes, before addition of water (2 mL). The mixture was extracted with CH2Cl2 dried (Na2SO4) and evaporated in vacuo to give the title compound as a solid (125 mg). 1H NMR (400 MHz, d6-DMSO): δ 8.72 (1H, s), 8.43 (1H, t, J=2.3 Hz), 8.38 (1H, s), 8.34 (1H, d, J=8.7 Hz), 8.23 (2H, dd, J=8.2, 10.2 Hz), 8.04 (1H, dd, J=1.8, 8.6 Hz), 7.95-7.91 (3H, m), 7.69 (1H, dd, J=4.6, 8.0 Hz), 7.38 (2H, t, J=8.8 Hz), 5.98 (1H, t, J=6.5 Hz), 4.88-4.78 (2H, m), 1.18 (9H, s). m/z (ES+) 497 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][NH:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:30][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(=O)NCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1
Yield: 73.5 %

Procedure:
A solution of Ethyl 2-(2-(4-nitrophenyl)-2-oxoethylamino)-2-oxoacetate (Intermediate 1, step C, 5 g) and Lawesson's reagent (7.22 g) in 1,4-Dioxane (100 ml) was refluxed for 2 hours. The reaction mixture was cooled, water was added and the mixture was neutralized with saturated solution of Na2CO3. This was followed by addition of EtOAc and then the layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to get dark brown residue. The residue was chromatographed on silica gel in 0.5:9.5 EtOAc:CHCl3 to get dark yellow colored solid which was crystallized in CHCl3/pet ether to yield 3.65 g (73%) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 8.33 (d, 2H), 8.3 (s, 1H), 7.83 (d, 2H), 4.54 (q, 2H), 1.49 (t, 3H); MS (ES+) m/z 279 (M+1).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH3:12])[C:5]2=[N:4][CH:3]=1.[S:13]1C=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCCC1.O>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[NH:11][C:10]1[C:5]2[N:6]([CH:2]=[CH:3][N:4]=2)[CH:7]=[CH:8][N:9]=1
Reactant: OB(O)c1cccs1
Reactant: CNc1nccn2c(Br)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1csc(Nc2nccn3ccnc23)c1
Temperature: 70 °C
Yield: 100 %

Procedure:
To a solution of (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine (50 mg, 0.2 mmol) in tetrahydrofuran (2 ml) under nitrogen was added 2-thiopheneboronic acid (41 mg, 0.3 mmol), K2CO3 (1.1 ml of a 1 M solution in water) and 16 mg (0.1 mmol) of PdCl2(Dppf)CH2Cl2 (16 mg, 0.1 eq). The mixture was heated at 70° C. in a sealed tube overnight. The product was precipitated by adding methanol. The filtrate was evaporated and purified by preparative thin layer chromatography on silica gel to give additional title compound for a total of 45 mg (100% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](=[O:19])(=[O:18])[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:8]=2)[C:3]=1[CH:20]=O.Cl.[NH2:23][OH:24].[C:25]([O-])(=O)C.[Na+]>>[CH3:25][O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](=[O:18])(=[O:19])[N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[CH:8]=2)[C:3]=1[CH:20]=[N:23][OH:24]
Reactant: CC(=O)[O-]
Reactant: CCN(CC)S(=O)(=O)c1ccc2c(C=O)c(O)ccc2c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Product: CCN(CC)S(=O)(=O)c1ccc2c(C=NO)c(OC)ccc2c1

Procedure:
The 2-hydroxy-6-(N,N-diethylsulfamoyl)-1-naphthaldehyde thus-obtained was methylated and then reacted using hydroxylamine hydrochloride and sodium acetate in the same manner as described in Synthesis Example 2 to obtain 2-methoxy-6-(N,N-diethylsulfamoyl)-1-naphthaldoxime.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:33])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C2CCCCC2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C2CCCCC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-cyclohexylpiperazin-1-yl)quinolin-7-yl]ethanone (0.094 g, 0.25 mmol) and ammonium acetate (0.195 g, 2.53 mmol) in methanol (1 mL) and acetonitrile (1 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.632 mL, 0.632 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H30ClN4 (M+H)+: m/z=373.2; Found: 373.3.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][C:9](=O)[CH3:10])[C:3]([O:5]C)=O.[CH2:12]([NH2:15])[CH2:13][NH2:14]>CCCCCCC>[CH3:10][CH:9]1[CH:8]2[N:15]([C:3](=[O:5])[CH:2]([CH3:1])[CH2:7]2)[CH2:12][CH2:13][NH:14]1
Reactant: NCCN
Reactant: COC(=O)C(C)CCC(C)=O
Solvent: CCCCCCC
Product: CC1CC2C(C)NCCN2C1=O
Temperature: 38 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
124.2 g (0.75 mole) of methyl 2-methyl-5-oxohexanoate in 450 ml of n-heptane are initially taken. 52.2 g (0.87 mole) of ethylenediamine are then added dropwise at room temperature in the course of 10 minutes. As a result of the exothermic reaction, the temperature increases to 38° C. 49 ml of the lower phase (aqueous methanol) are separated off. The mixture is cooled to 2° C. and stirred for 1 hour, and the product is filtered off under suction, washed with cold n-heptane and dried. 116.3 g of racemic 5,8-dimethyl-9-oxo-1,4-diazabicyclo[4.3.0]nonane are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13](O)=O)[CH:10]=2)[N:5]=[CH:4][NH:3]1.[C:16]1([C:22]2[N:27]=[N:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[C:16]1([C:22]2[CH:23]=[CH:24][C:25]3[N:26]([C:13]([CH2:12][C:9]4[CH:10]=[C:11]5[C:6](=[CH:7][CH:8]=4)[N:5]=[CH:4][NH:3][C:2]5=[O:1])=[N:29][N:28]=3)[N:27]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)Cc1ccc2nc[nH]c(=O)c2c1
Reactant: NNc1ccc(-c2ccccc2)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]cnc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc12
Temperature: 150 °C

