Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([NH2:29])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1.ClCCCl.CO[CH:43]1[CH2:47][CH2:46][CH:45](OC)O1>O>[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([N:29]4[CH:43]=[CH:47][CH:46]=[CH:45]4)[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: COC1CCC(OC)O1
Agent: Br
Solvent: ClCCCl
Solvent: O
Product: CC(C)N1CC2N(C(=O)C(n3cccc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
64 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were suspended in 1 ml of water, and 1 ml of DCE was added. This mixture was mixed with 2 equivalents of 2,5-dimethoxytetrahydrofuran and stirred at 80° C. for 1 hour. The DCE phase was removed and the aqueous phase was extracted twice with DCE. The combined extracts were evaporated, and the crude substance was dissolved in a mixture of acetonitrile and water and freeze dried. The pure title compound was removed after purification by HPLC. The system and process described under “general processes” was used for this. MW=608.08 (calculated, monoisotopic); measured value (M+H)+: 609.4.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:44])[C@H:7]([NH:25][C@H:26]([C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-])=O)[CH:36]=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])([CH3:4])[CH3:3].C(O)C.O>[Pd].C(OCC)(=O)C>[CH3:1][C:2]([O:5][C:6](=[O:44])[C@H:7]([NH:25][C@H:26]([C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[CH:36]=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])([CH3:4])[CH3:3]
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1cccc(N)c1
Temperature: 25 °C

Procedure:
200 mg of 4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-(S)-[[(3-nitrobenzyl)amino]carbonyl]butyl]amino]-butanoic acid-1,1-dimethylethyl ester, prepared as in Example 30 where the protecting group Rp, 1,1-dimethylethyl was not removed following the condensation reaction seen in Scheme 1, was added to ethanol:H2O (20:1). 10 mL of ethyl acetate was added and the mixture was stirred with heating until the solid dissolved. The mixture was cooled to RT and 20 mg of 10% palladium over activated carbon was added. The mixture was purged with nitrogen. The mixture was purged with hydrogen, and stirred under hydrogen for 3 h. The mixture was filtered and washed with ethyl acetate. The solvents were removed by evaporation and the residue was purified by reverse phase H.P.L.C. to give a white solid; 83 mg
Reaction SMILES: [C:1]([C:5]1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=[CH:7][CH:6]=1)(C)(C)[CH3:2].C([C:41]1[CH:74]=[CH:73][C:44]([C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:62]=[C:61]4[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([O:67]C)=[O:66])[C:60]4=[O:63])=[CH:56][CH:55]=3)=[CH:50][C:49]=2[F:72])=[O:46])=[CH:43][CH:42]=1)(C)(C)C>>[F:72][C:49]1[CH:50]=[C:51]([C:54]2[CH:62]=[C:61]3[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:70])[CH3:71])[C:65]([OH:67])=[O:66])[C:60]3=[O:63])=[CH:56][CH:55]=2)[CH:52]=[CH:53][C:48]=1[NH:47][C:45](=[O:46])[C:44]1[CH:73]=[CH:74][C:41]([CH2:2][CH2:1][CH2:5][CH2:6][CH3:7])=[CH:42][CH:43]=1
Reactant: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)c(F)c3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2F)cc1
Yield: 83 %

Procedure:
The compound of example 446 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 443.
