Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][NH:11][C:12]([N:14]([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].[CH3:24]I>CN(C)C=O>[CH2:3]([O:10][N:11]([CH3:24])[C:12]([N:14]([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CI
Reactant: CN(C(=O)NOCc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(OCc1ccccc1)C(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, a flask was charged with sodium hydride (0.29 g 60% NaH in mineral oil, 7.3 mmole). The mineral oil was washed from the sodium hydride using several portions of hexanes. N,N-Dimethylformamide (60 mL) was added followed by the slow addition of a solution of 1-benzyloxy-3-methyl-3-phenylurea (1.69 g, 6.6 mmole) in N,N-dimethylformamide (40 mL). Hydrogen evolution was observed. After about 30 minutes methyl iodide (480 μL) was added then the reaction was stirred at ambient temperature for about 1.5 hours. The reaction was quenched with water (about 65 mL). The aqueous layer was salted then extracted with diethyl ether (4×80 mL). The extracts were combined, dried over magnesium sulfate then concentrated to provide crude product as an oil. The crude product was purified by silica gel chromatography (5:1 hexanes:ethyl acetate) to provide 1.54 g of 1-benzyloxy-1,3-dimethyl-3-phenylurea.
Reaction SMILES: O[CH2:2][N:3]1[CH2:6][C:5]([CH3:8])([CH3:7])[C:4]1=[O:9].S(Cl)(Cl)=O.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([C:29]#[N:30])=[CH:24][CH:23]=3)[CH:15]=1.[H-].[Na+].[Cl-]>CN(C=O)C.ClCCl>[CH3:7][C:5]1([CH3:8])[CH2:6][N:3]([CH2:2][N:21]2[C:22]3[C:27](=[CH:26][C:25]([C:29]#[N:30])=[CH:24][CH:23]=3)[CH:28]=[C:20]2[C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[C:4]1=[O:9]
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: CC1(C)CN(CO)C1=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)CN(Cn2c(-c3cccnc3)cc3cc(C#N)ccc32)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is charged with 1-hydroxymethyl-3,3-dimethyl-azetidin-2-one (0.179 g, 1.317 mmol) and dichloromethane (5 mL), and thionyl chloride (0.63 g, 5.27 mmol) is added. The mixture is stirred at room temperature overnight and concentrated in vacuo to yield an oil, which is redissolved in DMF (0.8 mL). 2-Pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 0.213 g, 0.922 mmol) is dissolved in DMF (5 mL), cooled to 0° C., and NaH (0.053 g, 1.317 mmol) is added portionwise. After 30 min, the chloride solution is added. After 1 h, NaH (0.027 g, 0.67 mmol) is added and the mixture is stirred overnight. The mixture is quenched with a few drops of water and diluted with methanol and DMSO. The mixture is purified on Xbridge C18 eluting with a 9:1 to 1:9 water-acetonitrile gradient to give 1-(3,3-dimethyl-2-oxo-azetidin-1-ylmethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 1.18 (s, 6H), 2.82 (s, 2H), 5.47 (s, 2H), 6.71 (s, 1H), 7.47-7.51 (m, 1H), 7.56 (dd, J=8.6, 1.5 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.80-7.83 (m, 1H), 8.01 (d, J=1.5 Hz, 1H), 8.75-8.76 (m, 2H). HRMS (ESI) m/z 331.1558 [(M+H)+ Calcd for C20H19N4O: 331.1559].
