Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.O>[NH2:18][C:16]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:17]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1N1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(N)cc1N1CCOCC1
Temperature: 80 °C
Yield: 47.6 %

Procedure:
A mixture of 1.16 g of ethyl 2-morpholin-4-yl-4-nitrobenzoate, 1.1 g of ammonium chloride, 1.0 g of reduced iron and 14 ml of ethanol-water (5:2) mixed solvent was stirred at 80° C. for 4Hours. The reaction solution was filtered while hot, and the white crystals precipitated after spontaneous cooling were collected by filtration to obtain 493 mg of ethyl 4-amino-2-morpholin-4-ylbenzoate. EP: 251.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:32][CH2:33][CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][N:17]([CH2:32][CH2:33][CH3:34])[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with iodopropane and cesium carbonate in N,N-dimethylacetamide to give N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-N-propyl-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 534.8 ([M+NH4]+)
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]>>[C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[Cl:1])[CH:9]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: CC(=O)c1cccc(N=C=O)c1
Product: COc1ccc(NC(=O)Nc2cccc(C(C)=O)c2)cc1-c1c(Cl)cnn1C
Yield: 6 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-Acetylphenyl isocyanate in a similar manner as described in Example 1.53, providing 3.7 mg (6%) of Compound 35 (Note: Compound 35 did not precipitate out. Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=401 (M+H37Cl, 27), 399 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.91 (s, 1H), 8.80 (s, 1H), 8.23 (s, 1H), 7.84 (d, J=8 Hz, 1H), 7.75 (dd, J1=12 Hz, J2=3 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 7.56 (d, J=4 Hz, 1H), 7.49 (s, 1H), 7.43 (t, J=8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 3.84 (s, 3H), 3.69 (s, 3H), 3.42 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH:3]1[C:15]([O:17]CC)=[O:16].[OH-].[Na+].Cl>C1COCC1.O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH:3]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CN(Cc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 4-hydroxy-1-(phenylmethyl)-3-piperidinecarboxylate (30 g, 114.4 mmol) in THF/water (800 ml/80 mL) was added 2N sodium hydroxide solution (126 mL). The reaction mixture was stirred at room temperature for 5 h and then the pH was adjusted to 7 with 5N hydrochloric acid solution.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1)#[CH:2].Br[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[OH:23]>C(N(CC)CC)C.C(NCC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]2[O:23][C:1]([C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=4)[CH:4]=3)=[CH:2][C:16]=2[CH:21]=1
Reactant: C#Cc1ccc2cc(OC)ccc2c1
Reactant: Oc1ccc(Cl)cc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CCN(CC)CC
Product: COc1ccc2cc(-c3cc4cc(Cl)ccc4o3)ccc2c1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
A mixture of 2-ethynyl-6-methoxynaphthalene (1.82 g, 10 mmol), 2-bromo-4-chlorophenol (2.01 g, 10 mmol), copper (I) iodide (0.1 g, 0.52 mmol), tetrakis(triphenylphosphine)palladium (0.58 g, 0.5 mmol) in triethylamine (10 mL) and diethylamine (10 mL) was heated at reflux for 1 hour under an atmosphere of nitrogen then cooled to room temperature. The solid was collected by filtration, washed with ether and dried to give the title compound as a solid (2.0 g). 1HNMR (300 MHz, DMSO-d6): δ8.4 (s, 1H), 8.0-7.9 (m, 3H), 7.75 (d, 1H, J=1.8 Hz), 7.69 (d, 1H, J=9.2 Hz), 7.46 (s, 1H), 7.38-7.32 (m, 2H), 7.24 (dd, 1H, J=9.2, 1.8 Hz), and 3.9 ppm (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)=O)[CH3:2].C(O)(=O)C.O.[NH2:30][NH2:31].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[NH:31][N:30]=1)=[O:24])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)[nH]n1
Yield: 63.8 %

