Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O.Cl>C(O)(C)(C)C>[Cl:11][C:10]1[C:3]2[C:2]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1c[nH]c2ncnc(Cl)c12
Reactant: C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CC(C)(C)O
Product: Clc1c[nH]c2ncnc(N3CCCCC3)c12
Temperature: 25 °C
Yield: 63.4 %

Procedure:
The product from Method R (57 mg, 0.3 mmol) was suspended in 3.0 mL of tert-butanol and to this solution was added piperidine (90 μL, 0.9 mmol) and the resulting system, heated at reflux for 1 h. The reaction mixture was cooled to room temperature and water was added (4.0 mL). The solution was adjusted to pH 1 with 1 N HCl and then washed with ether. The aqueous layer was removed and adjusted to pH 12 with 2 N NaOH. The solution was then extracted 2×15 mL with dichloromethane and the combined organics washed with water then brine and dried over MgSO4. Evaporation of solvent afforded 45 mg of a yellow solid that was purified by silica-gel chromatography (3:1 ethyl acetate/hexanes) to yield 23 mg (32%) of the title compound as a light yellow solid. Mp 170-172° C. 1H NMR (400 MHz, CDCl3) δ: 1.67-1.74 (m, 6H), 3.65-3.67 (m, 4H), 7.10 (s, 1H), 8.31 (s, 1H). LRMS: 237 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3]Br.C(=O)([O-])[O-].[K+].[K+].[N+:11]([C:14]1[CH:20]=[CH:19][CH:18]=[C:16]([OH:17])[C:15]=1[OH:21])([O-:13])=[O:12].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[N+:11]([C:14]1[C:15]2[O:21][CH2:3][CH2:2][O:17][C:16]=2[CH:18]=[CH:19][CH:20]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(O)c1O
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cccc2c1OCCO2
Temperature: 25 °C
Yield: 32.7 %

Procedure:
1,2-Dibromoethane (12.0 g, 0.064 mol), potassium carbonate (17.6 g, 0.127 mol) and tetra-n-butyl ammonium bromide (1.37 g, 0.0043 mol) were added to a stirred solution of 3-nitrocatechol (6.59 g, 0.043 mol) in toluene (210 ml). The solution was heated at reflux with azeotropic removal of water for 23 h, cooled to room temperature, washed with 2N sodium hydroxide solution (150 ml), dried (Na2SO4) and evaporated in vacuo to give an orange oil. Purification by column chromatography (silica; ether) gave the product (2.55 g) m.p. 55°-59° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.C(C1C=CC(C2N=CC(C(Cl)=O)=C[N:35]=2)=CC=1)CCC.N>O1CCOCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]([NH2:35])=[O:19])=[CH:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2ncc(C(=O)O)cn2)cc1
Reactant: CCCCc1ccc(-c2ncc(C(=O)Cl)cn2)cc1
Agent: N
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CCCCc1ccc(-c2ncc(C(N)=O)cn2)cc1