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].[CH3:16][O:17][P:18]([O-:21])[O:19][CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][O:5][C:1](=[O:4])[CH:2]([P:18]([O:19][CH3:20])([O:17][CH3:16])=[O:21])[OH:3])=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COP([O-])OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COP(=O)(OC)C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a minute of 4.32 g of p-nitrobenzyl glyoxalate and 2.0 ml of dimethylphosphite in 25 ml of benzene is added a catalytic amount of p-toluenesulfonic acid. The reaction is heated at reflux temperature for 1.5 hours. The formed water is removed using a Dean-Stark trap. After cooling, the solvent is removed in vacuo and the resulting crystals are slurried in ethyl acetate and collected to give 3.48 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7](/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.[Mg].[CH:16](Br)=C>O1CCCC1>[CH3:16][CH:5]1[C:6]([CH3:14])([CH3:13])[CH:7](/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11])[C:2]([CH3:1])=[CH:3][CH2:4]1
Reactant: CC(=O)/C=C/C1C(C)=CCCC1(C)C
Reactant: C=CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)/C=C/C1C(C)=CCC(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 50 g (0.26 mol) of α-ionone in 150 ml of tetrahydrofuran was allowed to drop over a period of 20 minutes into a Grignard solution, which was cooled to 0° C. and which had been prepared from 9.72 g (0.4 mol) of magnesium shavings in 75 ml of tetrahydrofuran and 44.9 g (0.42 mol) of vinyl bromide in 180 ml of tetrahydrofuran, in such a manner that the temperature lay between 15° C. and 20° C. Subsequently, the mixture was stirred at room temperature for a further 3 hours and worked-up as described in Example 8. There were obtained 54.5 g of crude product which contained above 92% 9-vinyl-α-ionol according to GC and which was further processed directly in this form. In a manner analogous to the epoxidation of α-irone (Example 4), from 53.2 g (0.242 mol) of 9-vinyl-α-ionol there were obtained 59.0 g of crude 9-vinyl-α-ionol epoxide of which 58.0 g were dissolved together with 26.5 g (0.13 mol) of aluminium isopropylate in 175 ml of isopropanol. By following the procedure described in Example 1 there were obtained 57 g of a crude product. From this crude product there were obtained by distillation over a 20 cm Widmer column 15.0 g (26%) of olfactorily good product of boiling point 73°-74° C./0.3 mmHg which contained above 85% 20a and 20b in the approximate ratio of 3:2. In addition, there were present small amounts of the corresponding 7-oxa-bicyclooctane 20c. ##STR33##
Reaction SMILES: [Cl:1][C:2]1[C:15]([F:16])=[C:14]([Cl:17])[C:13]([F:18])=[C:12]([Cl:19])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:20](OCC)(OCC)OCC.C(OC(=O)C)(=O)C.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[Cl:1][C:2]1[C:15]([F:16])=[C:14]([Cl:17])[C:13]([F:18])=[C:12]([Cl:19])[C:3]=1[C:4]([C:6](=[CH:20][NH:40][CH:37]1[CH2:39][CH2:38]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: NC1CC1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1c(Cl)c(F)c(Cl)c(F)c1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(Cl)c(F)c(Cl)c(F)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
82.9 g of ethyl 2,4,6-trichloro-3,5-difluorobenzoylacetate (0.25 mol), 66.6 g of triethyl orthoformate (0.45 mol) and 77.4 g of diacetyl oxide (0.72 mol) were stirred at 150° C. for 2.5 hours. Fractions having a lower boiling point were evaporated under reduced pressure. To the residue was added 250 ml of anhydrous ethanol. 14.5 g of cyclopropylamine (0.25 mol) was added to the solution under cooling of ice water and the reaction was then carried at room temperature for 2 hours. The resultant mixture was filtered under suction. The residue was re-crystallized from a mixture of petroleum ether and cyclohexane to yield 74.5 g (0.187 mol) of ethyl 2-(2,4,6-trichloro-3,5-difluorobenzoyl)-3-cyclopropylaminoacrylate in 74.6% yield.
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C(Cl)Cl>[C:27]([NH:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A portion (70 mg) of the compound obtained in Example 81 was dissolved in anhydrous methylene chloride (15 ml) and to the solution were added triethylamine (69 μl) and benzoyl chloride (29 μl). The mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water, followed by extraction with methylene chloride. The organic layer was washed with 1N aqueous solution of sodium hydroxide, water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to yield 90 mg (91%) of the titled compound.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18].N1CCCCC1>C(O)C>[C:17]([C:19]1[C:20](=[O:21])[NH:22][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH2:9]2)#[N:18]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C1CC(c2ccncc2)CCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(=O)c(C#N)c2c1CC(c1ccncc1)CC2
Yield: 34.7 %

Procedure:
