Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH3:19])[CH:13]=1)[NH:8][CH:7]=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2=[O:25].C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33]>CN(C)C=O>[CH2:32]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([C:12]3[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH3:19])[CH:13]=3)[CH:10]=2)[C:5](=[O:25])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7]1)[CH3:33]
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Reaction time: 0.33 h

Procedure:
A mixture containing 34 g of ethyl 6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylate, finely divided anhydrous potassium carbonate and 250 ml of dimethylformamide was heated with stirring on a steam bath for 20 minutes and then 9 ml of ethyl iodide was added over a 20 minute period. The reaction mixture was heated on a steam bath with stirring for 2 and 1/2 hours and then concentrated to dryness on a rotary evaporator. The residue was shaken well with 300 ml of water and 500 ml of chloroform. The layers were separated and the aqueous layer was extracted with another 200 ml portion of chloroform. The combined chloroform extracts were concentrated in vacuo to remove the chloroform. The remaining solid was dissolved in 150 ml of hot isopropyl alcohol, the hot solution treated with decolorizing charcoal and filtered. The filtrate was concentrated on a rotary evaporator to a volume of about 50 ml which was diluted with ether until turbid. The mixture was allowed to cool and the separated crystalline solid was collected, washed with ether and dried at 80°-85° C. to yield 18.5 g of ethyl 1-ethyl-6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylate, m.p. 221°-224° C. Further concentration of the mother liquor yielded another 3.4 g (60%) of product, m.p. 220°-223° C. A larger run (0.3 mole scale) gave the above compound, m.p. 222°-225° C., in 80% yield.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11].Cl[C:20]([O:22][CH:23]1[CH2:28][CH:27]([CH3:29])[CH2:26][CH2:25][CH:24]1[C:30]([CH3:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31])=[O:21].[F:39][C:40]1[CH:45]=[CH:44][C:43]([Mg]Br)=[CH:42][CH:41]=1.C1COCC1.Cl>C1(C)C=CC=CC=1>[CH3:29][CH:27]1[CH2:28][CH:23]([O:22][C:20]([N:6]2[CH:5]=[C:4]([Si:9]([CH:16]([CH3:17])[CH3:18])([CH:13]([CH3:14])[CH3:15])[CH:10]([CH3:11])[CH3:12])[C:3](=[O:2])[CH2:8][CH:7]2[C:43]2[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=2)=[O:21])[CH:24]([C:30]([CH3:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[CH2:25][CH2:26]1
Reactant: COc1ccncc1[Si](C(C)C)(C(C)C)C(C)C
Reactant: CC1CCC(C(C)(C)c2ccccc2)C(OC(=O)Cl)C1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)(C)c2ccccc2)C(OC(=O)N2C=C([Si](C(C)C)(C(C)C)C(C)C)C(=O)CC2c2ccc(F)cc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
Following the procedure reported in JACS 1994, 116, 4719-4728, to a solution of 4-methoxy-3-triisopropylsilanyl-pyridine (6.06 g, 22.8 mmol) in toluene (160 mL) at −25° C. was added a solution of 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl chloroformate (6.73 g, 26.2 mmol) in toluene (140 mL). After 15 minutes the mixture was cooled to −78° C. and 1.0M 4-fluorophenyl magnesium bromide in THF (26.1 mL, 26.2 mmol) was added slowly. The mixture was stirred at −78° C. for 1 hour. 2N HCl was added and the mixture was allowed to warm to room temperature and was stirred for additional 15 minutes. The mixture was extracted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness. Purification of the residue by flash chromatography (hexane/ethyl acetate 9:1) gave 2-(4-fluoro-phenyl)-4-oxo-5-triisopropylsilanyl-3,4-dihydro-2H-pyridine-1-carboxylic acid 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl ester (1.06 g, 48%) as a white solid.