Procedure:
8.3 G. of 2-(p-n-butylphenyl)-5-pyrimidinecarboxylic acid are reacted with 50 ml. of thionyl chloride with the exclusion of moisture and worked up in a manner analogous to that given in Example 7. The remaining 2-(p-n-butylphenyl)-5-pyrimidinecarboxylic acid chloride is dissolved in 100 ml. of absolute dioxane and added to a solution of 200 ml. of absolute dioxane saturated with ammonia at room temperature with stirring and further treated in a manner analogous to that described in Example 7. The obtained crude 2-(p-n-butylphenyl)-5-pyrimidinecarboxamide can be sublimed in a high vacuum at 185° C. for purification; melting point 264.0°-266.0° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[CH3:11]O>>[NH2:1][CH2:2][CH2:3][S:4][CH2:5][C@@H:6]([C:8]([O:10][CH3:11])=[O:9])[NH2:7]
Reactant: NCCSC[C@H](N)C(=O)O
Reactant: CO
Product: COC(=O)[C@@H](N)CSCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 10 g (50 mmol) sample of S-(2-aminoethyl)-L-cysteine was dissolved in 400 mL of methanol. Into this cooled solution was bubbled in anhydrous HCl for 30 minutes. After stirring at room temperature overnight, the solution was concentrated to afford 12.7 g of the title compound.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.P(Br)(Br)([Br:14])=O>ClC(Cl)C>[Br:14][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(O)ncc1[N+](=O)[O-]
Solvent: CC(Cl)Cl
Product: Cc1cc(Br)ncc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a suspension of 2-hydroxy-4-methyl-5-nitropyridine (1 g, 6.5 mmol) in dichloroethane (10 mL) was added a solution of phosphorus oxybromide (2.8 g, 9.7 mmol) in dichloroethane (10 mL). The reaction mixture was heated under reflux for 4 h, then cooled to rt and quenched with water (40 mL). The layers were separated and the aqueous layer extracted into dichloromethane (2×30 mL). The combined organics were dried (MgSO4), concentrated in vacuo and chromatographed on silica gel eluting with dichloromethane to give the title compound as a pale yellow solid. δH (CDCl3): 2.63 (3H, s), 7.52 (1H, s), 8.96 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH:19]=[C:20]([CH3:22])[O:21][C:17]=3[C:16]([C:23]([OH:25])=O)=[CH:15][C:13]=2[N:14]=1.F[B-](F)(F)F.[N:31]1(OC(N(C)C)=[N+](C)C)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2N=N1.C1COCC1.C1(N)CCCCC1>CN(C=O)C>[CH:35]1([NH:31][C:23]([C:16]2[C:17]3[O:21][C:20]([CH3:22])=[CH:19][C:18]=3[C:12]3[NH:11][C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])=[N:14][C:13]=3[CH:15]=2)=[O:25])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:34]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1cc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Agent: F[B-](F)(F)F
Solvent: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc2c(o1)c(C(=O)NC1CCCCC1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 13.3 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(2,6-dichlorophenyl)amino]-7-methyl-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-9, 0.050 g, 0.132 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.085 g, 0.265 mmol), TEA (1 mL), THF (5.0 mL), DMF (1.0 mL) and cyclohexyl amine (0.026 g, 0.265 mmol) to afford 0.008 g of the desired product. 1HNMR (DMSO-d6): δ 1.23-1.30 (m, 2H), 1.31-1.36 (m, 4H), 1.89 (m, 4H), 3.85 (m, 1H), 4.19 (s, 3H), 6.74 (s, 1H), 7.41-7.94 (m, 4H), 9.07 (s, 1H), 11.00-12.00 (s, 2H).
Reaction SMILES: C([O:4][C:5]1[C:15]([CH3:16])=[CH:14][C:8]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[C:7]([CH3:17])[C:6]=1[CH3:18])(=O)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>O1CCOCC1>[CH3:17][C:7]1[C:6]([CH3:18])=[C:5]([OH:4])[C:15]([CH3:16])=[CH:14][C:8]=1[O:9][CH2:10][CH:11]([OH:13])[CH2:12][N:30]1[CH2:29][CH2:28][N:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH2:32][CH2:31]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(=O)Oc1c(C)cc(OCC2CO2)c(C)c1C
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(CC(O)COc2cc(C)c(O)c(C)c2C)CC1
Yield: 33.2 %

Procedure:
Using 3.88 g of 1-(4-acetoxy-2,3,5-trimethylphenoxy)-2,3-epoxypropane, 3.58 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup were carried out as in Examples 1-A and 4. After hydrolysis and workup, the residue obtained was recrystallized from benzene-hexane to give 2.06 g of white crystals, m.p. 163-165° C.
Reaction SMILES: [C:1]1([C:7](O)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[C:13]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[CH:14][C:15]([SH:20])=[C:16]([O:18][CH3:19])[CH:17]=1.O>ClCCCl.[I-].[Zn+2].[I-]>[Cl:11][C:12]1[C:13]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[CH:14][C:15]([S:20][C:7]([CH3:9])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[C:16]([O:18][CH3:19])[CH:17]=1
Reactant: CC(C)(O)c1ccccc1
Reactant: COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1S
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCCl
Product: COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1SC(C)(C)c1ccccc1
Yield: 96.4 %