1.65 g of 2-acetyl-4-(4-pyridyl)cyclohexanone and 0.64 g of cyanoacetamide were dissolved in ethanol and a small amount of piperidine was added thereto. The obtained reaction mixture was heated under reflux for seven hours. After the completion of the reaction, crystals thus precipitated out were filtered to give 0.7 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:15][CH2:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 42 h
Yield: 127.1 %

Procedure:
A mixture of methyl 3-nitro-4-methylbenzoate (4.147 g), N-bromo-succinimide (7.12 g) and AIBN (0.40 g) in carbon tetrachloride (30 ml) was stirred at 70° C. for 42 hr. After cooling, the insoluble matter was filtered off and the filtrate was concentrated to give an oil (7.40 g) containing the object compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[N:13]1([CH2:18][CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:17]=[CH:16][N:15]=[N:14]1.[H-].[Na+].O>CN(C=O)C.ClCCl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][CH2:19][CH2:18][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Reactant: C=CCOc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: C=CCOc1ccc(CSCCn2ccnn2)cc1
Temperature: -30 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
1.58 g (6.14 mmol) (4-allyloxy-phenyl)-methanethiol and 1.64 g (6.14 mmol) toluene-4-sulfonic acid 2-[1,2,3]triazol-1-yl-ethyl ester were dissolved in 15 ml DMF and cooled to −30° C. 294 mg (12.3 mmol) 95% Sodium hydride were added, the mixture allowed to warm to r.t. and stirred for 12 h. 10 ml Water were added and the residue dissolved in dichloromethane. The organic phase was dried over Na2SO4, solvents removed and the remaining material purified by chromatography on silica gel (ethyl acetate/n-heptane 1:1) to yield 1.33 g (79%) yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(SC)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].C1(S)C=CC=CC=1.C(N(CC)CC)C.C(Cl)Cl>CO>[C:1]([NH:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(NC(C)=O)(SC)c1ccccc1
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(NC(C)=O)c1ccccc1
Yield: 99 %

Procedure:
113 Milligrams of methyl α-acetylamino-α-methylthiophenylacetate and 41 mg of thiophenol were dissolved in 5 ml of methanol, and to the solution 0.5 ml of triethylamine was added, followed by an hour's refluxing. After a reduced pressure concentration of the reaction mixture, the residue was parted by a column chromatography (silice gel and methylene chloride). Thus 92 mg of methyl α-acetylaminophenylacetate was obtained. The yield was 99%.
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[OH:10][CH2:9][C@H:7]([NH:8][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=S)N1
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CSC(N[C@@H](CO)c2ccccc2)=N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
To a suspension of (R)-(−)-2-phenylglycinol (15.34 g, 111.82 mmol) and rhodanine (14.65 g, 110 mmol) in acetonitrile (200 mL) was added DIPEA (20.03 mL, 115 mmol) at room temperature. Then, it gave a clear solution within 2 min and this solution was cooled to 0° C. To this, mercuric chloride (31.22 g, 115 mmol) was added in three portions within a period of 15 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (500 mL) and methanol (1.0 L). The combined solvents were removed under the vacuum and the crude residue was diluted with water (250 mL) and ethyl acetate (250 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL). The two organic extracts were washed separately with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude yellow solid. This solid was dissolved in acetonitrile (˜100 mL) at hot condition and then stored in the refrigerator overnight. The solids were collected by filtration and washed with cold acetonitrile. After drying in air, 12.99 g (50% yield) of 2-(2-hydroxy-1-(R)-phenyl-ethylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C11H12N2O2S (M-H2O) 218.0514, found 218.0511.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][NH:13][CH3:14])[CH3:2].[O:15]=[C:16]1[CH2:21][O:20][C:19]2[CH:22]=[C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)[CH:24]=[N:25][C:18]=2[NH:17]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][N:13]([CH3:14])[C:28](=[O:30])/[CH:27]=[CH:26]/[C:23]1[CH:24]=[N:25][C:18]2[NH:17][C:16](=[O:15])[CH2:21][O:20][C:19]=2[CH:22]=1)[CH3:2]
