Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:36]=[CH:37][CH:38]=1)[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:36]=[CH:37][CH:38]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cccc(COCCCCCBr)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cccc(COCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-(3-methoxybenzyloxy)pentyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-2-methoxy-N-((1-(5-(3-methoxybenzyloxy)pentyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH:22]([CH3:27])[CH2:23][C:24]([OH:26])=[O:25])[CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([CH3:28])[CH:4]=1)#[N:2].[OH-:29].[Na+].OO>CS(C)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH:22]([CH3:27])[CH2:23][C:24]([OH:26])=[O:25])[CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([CH3:28])[CH:4]=1)(=[O:29])[NH2:2]
Reactant: [OH-]
Reactant: COc1ccc(-c2ccn(C(C)CC(=O)O)c2-c2ccc(C#N)cc2C)cc1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-c2ccn(C(C)CC(=O)O)c2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of the crude 3-(2-(4-cyano-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)butanoic acid (120 mg) in DMSO (5 mL) was added a solution NaOH (26 mg, 0.65 mmol) in a mixture of water (0.5 mL) and H2O2 (0.33 mmol). After being stirred at room temperature for 2 hours, the mixture was purified by preparative HPLC to give 26 mg of 3-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)butanoic acid (yield 20% in two steps) as a grey solid.
Reaction SMILES: [C:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([C:27]([O:29]C)=[O:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]1[O:39]C2C=CC([Mg]Br)=CC=2[O:32]1>>[CH2:31]1[O:39][C:5]2[CH:4]=[CH:3][C:2]([C:1]([C@H:9]3[CH2:14][CH2:13][C@H:12]4[C@H:15]5[C@H:24]([CH2:25][CH2:26][C@:10]34[CH3:11])[C:23]3[CH:22]=[CH:21][C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=3[CH2:17][CH2:16]5)=[O:8])=[CH:7][C:6]=2[O:32]1
Reactant: Br[Mg]c1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)c3ccccc3)CC[C@@H]12
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)c1ccc2c(c1)OCO2

Procedure:
The title compound was prepared by the method of Example 19 (iv) by replacing benzylmagnesium chloride with 3,4-methylenedioxyphenylmagnesium bromide.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9](O)=[O:10]>C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9]([Cl:3])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)cc(C(=O)O)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(C(=O)Cl)c1
Reaction time: 5 h

Procedure:
2.0 kg. (16.3 moles) of thionyl chloride is added dropwise over a period of 45 minutes to a suspension of 2.0 kg. (13.32 moles) of 3,5-dimethylbenzoic acid in 8 l. of toluene stirred at 65° C. under nitrogen during the course of which the temperature is kept below 80° C. The reaction mixture is stirred at 110°-115° C. under nitrogen for 5 hours and cooled, and the toluene and excess thionyl chloride are vacuum distilled at 55°-60° C. to obtain 2.247 kg. of crude product. A small sample is purified by vacuum distillation. B.p. 52°-57° C./0.25 mm Hg.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C([O-])(=O)C.[Na+].CO[CH:16]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH:18](OC)O1>O.C(O)(=O)C>[C:21]1([C:20]2[CH:19]=[CH:18][N:7]([CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[CH:16]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CN
Reactant: COC1CC(c2ccccc2)C(OC)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cn1ccc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
Glycine ethyl ester hydrochloride (0.44 g, 3.17 mmol), sodium acetate (0.47 g, 5.76 mmol) were dissolved in minimum amount of water (5 mL) and added to glacial acetic acid (5 mL). The mixture was heated to 80° C. and then added to a solution of 2,5-dimethoxy-3-phenyl-tetrahydrofuran (0.6 g, 2.88 mmol) in glacial acetic acid (5 mL). The reaction was stirred at 80° C. for 2 h and then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with copious amount of water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford ethyl 2-(3-phenylpyrrol-1-yl)acetate (0.55 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH3:9])=[C:4](Cl)[N:3]=1.[NH2:11][CH2:12][CH2:13][C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1>COCCOC>[CH3:1][C:2]1[NH:3][C:4]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)=[C:5]([CH3:9])[C:6](=[O:8])[N:7]=1
Reactant: Cn1cccc1CCN
Reactant: Cc1nc(O)c(C)c(Cl)n1
Solvent: COCCOC
Product: Cc1nc(=O)c(C)c(NCCc2cccn2C)[nH]1
Temperature: 90 °C
Yield: 82.9 %