Procedure:
To a solution of 2-phenyl-2-propanol (0.45 g) in 1,2-dichloroethane (5 mL) were added zinc iodide (0.53 g) and a solution of 5-chloro-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-mercaptoanisole (1 g) in 1,2-dichloroethane (5 mL) successively, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give 5-chloro-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-(1-methyl-1-phenylethylthio)anisole (1.32 g). This material was dissolved in tetrahydrofuran (20 mL). To the solution was added hydrazine monohydrate (0.73 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. To the filtrate were added water and ethyl acetate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (0.74 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24]Cl)[CH3:21].[OH-].[K+]>CC(C)=O>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][N:4]([C:1](=[O:3])[CH3:2])[C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:6]=1)[CH3:21]
Reactant: CCN(CC)CCCl
Reactant: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCN(CC)CCN(C(C)=O)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
Combine N-acetyl-4-aminobenzophenone (4.0 g, 16.7 mmol), 2-diethylaminoethyl chloride hydrochloride (3.97 g, 23.1 mmol), and powdered potassium hydroxide (2.81 g, 50.1 mmol) in acetone (30 mL). Heat to reflux. After 2 hours, cool and decant the solvent. Evaporate the solvent in vacuo to give a residue. Partition the residue between water and ethyl acetate. Separate the organic layer and extract with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf =0.0-0.14 (streaks on silica gel, ethyl acetate).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[CH2:12][CH2:13][CH2:14][CH2:15][C:8]2=[N:7][C:6]=1[CH3:16].[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][O:24][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CN(C)C=O>[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:3][CH2:4][C:5]4[C:10](=[O:11])[N:9]5[CH2:12][CH2:13][CH2:14][CH2:15][C:8]5=[N:7][C:6]=4[CH3:16])[CH2:29][CH2:30]3)=[N:23][O:24][C:20]=2[CH:19]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of 5.3 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride, 4.4 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide was stirred overnight at 85°-90° C. After cooling, the reaction mixture was poured into water. The product was filtered off and crystallized from a mixture of N,N-dimethylformamide and 2-propanol. The product was filtered off and dried, yielding 3.8 parts (46%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 170.0° C. (compound 1).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.C(O)(=O)CCCCCCC/C=C\C/C=C\CCCCC>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)O
Yield: 8.83 %

Procedure:
The crushed oil from C458-5 contained about 80-82% oleic acid, 3-4.6 % linoleic acid (yielding an O/L ratio value range of 17.4-27.3), and about 5-5.3% palmitic acid. In comparison, Florunner crush oil contained less than 52% oleic acid, 29.75% linoleic acid (yielding an O/L ratio value of only 1.73), and 8.83% palmitic acid. The C458-5 crush oil may also be contrasted with Planter Peanut oil, another industry standard, which contains about 50.2% oleic acid, 29.6% linoleic acid (for an O/L ratio value of about 1.7), and 9.7% palmitic acid.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH:43]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: NC(=O)C1CCNCC1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCC(C(N)=O)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and piperidine-4-carboxamide (49 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (20 mg, yield 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][CH:9]([C:11]1[C:16]2[O:17][C:18]3([O:23][C:15]=2[C:14]([O:24][CH3:25])=[CH:13][CH:12]=1)[CH2:22][CH2:21][CH2:20][CH2:19]3)[OH:10].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[O:17][C:18]3([O:23][C:15]=2[C:14]([O:24][CH3:25])=[CH:13][CH:12]=1)[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:10]
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OC1(CCCC1)O2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OC1(CCCC1)O2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
Compound 138a (2.88 g) obtained in Step A was dissolved in acetone (200 ml) and 2.67M Jones' reagent (3.0 ml) was added thereto, followed by stirring at 0° C. for 15 minutes. The reaction solution was concentrated to about a half by volume, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10 to 5/1) to give Compound 140 (2.02 g, 70%) as colorless crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[CH3:6].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:30]=[N:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])[CH:18]=[CH:19][CH:20]=1.[OH-].[NH4+]>C(OCC)(=O)C.ClCCl>[CH3:6][C:5]1[N:14]([C:15]2[CH:16]=[C:17]([C:21]3[CH:30]=[N:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH2:2][CH2:3][N:4]=1
Reactant: CC(=O)NCCCl
Reactant: COC(=O)c1ccncc1-c1cccc(N)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccncc1-c1cccc(N2CCN=C2C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.3 %