Reactant: CCc1c(CNC)oc2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(=O)N3)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a solution of (3-ethylbenzofuran-2-yl)-N-methylmethanamine (115 mg, 0.6 mmol) in DMF (5 mL) were added in sequential order (E)-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (140 mg, 0.54 mmol), 1-hydroxybenzotriazole (84 mg, 0.6 mmol), diisopropylethylamine (282 uL, 1.62 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (120 mg, 0.6 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product precipitated and was filtered, triturated with ether and dried to yield the title compound as a white solid (113 mg, 52%): 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.19 (s, 1H), 7.88 (d, J=6.4 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.51-7.49 (m, 2H), 7.29-7.25 (m, 3H), 4.99-4.79 (rotamers, 2s, 2H), 4.68 (s, 2H), 3.39 (s, 3H), 2.79-2.73 (m, 2H), 1.23-1.20 (m, 3H); MS (ESI) m/e 392 (C22H21N3O4+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:11][CH:10]=2)[C:6]2[CH:23]=[C:24]([C:27]3[N:31]([CH3:32])[C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[N:28]=3)[CH:25]=[CH:26][C:5]=2[N:4]=1)[CH3:2].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C)C=O>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:39][N:38]=[N:37][N:22]=3)=[CH:13][CH:14]=2)[C:6]2[CH:23]=[C:24]([C:27]3[N:31]([CH3:32])[C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[N:28]=3)[CH:25]=[CH:26][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2ccc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 41 from 4'-[[2-ethyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].ClC1C=C(Cl)C=C(Cl)C=1[O:19][C:20](=O)[CH2:21][C:22](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:23]>C1(C)C(C)=CC=CC=1>[OH:23][C:22]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[S:6][CH2:7][CH2:8][N:9]2[C:20](=[O:19])[CH:21]=1
Reactant: O=[N+]([O-])C=C1NCCS1
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: Cc1ccccc1C
Product: O=c1cc(O)c([N+](=O)[O-])c2n1CCS2
Yield: 31.5 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Intermediate (I-19b), 2-nitromethylene-thiazolidine (0.65 g, 4.45 mmol) was reacted with malonic acid bis-(2,4,6-trichloro-phenyl) ester (1.5 g, 4.45 mmol) in Xylene (10 mL) to afford the crude product. Purification by column chromatography on silica gel (100% ethylacetate) afforded 0.3 g of the product (33% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C.O>[N:23]1([CH2:22][CH2:21][N:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=3)[CH2:8][CH2:9][CH2:10]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: ICCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)N(CCN1CCOCC1)CCC2
Temperature: 70 °C
Yield: 7.2 %

Procedure:
To a solution of 7-nitro-1,2,3,4-tetrahydroquinoline (D1) (246 mg, 1.38 mmol) in DMF (2.7 ml) was added potassium carbonate (574 mg, 4.15 mmol) followed by a solution of 4-(2-iodoethyl)morpholine (500 mg, 2.07 mmol) in DMF (2 ml) and the reaction heated to 70° C. After cooling to ambient temperature the reaction mixture was diluted with water and extracted with EtOAc which was washed with water, dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by silica SPE chromatography. Elution with 80% EtOAc/petroleum ether gave the title compound as an orange gum (29 mg). 1H NMR (250 MHz, CDCl3) δ (ppm): 7.39 (m, 2H), 7.00 (d, 1H), 3.73 (m, 4H), 3.47 (m, 2H), 3.38 (m, 2H), 2.79 (t, 2H), 2.49-2.59 (m, 6H), 1.96 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]([CH3:17])[C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14]O)[CH2:2][CH2:3][CH3:4].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:19][CH2:14][C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:17])=[O:16]
Reactant: CCCCN(C)C(=O)CCCCCC#CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)CCCCCC#CCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of 1.65 g of the product of Step B in 16.5 ml of methylene chloride cooled to -5° C. there were added 2.85 g of carbon tetrabromide and 2.25 g of triphenylphosphine. The reaction solution was stirred for 30 minutes at 0° C. and chromatographed on silica (eluant: methylene chloride-ethyl acetate 90-10) to obtain 1.82 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[F:11][C:12]([F:24])([F:25])[C:13]1[CH:14]=[C:15]([NH:16][C:8]([C:3]2[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:10])[CH:17]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:19]=1
Reactant: O=C(O)c1ncccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncccc1O
Yield: 45 %

Procedure:
Using 3-hydroxypyridine-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([N:32]2[CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33]2)=[O:26])=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1
Reaction time: 5 h
Yield: 68.7 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (10.94 mmol, 6.51 mL, 6.96 g, 50% solution in ethyl acetate) was added to a stirred solution of 4-aminobenzoic acid (7.29 mmol, 1 g), tert-butyl piperazine-1-carboxylate (7.29 mmol, 1.358 g) and triethylamine (14.58 mmol, 1.969 mL, 1.473 g) in dichloromethane (30 mL). The reaction mixture was stirred for 5 hours, then was washed with sodium bicarbonate and filtered through silica, eluting with ethyl acetate. Evaporation of solvent afforded the title compound (1.53 g). 1H NMR (MeOD, 400 MHz): δ 1.4 (9H, s), 3.4 (4H, m), 3.6 (4H, m), 6.7 (1H, m), 7.2 (2H, m)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:29])[CH3:22]
Reactant: CN(C)CCCCN
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)CCCCN/C=C1\C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and N1,N1-dimethylbutane-1,4-diamine (29.1 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light salmon solid, 65.5 mg, (73% yield) MS (ES+): 366.2, (M+H).