Procedure:
A mixture of 2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetic acid (0.10 g, 0.5 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.1 g, 0.6 mmol) and p-toluenesulfonic acid monohydrate (0.09 g, 0.5 mmol) in 3 mL of dioxane was heated with microwave at 150° C. for 1 hour in a microwave tube. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3 solution. The organic phase was separated and was washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc) to give light yellow solid as desired product 6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinazolin-4(3H)-one. MS (ESI, pos. ion) m/z: 355.1 (M+1).
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].N12CCCN=C1CCCCC2>C(#N)C>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][S:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: C=CC(=O)OC
Reactant: O=C(O)c1cccc(CS)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CCSCc1cccc(C(=O)O)c1

Procedure:
Into a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(mercaptomethyl)benzoic acid (500 mg, 2.97 mmol, 1.00 equiv) in acetonitrile (10.0 mL), then methyl acrylate (10.0 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.0 g, 6.57 mmol, 2.00 equiv) were added in series. The resulting solution was heated to reflux overnight. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (0˜1:6). This resulted in 220 mg (28%) of 3-((3-methoxy-3-oxopropylthio)methyl)benzoic acid as a light-red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH2:11][CH:12]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH2:13]O.C(N(CC)CC)C.S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH2:13][CH:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[N:11]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc(CC(N)CO)cc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(CC2COC(c3cccc(Cl)c3)=N2)cc1
Temperature: 25 °C

Procedure:
A solution of 1.75 g (10 millimoles) of 3-chlorobenzoyl chloride in 15 ml of tetrahydrofuran was added with ice cooling and stirring to a 100 ml egg-plant-shaped flask containing 1.61 g (10 millimoles) of 2-amino-3-(4-methyl-phenyl)-1-propanol, 1.01 g (10 millimoles) of triethylamine and 30 ml of tetrahydrofuran over the course of 30 minutes. The mixture was further stirred at 20° C. for 3 hours. The resulting triethylamine hydrochloride was removed by a glass filter, and the filtrate was concentrated under reduced pressure. Thionyl chloride (5 ml; 68 millimoles) was added all at once to a 100 ml eggplant-shaped flask containing this concentrate and 30 ml of benzene. With stirring, the mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The concentrate was dissolved in 100 ml of ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A 100 ml eggplant-shaped flask containing this concentrate and 30 ml of ethanol was heated to 70° C. over an oil bath with stirring, and 15 ml of a 3 % aqueous solution of sodium hydroxide was added over 10 minutes. The mixture was further stirred at 70° C. for 20 minutes, and concentrated under reduced pressure. Benzene (100 ml) was added to the concentrate, and the mixture was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=7/3) to give 2-(3-chlorophenyl)-4-(4-methylbenzyl) -2-oxazoline (compound No. 108) as a yellow viscous oil. Yield 1.7 g (59.5 %).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([NH2:19])=[C:17]([OH:20])[C:16]([Br:21])=[CH:15][C:14]=2[F:22])[C:3]1=[O:23].[C:24]([O:27][C:28]([C:31](Cl)=O)([CH3:30])[CH3:29])(=[O:26])[CH3:25].C(N(CC)CC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]3[N:19]=[C:29]([C:28]([O:27][C:24]([CH3:25])=[O:26])([CH3:31])[CH3:30])[O:20][C:17]=3[C:16]([Br:21])=[CH:15][C:14]=2[F:22])[C:3]1=[O:23]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c(O)c2N)c1=O
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)OC(C)(C)c1nc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Br)c2o1
Temperature: 25 °C
Yield: 109 %

Procedure:
A stirred solution of 0.50 gram (0.0013 mole) of 1-methyl-6-trifluoromethyl-3-(6-amino-4-bromo-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 0.21 gram (0.0013 mole) of 1-chlorocarbonyl-1-methylethyl acetate, 0.14 gram (0.0014 mole) of triethylamine, and 0.16 gram (0.0006 mole) of pyridinium p-toluenesulfonate in 50 mL of xylene was heated at 150 ° C. for about 18 hours. The reaction mixture was then cooled to ambient temperature and taken up in ethyl acetate. The solution was washed with water and an aqueous solution saturated with sodium chloride; then it was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 0.72 gram of Compound 104. The NMR spectrum was consistent with the proposed structure.