Procedure:
A stirred suspension of 2.00 g (12.9 mmol) of 2,5-dimethyl-4-hydroxy-6-chloropyrimidine and 6.5 mL (52 mmol, 4 equiv.) of 2-(2-aminoethyl)-1-methylpyrrole in 10 mL of DME was heated at 90° C. for 18 hours under a dry atmosphere. The reaction mixture was cooled to 23° C. and filtered. The isolated solids were rinsed with Et2O, H2O, and MeOH and then recrystallized from MeOH to afford 2.63 g 83% (10.7 mmol) of pure product, m.p. 246°-247° C. as a white powder.
Reaction SMILES: [S:1](=[O:3])=[O:2].[OH-].[Na+:5].[S:6]([O-:9])([O-:8])=[O:7].[Na+].[Na+]>>[S:6]([S:1]([O-:3])=[O:2])([O-:9])(=[O:8])=[O:7].[Na+:5].[Na+:5]
Reactant: O=S=O
Reactant: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=S([O-])S(=O)(=O)[O-]

Procedure:
Sulfur dioxide is introduced into a solution of sodium sulfite and sodium bisulfite to form sodium bisulfite in a solution having dissolved sulfur dioxide present with a pH between 3.5 and 4.2. The solution is drawn to a cooling crystallizer where an alkali such as soda ash, caustic soda, sodium sulfite, and mixtures thereof is added to produce additional sodium metabisulfite that increases the yield of sodium metabisulfite crystallizing per pass. The mother liquor is recycled.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([CH3:31])[CH:23]=1>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:27])=[C:24]([CH3:31])[CH:23]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: Cc1cc(Cl)ccc1C(=O)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-chloro-2-methylbenzoic acid.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:8]=[C:7]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)[N:6]=1)([CH3:3])[CH3:2].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)([O:26][CH3:27])=[O:25]>C(N(CC)CC)C>[CH:1]([O:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:8]=[C:7]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([C:24]([O:26][CH3:27])=[O:25])=[CH:29][CH:30]=3)=[O:36])=[CH:19][CH:18]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1nc(-c2ccc(N)cc2)nc(N2CCOCC2)n1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(OC(C)C)nc(N4CCOCC4)n3)cc2)cc1
Reaction time: 48 h

Procedure:
A mixture of 4-(4-isopropoxy-6-morpholino-1,3,5-triazin-2-yl)aniline (1.3 g, 4.1 mmol), triethylamine (2 ml) and 4-carbomethoxy-phenylisocyanate (1451 mg, 8.2 mmol) was stirred for 48 hours and quenched with water and washed well. The organic layer was dried and filtered. It was concentrated and purified by column chromatography by eluting it initially with 10% ethyl acetate:hexane and latter with 40% ethyl acetate:hexane. White solid; 600 mg, 30%; MS (ESI) m/z 492.5.
Reaction SMILES: [NH2:1][C:2]([CH2:23][OH:24])([CH2:21][CH3:22])[CH2:3][S:4]([C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(=[O:6])=[O:5].Cl>N1C(C)=CC=CC=1C.C(OCC)C>[CH2:21]([C:2]1([CH2:23][OH:24])[N:1]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[S:4](=[O:6])(=[O:5])[CH2:3]1)[CH3:22]
Reactant: CCC(N)(CO)CS(=O)(=O)c1ccccc1C(=O)c1ccccc1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Product: CCC1(CO)CS(=O)(=O)c2ccccc2C(c2ccccc2)=N1
Yield: 70 %