Procedure:
To a solution of 1-(4-hydroxy-phenyl)-ethanone (10 g, 0.0735 mole) in DMF (50 mL) was added K2CO3 (20.2 g, 0.147 mole) at ambient temperature. Benzyl bromide (13.83 g, 0.0808 mole) was then added and the resulting mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then quenched with iced water. The resulting precipitate was isolated by filtration and dried to afford 16.2 g (98%) of 1-(4-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 98.38%. A mixture of THF (130 mL) and NaH (60% w/w dispersion in oil) (5.28 g, 0.132 mole) was cooled to 0° C. with stirring for 5 minutes. Diethyl oxalate (12.87 g, 0.0886 mole) was added and the mixture was heated to reflux for 15 minutes. after cooling to ambient temperature 1-(4-benzyloxy-phenyl)-ethanone (10 g, 0.0442 mole) in THF (50 mL) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 70° C. for 1 hour. The reaction mixture was then quenched with cold aqueous NH4Cl solution. The resulting precipitate was isolated by filtration and dried to afford 21.2 g of 4-(4-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 36.5%. A solution of 4-(4-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (10 g, 0.03064 mole), acetic acid (20 mL) and hydrazine hydrate (1.685 g, 0.0337 mole) was heated to reflux for 8 hours. The reaction mixture was then poured into iced water and basified with saturated aqueous NaHCO3 solution. The product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 6.3 g (64%) of 5-(4-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 95.10%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:22][N+:23]([O-])=O)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:23][CH2:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(F)cc1)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(F)cc1)OCC

Procedure:
A solution of 5.0 g of ethyl 2-(4-fluorophenyl)-3-nitropropyl(diethoxymethyl)phosphinate in 50 ml of ethanol is added to 40 g of an 8% solution of ammonia in ethanol. To this are added 7 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-fluorophenyl)propyl(diethoxymethyl)phosphinate as a viscous oil, 31 p=+44.4 ppm (CDCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[C:40]([O-])(O)=[O:41].[Na+].C(Cl)(Cl)=O>C(Cl)Cl>[N:1]([C:2]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:31])=[O:32])[C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:7])[CH3:8])=[O:5])=[C:40]=[O:41]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Reactant: O=C([O-])O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12

Procedure:
Into a 50 mL round bottomed flask were added 2-amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (500 mg, 0.926 mmol), methylene chloride (10 mL) and sat'd NaHCO3(10 mL). The solution was cooled in an ice-water bath for 5 min then phosgene (2.5 mL, 20% w/w solution in toluene, Fluka) was added to the lower (organic) layer. The solution was stirred rapidly and the ice-bath was removed. The reaction mixture was stirred rapidly for 1 h, then the layers were separated and the aqueous phase was extracted 2× with methylene chloride. The combined organic fraction was treated with NaSO4, filtered and concentrated. The residue was triturated with anhydrous ether to give a light yellow/tan powder, which was used directly in the next step. Note: treatment of a small aliquot of the title compound with excess dimethylamine (2M, THF) followed by HPLC analysis provided evidence of isocyanate formation via transformation to the corresponding N,N-dimethyl urea; m/z=612.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)=[O:3].[CH2:17]([O:19][C:20](=[O:23])[CH2:21]Br)[CH3:18].C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20](=[O:23])[CH2:21][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([OH:3])[CH3:1])[CH3:18]
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(Oc2ccccc2)cc1
Reaction time: 1 h

Procedure:
21.2 g. of 4-phenoxyacetophenone and 11.1 ml. of bromoacetic acid ethyl ester are dissolved in a mixture of 75 ml. of benzene and 75 ml. of toluene. 40 ml. of this solution are added to 7 g. of zinc powder (previously washed successively with 1% hydrochloric acid, water and acetone, and then dried) and the mixture is heated to 70° while stirring and passing in nitrogen. After the reaction has begun, the remainder of the solution is added dropwise, the mixture is boiled for one hour and cooled and 40 ml. of 20% sulfuric acid are added dropwise in order to decompose the resulting alcoholate of the formula C6H5O--p--C6H4 --C(CH3)--(OZnBr)--CH2 --COOC2H5. The organic phase is separated off and standard working up gives 3-p-phenoxyphenyl-3-hydroxy-butyric acid ethyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.CC(OC([N:15]1[CH2:22][C:21]2[O:20][C:19]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][C:17]=2[CH2:16]1)=O)(C)C>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[O:24]([CH2:23][C:19]1[O:20][C:21]2[CH2:22][NH:15][CH2:16][C:17]=2[N:18]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(COc3ccccc3)oc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(OCc2nc3c(o2)CNC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
Trifluoroacetic acid (0.5 mL, 0.65 mmol) was added to a solution of 4,6-dihydro-2-(phenoxymethyl)-5H-pyrrolo[3,4-d]oxazole-5-carboxylic acid 1,1-dimethylethyl ester (0.075 g, 0.19 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 15 minutes and diluted with a saturated solution of Na2CO3. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 5,6-dihydro-2-(phenoxymethyl)-4H-pyrrolo[3,4-d]oxazole (22 mg, 53% yield, 30% pure) as a clear oil that was used in the next step without further purification. C12H12N2O2LCMS: Rt 1.04, m/z 217 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[C:20]4[O:22][CH2:23][O:24][C:19]4=[CH:18][C:16]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[N+]([O-])=O.C[O-].[Na+].[C:28](O)(=[O:30])C>CO>[CH3:28][O:30][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[C:20]4[O:22][CH2:23][O:24][C:19]4=[CH:18][C:16]=3[N:17]=2)[C:2]=1[CH3:1]
Reactant: CC(=O)O
Reactant: Cc1c([N+](=O)[O-])ccnc1CSc1nc2cc3c(cc2[nH]1)OCO3
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)OCO4)c1C