Reaction SMILES: Cl.[NH2:2]O.[C:4]1([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCO.[Ni]>[C:4]1([CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[NH2:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NO
Reactant: O=C(CCc1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: NC(CCc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28 %

Procedure:
Hydroxylamine hydrochloride (2.1 g, 0.03 mol) was added to a solution of 3-phenyl-1-[4-(trifluoromethyl)phenyl]propan-1-one (Journal of the American Chemical Society 1994, 116(6), 2312-17, 2.8 g, 0.01 mol) in EtOH (30 ml). The solution was heated to reflux temperature for 18 hours. After cooling to RT, the solvent was evaporated under reduced pressure and the residue diluted with EtOAc (30 ml). The organic phase washed with water (3×20 ml), dried over Na2SO4 and concentrated. The crude reaction was then dissolved in EtOH (20 ml) and Raney Nickel (5 spoons) added. The reaction mixture was stirred for 2 days under a balloon of nitrogen and then filtered through a pad of celite. The filtrate was concentrated and purified by chromatography on silica gel eluting with 50% AcOEt/Hexane to afford the title compound (0.8 g, 28%); 1H NMR δ (ppm)(CDCl3, 360 MHz): 7.64 (2 H, d, J=7.7 Hz), 7.47 (2 H, d, J=7.7 Hz), 7.32 (2 H, m), 7.22-7.19 (3 H, m), 4.00 (1 H, t, J=6.7 Hz), 2.73-2.57 (2 H, m), 2.07-2.00 (2 H, m).
Reaction SMILES: I[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:24]([C:28]1[O:37][C:31]2[CH:32]=[N:33][C:34](=[O:36])[NH:35][C:30]=2[CH:29]=1)[CH2:25][CH2:26][CH3:27]>CN(C=O)C.[OH-].[K+]>[C:10]([C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:24]([C:28]1[O:37][C:31]2[CH:32]=[N:33][C:34](=[O:36])[NH:35][C:30]=2[CH:29]=1)[CH2:25][CH2:26][CH3:27].[CH2:16]([N:35]1[C:30]2[CH:29]=[C:28]([CH2:24][CH2:25][CH2:26][CH3:27])[O:37][C:31]=2[CH:32]=[N:33][C:34]1=[O:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: C#CCCCC
Reactant: BrCc1ccccc1
Agent: CCCCc1cc2[nH]c(=O)ncc2o1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCC#Cc1c[nH]c(=O)[nH]c1=O
Product: CCCCc1cc2c(cnc(=O)n2Cc2ccccc2)o1
Temperature: 65 °C

Procedure:
As above, 5-hexynyluracil and 6-n-butylfuranopyrimidin-2-one was prepared from 3.0 g of 5-iodouracil and 3.0 mL of 1-hexyne at 50° C. for 24 hours. Triethylamine solvent was completely distilled off at reduced pressure and a pale yellow slurry was obtained. This slurry was dissolved in 50.0 mL of DMF containing 0.70 g of KOH, and the resulting dark red solution was heated in an oil bath at 65° C. for 10 minutes. Then, 3.0 mL of benzylbromide was added to the red solution and the reaction was allowed to proceed under an Ar atmosphere until complete benzylation of 6-n-butylfuranopyrimidin-2-one to yield 1-benzyl-6-n-butylfuranopyrimidin-2-one. This alkylation took approximately 9 hours and it was monitored by TLC, as both 6-n-butylfuranopyrimidin-2-one and 1-benzyl-6-n-butylfuranopyrimidin-2-one are fluorescent under UV light but have significantly different Rf values in various solvent systems including EtOAc MeOH/Hexanes:10/1/4 and EtOAc/Ether:2/1. Once the alkylation was complete, DMF solvent was distilled off under reduced pressure and 50.0 mL of dry acetone was added to the resulting slurry to precipitate potassium bromide that was removed by gravity filtration. The filtrate was evaporated to a dark red viscous oil that was dissolved in 40.0 mL of chloroform and extraction was performed with 5% aqueous solution of EDTA (sodium salt) 2×40.0 mL and then once with 40.0 mL of distilled water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=O)[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:22][NH:23][NH2:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:7])[N:24]([NH:23][CH3:22])[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Reactant: CNN
Product: CNn1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