Procedure:
The product from step (b) (38.7 g) was dissolved in 600 ml of 2,6-lutidine and 120 ml of 1.0M HCl in diethyl ether was then added. The reaction mixture was refluxed overnite, using a Dean Stark trap, then concentrated in vacuo. The residue was taken up in 5% NaHCO3 whereupon solidification took place. The solids were filtered and washed with ether to afford the desired product as a light brown solid (25.7 g), mp 170°-171° C. 1H NMR consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH3:2]
Reactant: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1OCC
Temperature: 60 °C
Reaction time: 14 h
Yield: 381.2 %

Procedure:
To methyl 7-(3,4-diethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (818 mg) dissolved in THF-methanol (15-7.5 ml) was added a 2 M aqueous solution of potassium carbonate (1.5 ml), and the resulting mixture was stirred at 60° C. for 14 hours. The reaction mixture was treated with 1 N hydrochloric acid to bring the pH to 2. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the precipitated crystals were washed with hexane-ethyl acetate to obtain 7-(3,4-diethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (3.02 g) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[C:20]([CH2:22]O)[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH3:2].C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:25][CH2:22][C:20]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:4]([O:3][CH2:1][CH3:2])[CH:21]=1
Reactant: CCOc1cc(CO)ccc1Oc1ccccc1CC(=O)OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1cc(CBr)ccc1Oc1ccccc1CC(=O)OC
Temperature: 25 °C
Yield: 87.7 %

Procedure:
To a stirred and cooled (0° C.) solution of 1.15 g (3.64 mmol) of the product of Step B dissolved in 18 mL of CH2Cl2 was added 1.51 g (4.55 mmol) of carbon tetrabromide and 1.19 g (4.55 mmol) of triphenylphosphine. After the addition the reaction mixture was stirred 30 minutes and allowed to warm to room temperature. The mixture was then evaporated in vacuo and purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 1.21 g (88%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]=[N+:8]=[N-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:25])[C:18]#[C:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]([N+:26]([O-:28])=[O:27])[CH:12]=1>C1COCC1>[C:1]1([C:7]2[C:18]([CH:17]([C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][C:13]=3[N+:26]([O-:28])=[O:27])[OH:25])=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=Cc1ccccc1
Reactant: CCOC(=O)C#CC(O)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]nc(-c2ccccc2)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.1 %

Procedure:
A solution of freshly generated phenyldiazomethane (2.44 g, 20.7 mmol) in 10 mL of anhydrous THF was added to ethyl 4-(4-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate (5.86 g, 20.7 mmol) in 10 mL THF and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with excess ethereal acetic acid and concentrated via rotary evaporation to an oil (12.24 g) which solidified on cooling. This was filtered to yield the title compound as a pale yellow solid (2.42 g). The filtrate was concentrated via rotary evaporation to an oil which was triturated with hexane:ethyl acetate (4:1) to yield an additional 1.52 g of the title compound (48% combined yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Cl[C:14]1[N:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=1.C(=O)(O)[O-].[K+].O>CN(C=O)C>[NH2:20][C:18]1[N:19]=[C:14]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH:15]=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCNc1ccc([N+](=O)[O-])c(N)n1
Temperature: 90 °C