Reaction SMILES: FC(F)(F)C(O)=O.NN.[CH3:10][O:11][C:12](=[O:31])[CH2:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:17]=1)[NH2:15].[O-:32][C:33]#[N:34].[Na+]>C1(C)C=CC=CC=1>[NH2:34][C:33]([NH:15][N:14]([CH2:13][C:12]([O:11][CH3:10])=[O:31])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH:17]=1)=[O:32]
Reactant: N#C[O-]
Reactant: COC(=O)CN(N)c1cccc(OCc2ccc(F)cc2)c1
Agent: NN
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(NC(N)=O)c1cccc(OCc2ccc(F)cc2)c1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2.75 ml, 35.8 mmol) was added at 25° to a stirred suspension of the hydrazine (Intermediate 79, 3.7 g, 12.2 mmol) and sodium cyanate (2.71 g, 41.75 mmol) in toluene (70 ml). The mixture was stirred at 25° for 1 h, during which time a white solid precipitated. 8% sodium bicarbonate (100 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined extracts were then washed with water (2×100 ml) and brine (100 ml) before drying (Na2SO4) and evaporating in vacuo to a yellow oil. Trituration with hexane/ether/ethyl acetate (1:1:4) gave the title compound (Intermediate 80) as a white crystalline solid (2.9 g; 68%) m.p. 119°-121°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][N:12]2[C:23]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=2)=O)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:10])[N:11]3[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:13][N:12]3[C:23]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=2)=[CH:6][CH:7]=1
Reactant: CSc1nccc(C(=O)N2CC(OC(=O)C(C)(C)C)CN2C(=O)Cc2ccc(F)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CC(OC(=O)C(C)(C)C)C3)n1
Temperature: 0 °C
Yield: 30 %

Procedure:
2,2-Dimethyl-propionic acid 1-[2-(4-fluorophenyl)acetyl]-2-(methylsulfany-pyrimidine-4-carbonyl)-pyrazolidin-4-yl ester, 33, (300 mg, 0.651 mmol) is dissolved in THF (6 mL). This solution is then added dropwise via cannula to a suspension of NaH (29 mg of a 60% dispersion in mineral oil, 0.716 mmol) at −30° C. The reaction is allowed to gradually warm to 0° C. over 3 hours. The reaction is quenched with NH4Cl (sat. aq.) (1 mL). The mixture is stirred at room temperature, then concentrated in vacuo. The residue is diluted with tetrahydrofuran (50 mL) and the mixture filtered through Celite. The filtrate is concentrated in vacuo to give an orange oil. The crude product is purified over silica (100% ethyl acetate to 5% to 10% to 20% methyl alcohol/ethyl acetate) to afford 87 mg (30% yield) of the desired product as a yellow solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[C:27]1([CH2:33][O:34][C:35](=[O:48])[C@@H:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:38]O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:27]1([CH2:33][O:34][C:35](=[O:48])[C@@H:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:38][I:25])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCI)C(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
To a mixture of PPh3 (4.19 g, 16 mmol) and imidazole (1.09 g, 16 mmol) in anhydrous CH2Cl2 (40 mL) was added slowly iodine (4.07 g, 16 mmol) at rt. After 5 min, a solution of (2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-hydroxy-butanoic acid phenylmethyl ester (4.12 g, 13.3 mmol) in CH2Cl2 (20 mL) was added at 0° C. After 2 h at rt, the reaction mixture was filtered through a short silica gel column. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash chromatography (hexane-EtOAc, 95:5 to 9:1) to afford the product as light yellow oil (3.22 g, 58%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 2.20 (m, 1H), 2.40 (m, 1H), 3.13 (m, 2H), 4.35 (br.s, 1H), 5.10 (br.s, 1H), 5.20 (AB, 2H), 7.30–7.40 (m, 5H). LC-MS: 420 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[OH2:20].[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22]>>[CH3:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:3]=1[NH:4][C:22](=[O:20])[C:21]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(F)(F)F)ccc1N
Reactant: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc(C(F)(F)F)cc1C
Reaction time: 2 h

Procedure:
A solution of 37.5 g (214 mmol) of 2-methyl-4-trifluoromethylaniline (DE 2750170 A1) and 44.7 ml (321 mmol) of triethylamine in 750 ml of ethyl acetate is cooled to +3° C. by means of an icebath. Ethyl oxalyl chloride (26.2 ml, 235.5 mmol) is slowly added dropwise so that the temperature does not rise above +10° C. The mixture is then stirred for a further 2 hours. The mixture is treated with water, washed with a 10% aqueous sodium hydrogencarbonate solution and with brine, dried over sodium sulfate and concentrated. Crystallization of the crude product affords 52.75 g of the title compound as white crystals.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2.[CH3:16]C1C=CC(S(O)(=O)=O)=CC=1.C(OC)(OC)OC.C([O-])(O)=O.[Na+]>CO.OS(O)(=O)=O>[OH:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)c1cc2cccc(O)c2cc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: COC(=O)c1cc2cccc(O)c2cc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 4404.1 %

Procedure:
To a solution of 3,5-dihydroxy-2-naphthoic acid (5.05 g) in MeOH (100 mL) was added TsOH (93 mg). Tho reaction mixture was stirred at reflux for 18 hours and then CH(OMe)3 (1 mL) was added. The reaction mixture was stirred at reflux for an additional 5 hours, at which point H2SO4 (10 drops) was added. After an additional 18 h, the reaction mixture was cooled to rt, poured into saturated aqueous NaHCO3 and extracted with EtOAc. The extract was dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow-white solid (5.19 g, 96%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][NH:7][NH2:8].C([C:11](CC)([C:15]([C:17]([O-:19])=[O:18])=O)[C:12]([O-:14])=O)C.[Na+].[Na+].[CH2:24](O)[CH3:25]>>[CH2:24]([O:19][C:17]([C:15]1[CH:11]=[C:12]([OH:14])[N:7]([CH3:6])[N:8]=1)=[O:18])[CH3:25]
Reactant: CCO
Reactant: CCC(CC)(C(=O)[O-])C(=O)C(=O)[O-]
Reactant: CNN
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc(O)n(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 800 ml of ethanol were added 108 g (1.1 mol) of sulfuric acid, 92.1 g (2.0 mol) of methylhydrazine, and 462.4 g (2.20 mol) of sodium diethyloxalacetate. This mixture was stirred at room temperature for 2 hours, and then heated with refluxing and stirring for 3 hours. After the ethanol was distilled off, 800 ml of water was added to the residue. The resulting mixture was allowed to stand at room temperature overnight, and the crystals yielded were taken out by filtration and washed with water. Yield: 279 g (82%). Melting point: 151°-153° C.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH3:13][CH2:14]O>>[O:1]=[C:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:13][CH3:14])=[O:4]
Reactant: CCO
Reactant: CCC(=O)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of 2-oxobutanoic acid (6.0 g, 58.8 mmol) in EtOH (100 mL) was added sulfuric acid (1 mL) at room temperature. The resulting mixture was stirred for 4 h under reflux. The solvent was removed, and the residue was diluted with water (50 mL) and the pH was adjusted to 7 with a solution of NaOH (1 N). The mixture was extracted with EtOAc (100 mL×3). The combined organic layer was dried over sodium sulfate and concentrated to give ethyl 2-oxobutanoate (7.5 g, 98% yield). ESI MS: m/z 131 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cccc(F)c3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(-c2ccc(CN3CCNCC3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A 100 mL round-bottom flask, was charged with tert-butyl 4-[[5-(3-fluorophenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate (950 mg, 2.56 mmol, 1.00 equiv), dichloromethane (15 mL), trifluoroacetic acid (2 mL). The resulting solution was stirred for overnight at room temperature. The resulting mixture was concentrated under reduced pressure to provide 500 mg (crude) of 1-[[5-(3-fluorophenyl)pyridin-2-yl]methyl]piperazine as yellow oil. LCMS (ESI, m/z): 272 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([Si](C)(C)C)[N:16]=[N:15]2)=[CH:10][CH:9]=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[N:14]1([C:11]2[CH:10]=[CH:9][C:8]([C:3]3[N:4]=[C:5]([NH2:7])[S:6][C:2]=3[Cl:1])=[CH:13][CH:12]=2)[CH:18]=[CH:17][N:16]=[N:15]1