Procedure:
N-(2-chloroethyl)acetamide (0.32 g) in ethyl acetate (5 ml) was added over 10 min. to a stirred suspension of phosphorus pentachloride (0.55 g) in ethyl acetate (2 ml) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min. at 0° C. a solution of methyl 3-(3-aminophenyl)isonicotinate (0.4 g) in dichloromethane (10 ml) was added over 15 min. at 0-5° C. The mixture was stirred at 0° C. for 10 min. and then allowed to warm up to 20° C. After 3 h the mixture was treated with ammonium hydroxide solution (28%, 5 ml) over 10 min. and stirring continued for ca. 1 h. The layers were allowed to separate, the organic layer was collected, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane:methanol:ammonia=100:10:1, v/v/v) to give 0.25 g (48%) of yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.[C@@H:28]1([NH2:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1.Cl.C(N=C=NCCCN(C)C)C>O1CCOCC1>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:37][C@@H:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: N[C@H]1CCc2ccccc21
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: O=C(N[C@H]1CCc2ccccc21)C1COCCN1c1nc(Cl)ncc1Br

Procedure:
To a 50 mL pear flask were added 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 300 mg, 0.930 mmol), 1-hydroxybenzotriazole (126 mg, 0.930 mmol), and (S)-2,3-dihydro-1H-inden-1-amine (0.119 mL, 0.930 mmol) in 1,4-dioxane (25 mL) to give a green solution. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (178 mg, 0.930 mmol) was added to the solution, which was allowed to reaction at room temperature for 6 hours. The reaction mixture was subsequently partitioned between aqueous saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C18H18BrClN4O2, 437.03; found 437.2.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Cl.[NH2:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Cl:1][C:2]1[C:11]([CH:12]=[N:19][OH:20])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C=NO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
15.00 g (54 mmol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate and 4.20 g (60 mmol) of hydroxylamine hydrochloride were taken up in 300 ml of methanol, and a solution of 3.18 g (30 mmol) of sodium carbonate in 80 ml of water was added dropwise. After the mixture had been stirred for 12 hours at room temperature, the methanol was distilled off, the residue was diluted with water and the mixture was extracted with diethyl ether. After the organic phase had been dried, the solvent was removed. This gave 14.40 g (91% of theory) of methyl 2-chloro-3-hydroxyiminomethyl-4-methylsulfonylbenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7]2.[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.CCOC(C)=O>[CH3:15][O:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=2)[N:10]=1)=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc2cncc(Br)c2n1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2cncc(Br)c2n1
Reaction time: 16 h

Procedure:
8-Bromo-[1,6]naphthyridine-2-carboxylic acid methyl ester (2) is prepared by combining compound 1 (1 equiv.), cesium carbonate (1.1 equiv.) and methyl iodide (1.1 equiv.) in DMF (10 mL) and stirring for 16 hrs. at room temperature. The reaction is concentrated in vacuo to give a brown solid, which is dissolved in EtOAc (50 mL) and washed with water (2×50 mL). The EtOAc layer is dried over sodium sulfate, filtered, and concentrated in vacuo to afford a purple solid. The crude product is purified via silica gel chromatography (EtOAc) to yield (2) as a yellow solid, 65%, LC/MS (M+H) 269.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:16]([O:18][CH3:19])=[O:17].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([NH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:2]([Cl:1])[CH:3]=1)[C:7]([C:16]([O:18][CH3:19])=[O:17])=[CH:8]2)(=[O:26])[CH3:25]
Reactant: COC(=O)c1cc2cc(N)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1cc2cc(NC(C)=O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Yield: 32 %

Procedure:
Methyl N-(3,4-dichlorobenzyl)-5-aminoindole-2-carboxylate (0.28 g) was dissolved in acetic anhydride and heated to 90° C. for 1 hour. Upon cooling, the title compound crystallised as white needles, was filtered off, washed with diethyl ether and dried in vacuo to yield the desired end product (0.1 g, 32%); NMR δ(CD3SOCD3) 2.03 (s, 3H), 3.80 (s, 3H), 5.80 (s, 2H), 6.88 (m, 1H), 7.36 (m, 3H), 7.52 (d, 2H), 8.08 (s, 1H), 9.88 (s, 1H); M/z (−) 391 (M+), 389.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]=2[CH:21]=1)[CH3:2].[C:22]([NH:30][NH2:31])(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:30][N:31]=[C:11]3[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]=2[CH:21]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Product: CCc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(-c3ccccc3)n1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 7-ethyl-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with benzoic acid hydrazide and the resulting product heated to 250° C. to give 8-ethyl-1-phenyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.