In the same manner as in Reference Example 6, 6-chloro-4-phenylisocoumarin-3-carboxylic acid and methylhydrazine were reacted to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=3)=[CH:15][CH:14]=2)[CH2:11][C:10]([C:29]([C:35]([F:38])([F:37])[F:36])([C:31]([F:34])([F:33])[F:32])[OH:30])=[N:9]1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=3)=[CH:17][CH:18]=2)[CH2:11][C:10]([C:29]([C:31]([F:34])([F:32])[F:33])([C:35]([F:36])([F:38])[F:37])[OH:30])=[N:9]1
Reactant: COC(=O)c1cncc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cncc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a mixture of 1-(2-chloro-phenyl)-5-(4-(5-methoxycarbonyl-pyridin-3-yl)-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (6.0 mg, 0.01 mmol) prepared in Example 273 in methanol (0.5 mL), was added a solution of potassium hydroxide (2.0 mg, 0.03 mmol) in distilled water (0.5 mL). The reaction mixture was stirred at 70° C. for 2 hours and then washed with diethyl ether. A 1N hydrochloric acid solution was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 5.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [C:1]([C:3]1([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([F:27])[CH:16]=2)[CH:10]2[CH2:11][CH:6]3CC(C[CH:4]1[CH2:5]3)C2)#[N:2].C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)CCCCC1)#N.CS(N)(=O)=O.[CH:56]1([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:58][CH2:57]1>>[C:1]([C:3]1([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19]([NH:62][S:59]([CH:56]3[CH2:58][CH2:57]3)(=[O:61])=[O:60])=[O:21])=[C:17]([F:27])[CH:16]=2)[CH2:10][CH2:11][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCCCC1
Product: N#CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCCCC1

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid and making variations as required to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a colorless solid (0.092 g, 66% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.86 (br s, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.99 (d, J=12.8 Hz, 1H), 4.15 (s, 2H), 3.08-3.00 (m, 1H), 2.03-1.95 (m, 3H), 1.73-1.66 (m, 3H), 1.51-1.38 (m, 4H), 1.23-1.15 (m, 1H), 1.09-1.05 (m, 4H), 0.91-0.85 (m, 2H), 0.69-0.64 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ −112.3 (s, 1F); MS (ES−) m/z 419.2 (M−1).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Br:24][C:25]1[CH:26]=[C:27]([F:35])[CH:28]=[C:29]2[C:33]=1[NH:32][C:31](=[O:34])[CH2:30]2.N1CCCCC1>C(O)C>[Br:24][C:25]1[CH:26]=[C:27]([F:35])[CH:28]=[C:29]2[C:33]=1[NH:32][C:31](=[O:34])/[C:30]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3c(Br)cc(F)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 75.3 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (40 mg, 0.125 mmol) was dissolved in 2 mL of ethanol under stirring at room temperature, and 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 12b (25.8 mg, 0.112 mmol) was then added to the solution. Upon completion of the addition, the reaction mixture was stirred until all dissolved, and piperidine (0.05 mL, 0.5 mmol) was then added to the solution. Upon completion of the addition, the reaction mixture was heated to reflux in an oil bath for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the reaction mixture was naturally cooled down to room temperature, and filtered under reduced pressure to give the title compound (S,Z)-2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 12 (45 mg, 75.4%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][O:11][CH:10]([CH2:13]Br)[CH2:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=3[NH:23][C:22]2=[O:31])[CH2:17][CH2:16]1.[I-].[Na+].[C:34](=[O:37])([O-:36])[O-].[K+].[K+]>CN(C)C=O.O>[C:12]([OH:11])(=[O:31])/[CH:8]=[CH:9]\[C:34]([OH:36])=[O:37].