Reactant: C[Si](C)(C)c1cn(-c2ccc(-c3nc(N)sc3Cl)cc2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-c2ccc(-n3ccnn3)cc2)c(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-4-(4-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)thiazol-2-amine (0.70 g, 2.0 mmol), prepared in the previous step, in THF (10 mL) at 0° C. was added acetic acid (0.125 mL, 2.2 mmol) and tetrabutylammonium fluoride (2.2 mL, 1 M in THF, 2.2 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h, heated to 40° C. for 2 h, and additional AcOH (0.035 mL, 0.61 mmol) and TBAF (0.60 mL, 1 M in THF, 0.60 mmol) were added. Stirring was continued at 40° C. After 3 h, the reaction mixture was poured into water (300 mL). The precipitate that formed was collected by filtration, washed with water, and dried under high vacuum. Purification by flash column chromatography on silica gel (eluted with 50% to 100% EtOAc in hexanes gave 4-(4-(1H-1,2,3-triazol-1-yl)phenyl)-5-chlorothiazol-2-amine.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:9]([C:10](=[O:12])[N:11]=1)=[CH:8][C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=2.Cl.Cl.[CH2:19]([N:26]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[N:28]=[CH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>COCCO.O>[CH2:19]([N:26]1[C:34]2[CH2:33][CH2:32][N:31]([C:2]3[NH:11][C:10](=[O:12])[C:9]4[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=4)[N:3]=3)[CH2:30][C:29]=2[N:28]=[CH:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc2[nH]c(Cl)nc(=O)c2cc1OC
Reactant: c1ccc(Cn2cnc3c2CCNC3)cc1
Agent: Cl
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc2nc(N3CCc4c(ncn4Cc4ccccc4)C3)[nH]c(=O)c2cc1OC
Temperature: 120 °C
Reaction time: 6 h
Yield: 29.9 %

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1 (wherein R is methyl and Z is —C(O)—, 296 mg, 1.24 mmol), 1-benzyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine dihydrochloride 15a (440 mg, 1.54 mmol)) and diisopropylethylamine (1.2 g, 9.26 mmol) in 2-methoxyethanol (10 mL) was stirred at 120° C. for 6 hours. The reaction mixture was concentrated in vacuo to give an oil residue, which was diluted with water. The white precipitate that formed was collected by filtration to give 155 mg of 2-(1-benzyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-6,7-dimethoxy-3H-quinazolin-4-one 501, [M+H]+=418.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[CH:16]1([CH:22]=[CH:23][C:24](Cl)=[O:25])[CH2:21][CH2:20]CCC1.N1C=CC=C[C:28]=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:20](/[CH:21]=[CH:16]/[C:22]3[CH:23]=[CH:24][O:25][CH:28]=3)=[N:15][C:4]=2[CH:3]=1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Reactant: O=C(Cl)C=CC1CCCCC1
Reactant: Nc1cc(F)ccc1Nc1ccccn1
Product: Fc1ccc2c(c1)nc(/C=C/c1ccoc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 4-fluoro-2-amino-N-(2-pyridyl)aniline and (E)-3-(3-Cyclohexylacryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 305.31; mp: 168.0-170.0° C.; 1H-NMR (CDCl3) δ: 8.82-8.76 (1H, m), 8.15 (1H, d, J=16.0 Hz), 8.04 (1H, ddd, J=7.7, 7.7, 1.8 Hz), 7.71 (1H, s), 7.60-7.50 (3H, m), 7.43-7.33 (2H, m), 7.05 (1H, ddd, J=9.1, 9.1, 2.5 Hz), 6.74 (1H, d, J=16.0 Hz), 6.53 (1H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[F-:13].[K+].O>CC#N>[C:8]([C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([F:13])[N:7]=1)#[N:9]
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1nc(F)ccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A mixture of 6-chloro-2-cyano-3-nitropyridine [Colbry, N. L.; Elslager, E. F. ; Werbel, L. M.; J. Het. Chem., 1984, 21, 1521-1525] (10.0 g, 0.054 mol) and KF (9.48 g, 0.163 mol) in MeCN (200 mL) is heated under reflux with stirring for 18 h, then poured into water and extracted with EtOAc. The extract is washed with water and worked up, and the residue is chromatographed on silica gel, eluting with EtOAc/petroleum ether (3:7), to give after removal of the solvent under reduced pressure 2-cyano-6-fluoro-3-nitropyridine (7.2 g, 79%). 1H NMR (CDCl3) δ 8.79 (1H, dd, J=9.0, 6.0 Hz), 7.48 (1H, dd, J=9.0, 3.0 Hz).