Procedure:
150.6 mg (0.864 mmol) of tert-butyl (3-aminopropyl)carbamate, 300 mg (1.73 mmol) of 6-chloro-3-nitropyridine-2-amine and 173 mg (1.73 mmol) of potassium bicarbonate are suspended in 10 ml of DMF and heated at 90° C. for 16 h. Water is added to the mixture, which is then extracted three times with ethyl acetate. Purification of the crude product by preparative HPLC and drying under high vacuum result in 195 mg (65% of theory) of product.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].Br[CH2:17][CH2:18][CH:19]=[CH2:20].O>CS(C)=O>[CH2:20]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
This example illustrates a synthesis of 1-(3,4-Oxidobutyl)-3,7-dimethylxanthine (inventive compound no. 2513). Sodium hydride (95%) (1.26 g, 50 mmol) was added to a solution of theobromine (7.2 g, 40 mmol) in dimethylsulfoxide (300 mL). After 20 minutes of stirring, 4-bromobutene (5.4 g, 40 mmol) was added. After 16 hours of stirring at room temperature, the reaction was poured into a separatory funnel containing 1 L of water and extracted with dichloromethane (5×200 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using a 20% petroleum ether/ethyl acetate eluant to yield 6.3 g (67.7% yield) 1-(3-Butenyl)-3,7-dimethylxanthine (inventive compound no. 2503) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[C:8]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([CH3:14])=[CH:10][C:11]=2[CH3:13])[NH:6][CH2:5]1.I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:23]([N:6]1[C:7]2[C:12](=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=2[NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])[CH:4]([CH2:3][CH2:2][OH:1])[CH2:5]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCO
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CC(CCO)c2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Temperature: 70 °C
Reaction time: 10 h
Yield: 13.5 %

Procedure:
N-[3-(2-Hydroxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (1.6 g) was dissolved in DMF (15 ml) and 1-iodooctane (3.9 g) and K2CO3 (2.3 g) were added, which was followed by stirring at 70° C. for 10 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=5/1-1/2) to give 300 mg of the title compound.
Reaction SMILES: [CH2:1]1[C:7]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:3](=[O:4])[CH2:2]1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]2[C:7]=1[CH2:1][CH2:2][C:3](=[O:4])[NH:5]2
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: ClCC1CO1
Product: O=C1CCc2c(cccc2OCC2CO2)N1

Procedure:
5-Hydroxy-3,4-dihydro-2-quinoline (prepared in three steps from cyclohexane-1,3-dione and acrylonitrile) is allowed to react with epichlorohydrin to give 5-(2,3-epoxypropoxy)-3,4-dihydro-2-quinolinone [J. Med. Chem. 17,529 (1974)].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@H:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([NH2:28])=[O:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:31](OC)([N:33]([CH3:35])[CH3:34])[CH3:32]>C1(C)C=CC=CC=1>[CH3:34][N:33]([CH2:31][CH:32]=[N:28][C:26](=[O:27])[CH2:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C@H:14]1[CH2:13][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:15]1)[CH3:35]
Reactant: NC(=O)Cc1ccc2[nH]cc([C@H]3C[C@H](NC(=O)OCc4ccccc4)C3)c2c1
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)CC=NC(=O)Cc1ccc2[nH]cc([C@H]3C[C@H](NC(=O)OCc4ccccc4)C3)c2c1
Temperature: 120 °C

Procedure:
To a solution containing 3-[trans-N-benzyloxycarbonyl-3-aminocyclobutyl]indol-5-yl acetamide (4.68 g 13 mmol) in toluene (10 ml) was added N,N-dimethyl acetamide dimethyl acetal (40 ml). The mixture was then heated at 120° C. for 2 hours under Dean & Stark conditions. The solution becomes very dark. The solventis evaporated under vacuum to give N-[(dimethylamino)ethanylidene]-3-[trans-3-(benzyloxycarbonylamino)cyclobutyl]-1H-indol-5-yl acetamide. Yield: 5.7 g crude.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O-:7])=[O:6].[K+].[CH:13]([CH:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:14].CS(C)=O>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH:15]([CH:13]=[CH2:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6]
Reactant: C=CC(Cl)c1ccccc1
Reactant: O=C([O-])c1cc(O)cc(O)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CC(OC(=O)c1cc(O)cc(O)c1)c1ccccc1
Yield: 83.6 %