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][O:11][CH:10]([CH2:13][N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[C:25]5[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=5[NH:23][C:22]4=[O:31])[CH2:19][CH2:20]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(C2COC(CBr)C2)cc1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)/C=C\C(=O)O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CC2CC(c3ccc(F)cc3)CO2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of 3.1 g of 4-(4-fluorophenyl)-2-(bromomethyl)tetrahydrofuran, 3.5 g of 1-(4-piperidyl)-5-chloro-benzimidazolin-2-one, 2.5 g of sodium iodide and 2.0 g of potassium carbonate in 50 ml of dimethylformamide is heated with stirring at 60° C. for 24 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with chloroform eluant. The thus obtained oil is treated with maleic acid. The crystalline precipitate is collected by filtration and recrystallized from ethanol to give 1-[1-(4-(4-fluorophenyl)-tetrahydro-2-furylmethyl)-4-piperidyl]-5-chloro-benzimidazolin-2-one maleate, melting at 200°-201° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[N:6][C:5]([Cl:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH2:15])[CH2:13]C.O.[CH:17](O)(C)C>>[Cl:10][C:5]1[N:6]=[C:7]([CH:8]=[N:15][CH:12]([CH3:13])[CH3:17])[C:2]([NH2:1])=[N:3][C:4]=1[Cl:11]
Reactant: CCCN
Reactant: CC(C)O
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Solvent: O
Product: CC(C)N=Cc1nc(Cl)c(Cl)nc1N
Temperature: 25 °C
Reaction time: 20.5 h

Procedure:
In 1.2 ml of isopropyl alcohol there was dissolved 2-amino-5,6-dichloro-3-formylpyrazine (0.095 g; 0.0005M) prepared in Step B, after which n-propylamine (32 mg; 0.042 ml; 0.00055M) was added, and the reaction mixture was stirred at room temperature for 20.5 hours. When water was added to the reaction mixture, product precipitated, was filtered, and dried (23 mg). Additional product precipitated, was filtered, and dried (46 mg). The product was recrystallized from ethyl acetate/hexane. Elemental Analysis for C8H10N4Cl2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC)c(OCCCCl)c1
Temperature: 82.5 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
In a 100 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 10.2 g (54.9 mmol) of methyl 3-hydroxy-4-methoxybenzoate (purity: 98 wt. %), 11.5 g (71.4 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 8.5 g (60.4 mmol) of potassium carbonate (purity: 98 wt. %), and 30 mL of acetone. The resulting mixture was refluxed under stirring at 80-85° C. for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered. To the concentrate was added n-heptane, to precipitate a crystalline product. The crystalline product was collected and dried under reduced pressure, to give 13.7 g (isolated yield: 95.8%, purity: 99% in terms of area percentage by high performance liquid chromatography) of methyl 3-(3-chloropropoxy)-4-methoxybenzoate as a white crystalline product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[NH2:10][C:11]1[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1>C(O)=O.O.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:17]/[C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:10])[N:16]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: Cc1ccnc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: Nc1nccc(/C=C/c2cncc(Br)c2)n1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A solution of 5-bromo-pyridine-3-carbaldehyde (436 mg, 2.34 mmol) and 2-amino-4-methylpyrimidine (246 mg, 2.35 mmol) in formic acid (96%, 3 mL) was heated for 18 h. After cooling to rt, it was then diluted with water and basified to pH ˜13 with 1 N NaOH. The mixture was then extracted with methylene chloride. The combined extracts was washed with water (1×), dried over MgSO4 and concentrated. The residue was chromatographed on silica gel eluting with CH2Cl2:MeOH:NH4OH (100:5:0.5) to give the title compound (463 mg, 71%). MS (DCI/NH3) m/z 277, 279 (M+1)+.