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[NH:25][C:26](=[O:29])[CH2:27][O:28][C:23]=2[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[N:25]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:26](=[O:29])[CH2:27][O:28][C:23]=2[CH:22]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: O=C1COc2cc(Cl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)CN3C(=O)COc4cc(Cl)ccc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (331 mg, 1.1 mmol, 1 equiv) in 5 ml of DMF, 4H-Benzo[1,4]oxazin-3-one (28) (200 mg, 1.1 mmol, 1.0 equiv) and cesium carbonate (710 mg, 2.2 mmol, 2 equiv) was stirred at RT overnight. The reaction solution was diluted with EtOAc, and the organic solution was washed with water. Purification of the crude reaction mixture using flash chromatography provided 7-chloro-4-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-benzo[1,4]oxazin-3-one (29): LCMS Retention time, 2.58 min.; LCMS observed (M+H)+: 450.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([Cl:26])=[CH:7][C:8]([NH:19][CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[C:9]([CH:18]=1)[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])(=[O:4])=[O:3].[CH3:27][O:28][C:29](=[O:39])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37]Cl)=[O:35].C1CN2C(=NCCC2)C1.C(#N)C>ClCCl>[Cl:26][C:6]1[CH:7]=[C:8]([NH:19][CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[C:9]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:15])[Cl:16])=[O:11])=[CH:18][C:5]=1[S:2]([NH:1][CH2:37][O:36][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][C:29]([O:28][CH3:27])=[O:39])(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl
Reactant: COC(=O)CCCCC(=O)OCCl
Agent: C1CN=C2CCCN2C1
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2,2,2-trichloroethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate (0.060 mole), chloromethyl 6-methoxy-6-oxohexanoate (0.060 mole), DBN (1,5-diazabicyclo[4.3.0]non-5-ene, Aldrich) (0.060 mole) and dry acetonitrile (100 mL) is stirred at ambient temperature for 10 hours. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which is purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give methyl 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoate.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[O:9]=[C:7]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CCN
Reactant: CC(=O)SC/C(=C/c1ccccc1)C(=O)O
Product: COC(=O)CCNC(=O)/C(=C\c1ccccc1)CSC(C)=O
Yield: 60 %

Procedure:
The (E)-2-acetylthiomethyl-3-phenylpropenoic acid described in Example 1 (step C) is coupled with methyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield: 60% (after flash chromatography, eluent: ether/petroleum ether 6/4) m.p. 54° C. IR (nujol): 3280, 1720, 1680, 1630, 1610 cm-1 1H NMR: 7.20, (s, 5H); 6.80 (s, 1H); 5.90 (broad s, 1H); 3.85 (s, 2H); 3.50 (s, 3H); 3.60 to 3.30 (m, 2H); 2.35 (t, 2H, J=5.30 Hz); 2.25 (s, 3H). Microanalysis: C16H19O4NS Calc. % C=59.79 H=5.96 N=4.36 Found. % C=59.67 H=6.28 N=4.47
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.C[Si]([C:17]#[N:18])(C)C.[OH-:19].[Na+]>C(O)(=O)C>[CH:17]([NH:18][C:2]1([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1)=[O:19]
Reactant: C[Si](C)(C)C#N
Reactant: [OH-]
Reactant: CC1(C)CC(C)(C)CC(C)(O)C1
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)CC(C)(C)CC(C)(NC=O)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80 %

Procedure:
To a vigorously stirred solution of 1,3,3,5,5-pentamethylcyclohexanol (3-13) (2.7 g, 15.6 mmol) and trimethylsilyl cyanide (2.36 g, 23.8 mmol) in acetic acid (2.5 ml) under argon 98% sulfuric acid (4.66 g, 47.6 mmol) was added, keeping temperature below -5° C. The mixture was stirred at room temperature for 22 h, then it was poured onto ice (100 g), neutralised with 50% NaOH solution to pH ~7 and extracted with ether (3*30 ml). The combined ether phases were washed with saline (50 ml), then dried over MgSO4 and evaporated. A slightly yellow crystalline residue was treated with small amount of acetonitrile and filtered off to give 2.5 g (80%) of 14-1 as a white crystals, m.p. 104-106° C. 1H NMR (CDCl3, TMS) δ: 0.91 and 0.93 (total 6H, both s, 3,5-CH3eq); 1.08 (2H, m, 2,6-CHeq); 1.13 and 1.15 (total 6H, both s, 3,5-CH3ax); 1.25 (2H, m, 4-CH2); 1.32 and 1.38 (total 3H, both s, 1-CH3); 1.70 and 2.12 (total 2H, both d, 14.7 Hz, 2,6-CHax); 5.30 and 5.60 (total 1H, both br s, NH); 8.05 and 8.30 ppm (total 1H, both d, 2.0 and 12.7 Hz, resp., HCO).