Procedure:
A solution of 500 mg of 6-[[(3-methyl-4-nitro-2-pyridyl)methyl]thio]-5H-1,3-dioxolo[4,5-f]benzimidazole in 20 ml of absolute methanol was treated with 300 mg of sodium methylate, whereupon the mixture was boiled at reflux under argon for 18 hours. The reaction mixture was buffered by means of glacial acetic acid and concentrated in vacuo. The residue was treated with methylene chloride/sodium bicarbonate solution, whereupon the organic solution was dried and concentrated. By recrystallization from ethyl acetate there was obtained 6-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]-5H-1,3-dioxolo[4,5-f]benzimidazole of melting point 215°-220°.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([S:34]([N:22]2[CH2:21][C@@H:20]([CH3:25])[N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(S(=O)(=O)c3ccccc3)C2=O)CC1
Yield: 43 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and benzenesulfonyl chloride, to give the desired product as a yellow oil (43%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3.C(O)C.[OH-].[K+].[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)([F:26])([F:25])[F:24]>O>[F:24][C:23]([F:26])([F:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3
Reactant: FC(F)(F)CCCCCBr
Reactant: O=c1c2ccc(O)cc2oc2cc(O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1c2ccc(O)cc2oc2cc(OCCCCCC(F)(F)F)ccc12
Reaction time: 2 h

Procedure:
To 3,6-dihydroxy-xanthone (0.58 g, 1 equivalent) is added 10 ml of ethanol, then 117 mg of KOH 0.8 equivalents), followed by 0.58 g of CF3(CH2)5Br (1 equivalent); after two hours of boiling this mixture, the pH had dropped to the acidic range, and another 100 mg of KOH was added and heating continued overnight. The cooled mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml), the combined extracts washed with 5 ml of water and brought to dryness. Separation of the 3-component mixture was achieved by chromatography (100 g of silica gel, column diameter 5 cm) with solvents of increasing polarity: Solvents used: ethyl acetate (A), hexane (isomeric mixture) (B), ethanol (C)
Reaction SMILES: Cl[C:2]1C=C(C#N)C2C=C[N:8]([C:11]3[N:12]([CH2:22][CH3:23])[C:13](=[O:21])[NH:14][C:15](=[O:20])[C:16]=3[CH:17]([CH3:19])[CH3:18])[C:9]=2[CH:10]=1.[NH:26]1C=CC=N1>>[CH2:22]([N:12]1[C:11]([N:8]2[CH:9]=[CH:10][CH:2]=[N:26]2)=[C:16]([CH:17]([CH3:19])[CH3:18])[C:15](=[O:20])[NH:14][C:13]1=[O:21])[CH3:23]
Reactant: c1cn[nH]c1
Reactant: CCn1c(-n2ccc3c(C#N)cc(Cl)cc32)c(C(C)C)c(=O)[nH]c1=O
Product: CCn1c(-n2cccn2)c(C(C)C)c(=O)[nH]c1=O

Procedure:
This compound was made using a procedure similar to that used to prepare 6-chloro-1-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-1H-indole-4-carbonitrile (90), except that pyrazole was used instead of 6-chloro-1H-indole-4-carbonitrile. LC-MS shows 249.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 9.36 (br, 1H), 7.81 (m, 1H), 7.58 (m, 1H), 6.54 (m, 1H), 3.38 (m, 2H), 2.04 (m, 1H), 1.17 (m, 9H).
Reaction SMILES: [CH2:1]=[N:2][CH2:3][C:4]([CH3:11])([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH3:5].Cl.[OH-].[Na+]>>[CH3:5][C:4]1([CH3:11])[CH2:3][NH:2][CH2:1][C:7]2[S:8][CH:9]=[CH:10][C:6]1=2
Reactant: C=NCC(C)(C)c1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CNCc2sccc21