Procedure:
129.4 g of potassium 3,5-dihydroxybenzoate and 102.7 g of vinylbenzyl chloride were added to 700 ml of dimethylsulfoxide and stirred and reacted at 40° C. for 4 days. Then, 1,500 ml of water was added thereto, and the resulting mixture was extracted with 500 ml of ethyl acetate. After distilling off ethyl acetate, recrystallization of the residue from an ethyl acetate-toluene mixture solvent yielded 152 g of vinylbenzyl 3,5-dihydroxybenzoate (m.p. 117°-119° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([Cl:18])[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C(N(CCCC)CCCC)CCC>O1CCOCC1>[Cl:18][C:4]1[N:3]=[C:2]([C:20]2[NH:19][CH:23]=[CH:22][N:21]=2)[C:11]2[C:6]([C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: c1c[nH]cn1
Reactant: Clc1nc(Cl)c2ccccc2c1-c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: C1COCCO1
Product: Clc1nc(-c2ncc[nH]2)c2ccccc2c1-c1ccccc1

Procedure:
2.74 g (10 moles) of 1,3-dichloro-4-phenylisoquinoline, 1.02 g (15 mmoles) of imidazole and 2.7 g (15 mmoles) of tri-n-butylamine were heated for 18 hours in 5 ml of dioxane under reflux. Working was carried out as described under 1c.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([NH:15]C(=O)C)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=O)C.Cl>O>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([NH2:15])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(NC(C)=O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: Nc1cc(C(F)(F)F)c(N)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h

Procedure:
61 g (0.2 mol) of the 1,4-bisacetylamino-2-nitro-5-trifluoromethylbenzene prepared according to C. are heated at 98° C. together with 250 ml of water and 80 g of concentrated hydrochloric acid (36% strength), and the reaction mixture is stirred at this temperature for 2 hours. The mixture is then cooled to 60° C. and the pH is brought to 7.5 with an alkali. The mixture is now cooled to 5° C. and the product which has precipitated is filtered off with suction, washed with water and dried in a vacuum cabinet.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH:10]=O)[N:4]2[N:3]=1.[CH3:18][N:19]([CH3:26])[C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23].N1CCCCC1>>[CH3:18][N:19]([CH3:26])[C:20](=[O:25])[C:21]([C:22](=[O:23])[CH3:24])=[CH:10][C:9]1[N:4]2[C:5]([S:6][C:2]([CH3:1])=[N:3]2)=[N:7][C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)CC(=O)N(C)C
Reactant: Cc1nn2c(C=O)c(-c3ccccc3)nc2s1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1c(-c2ccccc2)nc2sc(C)nn12)C(=O)N(C)C

Procedure:
0.03 mole of 2-methyl-6-phenylimidazo[2,1-b]-1,3,4-thiadiazol-5-carbaldehyde, 0.1 mole (13.0 g) of acetoacetic acid dimethylamide and 0.6 ml of piperidine were heated to 120° C. for 4 hours. The mixture was then cooled and the precipitate formed was recrystallised from 30 ml of ethyl acetate. After drying, α-acetyl-β-(2-methyl-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazol-5-yl)-propenoic acid dimethylamide of melting point 185° to 187° C. was obtained.
Reaction SMILES: [Br:1][CH:2]([F:14])[C:3]([F:13])([F:12])[O:4][C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.S(=O)(=O)(O)[OH:16].N([O-])=O.[Na+]>O>[Br:1][CH:2]([F:14])[C:3]([F:13])([F:12])[O:4][C:5]1[CH:11]=[CH:10][C:8]([OH:16])=[CH:7][CH:6]=1
Reactant: Nc1ccc(OC(F)(F)C(F)Br)cc1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(OC(F)(F)C(F)Br)cc1
Temperature: 10 °C

Procedure:
40 g of 4-(2-bromo-1,1,2-trifluoroethoxy)-aniline were added dropwise, at 10° C., to 400 ml of 2.5N sulfuric acid, after which 11 g of sodium nitrite in 30 ml of water were added dropwise at 0° C., and the mixture was stirred for a further hour at 10° C.