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:18][C:19]([NH2:21])=[S:20].C(OCC)C>O1CCCC1>[NH2:21][C:19]1[S:20][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[N:18]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1sc(N)nc1-c1cccc(C#N)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 102.7 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (4.0 g, 13.5 mmol) in 100 mL of tetrahydrofuran was added thiourea (1.03 g, 13.5 mmol). The resulting mixture was stirred at 65° C. for 16 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was triturated with ether, taken up in ethyl acetate, washed with saturated aq Na2CO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with ethyl ether left the title compound as an off-white solid (3.79 g, 98%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH2:18][N:19]2[C:28](=[O:29])[C:27]3[N:26]([CH2:30][C:31]#[C:32][CH3:33])[C:25]([N:34]4[CH2:39][CH2:38][CH2:37][CH:36]([NH:40]C(OC(C)(C)C)=O)[CH2:35]4)=[N:24][C:23]=3[N:22]([CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:20]2=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:8]1([CH2:18][N:19]2[C:28](=[O:29])[C:27]3[N:26]([CH2:30][C:31]#[C:32][CH3:33])[C:25]([N:34]4[CH2:39][CH2:38][CH2:37][CH:36]([NH2:40])[CH2:35]4)=[N:24][C:23]=3[N:22]([CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:20]2=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1cccc3ccccc13)c(=O)n2CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCn1c(N2CCCC(N)C2)nc2c1c(=O)n(Cc1cccc3ccccc13)c(=O)n2CC(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.7 ml of trifluoroacetic acid are added to a solution of 200 mg 1-(naphth-1-ylmethyl)-3-(methoxycarbonylmethyl)-7-(but-2-ynyl)-8-(3-tert-butoxycarbonylamino-piperidin-1-yl)-xanthine in 3 ml dichloromethane. The solution is stirred for 3 h at ambient temperature and then added to ice-cooled aqueous potassium carbonate solution. The aqueous phase is extracted with dichloromethane, the combined organic extracts are dried over sodium sulphate, and the solvent is removed. The residue is purified by chromatography on a silica gel column with methylene chloride/methanol (7:3) as eluant.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:16][N:15]=3)[S:13][C:6]=12.[NH4+].[Cl-]>[Fe].CCO.O>[F:1][C:2]1[CH:31]=[C:30]([CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)=[CH:16][N:15]=3)[S:13][C:6]=12)[NH2:32]
Reactant: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)nc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)nc2)CC1
Yield: 100 %

Procedure:
To a solution of 401 (306 mg, 0.64 mmol) and NH4Cl (30 mg, 0.54 mmol) in 2:1 EtOH/water (10.5 mL) was added iron powder (304 mg, 5.43 mmol) and the suspension was heated to reflux for 1 hour. The reaction mixture was filtered through celite and concentrated to provide title compound 396, that was used without further purification (343 mg, 100% yield). MS (m/z): (M+1) 450.0 (100%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][C:9](OC)=O)[O:7][CH2:6][CH2:5][O:4]1)C.C(=O)([O-])[O-:14].[K+].[K+].O1CCCC1>O>[CH2:8]([C:3]1([CH2:1][OH:14])[O:4][CH2:5][CH2:6][O:7]1)[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CCC1(CC(=O)OC)OCCO1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CO)OCCO1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 71.5 %

Procedure:
A mixture of methyl (2-ethyl-1,3-dioxolan-2-yl)acetate (1.39 g, 7.94 mmol), potassium carbonate (2.19 g, 15.9 mmol), tetrahydrofuran (20 ml) and water (10 ml) was stirred at room temperature for 6 hours and 50 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, which was subjected to NH silica gel pad filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (0.75 g, 71.5%) as colorless oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])=O.O.[NH2:17][NH2:18]>CCO>[F:1][C:2]([F:15])([F:14])[C:3]1[C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[NH:18][N:17]=1
Reactant: O=C(O)c1ccccc1C(=O)C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(C(F)(F)F)c2ccccc12

Procedure:
A solution of 2-(2,2,2-trifluoroacetyl)benzoic acid (0.554 g, 2.54 mmol) and hydrazine hydrate (0.44 mL, 7.8 mmol) in EtOH (7.5 mL) was stirred at 80° C. overnight, concentrated, azeotroped with toluene, and dried in vacuo to give the crude title compound as a tan solid, which was used without purification). 1H NMR (300 MHz, DMSO-d6) δ 8.36 (dd, 1H), 7.91-8.10 (m, 3H).