Procedure:
6.0 g (36 mmol) methylene-(2-methyl-2-thiophene-3-yl-propyl)-amine, 11 mL (45 mmol) 4M HCl and 12 mL (0.14 mol) conc. HCl were stirred at RT over the weekend. The reaction mixture was made alkaline with a 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried. The substance was purified on Alox. The product-containing fractions were combined and concentrated to dryness by rotary evaporation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].F[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[Cl:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:3]=1
Reactant: Fc1cccc(C(F)(F)F)c1
Reactant: Oc1ccncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)cc1Cl
Temperature: 150 °C
Reaction time: 2 h

Procedure:
3-Chloropyridin-4-ol (0.259 g), 1-fluoro-3-(trifluoromethyl)benzene (0.126 mL) and potassium carbonate (0.276 g) were suspended in N-methyl-2-pyrrolidone (1.2 mL), and the suspension was stirred at 150° C. for 2 hr. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/hexane→methanol/ethyl acetate) to give the title compound (28.1 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([CH3:25])[C:21]=1[C:22]([NH2:24])=[O:23]>>[CH3:25][C:20]1[C:21]([C:22]([NH2:24])=[O:23])=[C:17]([NH:16][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:18][CH:19]=1
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Reactant: Cc1csc(N)c1C(N)=O
Product: Cc1csc(NC(=O)CN2C(=O)CCc3ccccc32)c1C(N)=O

Procedure:
4-Methyl-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxamide was prepared from 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (0.49 g, 2.38 mmol) and 2-amino-4-methylthiophene-3-carboxamide (0.37 g, 2.38 mmol) according to protocol B Retention time (min)=3.405, method [1], MS (ESI) 344.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].[CH2:16](O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:17]1[O:18][CH:5]([C:4]2[C:7]([N+:13]([O-:15])=[O:14])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:3]=2[O:2][CH3:1])[O:6][CH2:16]1
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C2OCCO2)c1OC

Procedure:
A mixture of 2,3-dimethoxy-6-nitrobenzaldehyde (16.0 g, 75 mM), ethylene glycol (64 g, 103 mM), and p-toluenesulfonic acid monohydrate (0.2 g) in benzene (750 ml) is refluxed in a Dean-Stark apparatus for 48 hours. The solution is then poured into water (1 l.). The organic phase is washed with saturated aqueous NaHCO3 (2×20 ml), dried over Na2SO4, filtered, and the solvent removed in vacuo. The crude product is recrystallized from n-hexane (2 l.); yield 15.2 g (78.2%); m.p. 74°-76° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23](=[N:26][CH3:27])SC)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:23]([NH:26][CH3:27])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]2[NH:5][CH:4]=[N:3][C:2]=2[CH3:1])(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C(NS(=O)(=O)c1ccc(Cl)cc1)SC
Solvent: CC#N
Product: CNC(=NCCSCc1[nH]cnc1C)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 59.1 %

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.33 g.) and N-(4-chlorobenzenesulphonyl)-N' ,S-dimethylisothiourea (5.40 g.) in acetonitrile was heated under reflux for 24 hours. Concentration, followed by recrystallisation from aqueous ethanol afforded N-(4-chlorobenzenesulphonyl)-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (4.6 g.), m.p. 153°-154°.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1.[Cl:37][C:38]1[CH:39]=[C:40]([CH:46]=[CH:47][CH:48]=1)[CH:41]([OH:45])[C:42](O)=[O:43]>CN(C)C=O>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH:36][C:42](=[O:43])[CH:41]([OH:45])[C:40]2[CH:46]=[CH:47][CH:48]=[C:38]([Cl:37])[CH:39]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)C(O)c1cccc(Cl)c1
Reactant: COc1ccc(CCN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)C(O)c2cccc(Cl)c2)cc1
Reaction time: 18 h

Procedure:
Dicyclohexylcarbodiimide (2.00 g) in N,N-dimethylformamide (10 ml) was added to a solution of 1-hydroxybenzotriazole (1.37 g), 2-(4-methoxyphenyl)ethanamine (1.51 g) and 3-chloromandelic acid (1.86 g) in N,N-dimethylformamide (40 ml) and the mixture stirred for 18 hours, filtered then evaporated to dryness. The residue was dissolved in dichloromethane, washed with aqueous 4M hydrochloric acid and sodium bicarbonate solution, dried (magnesium sulphate), filtered and evaporated to dryness to give the title compound as an oil which was used without further purification.