Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13]>CO>[OH:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: O=C(CBr)C(F)(F)F
Solvent: CO
Product: Oc1cccn2cc(C(F)(F)F)nc12
Yield: 17.9 %

Procedure:
A mixture of 2-amino-3-hydroxypyridine (2.18 g, 19.4 mmol), bromo-1,1,1-trifluoroacetone (9.1 g, 42.6 mmol), and molecular sieves (6.3 g, 8–12 mesh beads) in anhydrous methanol (50 mL) was refluxed for 24 h. After the molecular sieves were filtered off and the solvent was evaporated in vacuo, the residue was dissolved in water (150 mL) and the resultant mixture was extracted with diethyl ether (2×150 mL). The combined organic extracts were dried over anhydrous sodium sulphate and the solvent was evaporated in vacuo to provide the crude 8-hydroxy-2-(trifluoromethyl)imidazo[1,2-α]pyridine. Purification by column chromatography using as eluent a mixture of ethyl acetate and isopropylamine (98:2 v/v) yielded 0.7 g of pure 8-hydroxy-2-(trifluoromethyl)imidazo[1,2-α]pyridine.
Reaction SMILES: [OH:1][CH:2]([CH3:16])[CH2:3][CH2:4]OS(C1C(C)=CC=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]3[CH2:35][CH2:36][N:37]=[C:38]([CH3:39])[C:33]3=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.[OH-].[Na+].[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46]>CC(=O)CC.C(O)C>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46].[CH3:39][C:38]1[C:33]2[N:34]([C:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:4][CH2:3][CH:2]([OH:1])[CH3:16])=[CH:29][CH:28]=3)=[CH:31][CH:32]=2)[CH2:35][CH2:36][N:37]=1
Reactant: CC1=NCCn2c1ccc2-c1ccc(O)cc1
Reactant: Cc1ccccc1S(=O)(=O)OCCC(C)O
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCC(C)=O
Product: CC1=NCCn2c1ccc2-c1ccc(OCCC(C)O)cc1
Reaction time: 20 h
Yield: 90 %

Procedure:
Toluenesulphonic acid 3-hydroxybutan-1-yl ester (1.8 g) and 1.8 g of potassium carbonate was added at room temperature while stirring and under argon to a solution of 1.5 g of 3,4-dihydro-6-(4-hydroxyphenyl)-1-methylpyrrolo[1,2-a]pyrazine in 20 ml of 2-butanone and the mixture was boiled for 20 hours. The cooled reaction mixture was treated with 100 ml of 2N sodium hydroxide solution and extracted three times with 200 ml of methylene chloride each time. The organic phases were washed twice with 100 ml of water each time, combined, dried with MgSO4 and freed from solvent. The residue, 2.4 g of brown oil, was chromatographed on 50 g of silica gel with methylene chloride/methanol mixtures (50:1 to 20:1) as the eluent. There were obtained 1.2 g of an orange coloured, amorphous solid which was dissolved in a 25-fold amount of ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 1.5 g (90%) of 4-[4-(3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazin-6-yl)phenoxy]butan-2-ol fumarate (1:1); m.pt.: 156°-157° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([O:15][C:16]([NH:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:23]1[CH2:22][CH2:21][CH2:20][CH:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccncc2[N+](=O)[O-])C1
Yield: 89 %

Procedure:
The method of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, 3-N-Boc-amino piperidine and diisopropylethylamine yielding tert-butyl 1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (89%). LCMS (m/z): 323.1 (MH+); LC Rt=2.13 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([NH:11][CH2:12]C(OC(C)(C)C)=O)([CH3:10])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C(NC(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)(C)CO)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>>[C:1]([O:5][C:6](=[O:20])[C:7]([CH3:10])([NH:11][CH3:12])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CNC(C)(CO)C(=O)OC(C)(C)C
Agent: COc1ccc(C(NC(C)(CO)C(=O)OC(C)(C)C)c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Product: CNC(C)(CO)C(=O)OC(C)(C)C
Yield: 69.1 %

Procedure:
A 255 mg portion of alcohol 11 (0.88 mmol) was treated with 1 eq p-toluenesulfonic acid (167 mg) as described in the preparation of 12a. The resulting solid was added to 15 mL of 10% Na2CO3 and extracted with 3×15 mL of EtOAc. The combined organic layers were subject to the usual work up. Purification via silica gel column chromatography (10% CH3OH in CH2Cl2) afforded 12b (115 mg, 69%) as a colorless oil: 1H NMR (CDCl3) δ 1.24 (3H, s), 1.48 (9H, s), 2.32 (3H, s), 3.52 (1H, d, J=10.8), 3.64 (1H, d, J=10.8). HRMS Calcd for C9H19NO3: 189.13649. Found 189.13627. Anal. (C9H19NO3) Calcd C, 57.12; H, 10.12, N, 7.40. Found C, 55.87; H, 10.05, N, 7.18.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:28]=[CH:27][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[CH:21][N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[CH3:31][C:32]1([CH3:40])[CH2:36][CH2:35][NH:34][C@@H:33]1[C:37]([NH2:39])=[O:38]>>[CH:24]([N:23]1[C:19]([C:17]2[N:18]=[C:11]3[C:10]4[CH:27]=[N:28][C:7]([N:34]5[CH2:35][CH2:36][C:32]([CH3:40])([CH3:31])[C@H:33]5[C:37]([NH2:39])=[O:38])=[CH:8][C:9]=4[O:15][CH2:14][CH2:13][N:12]3[CH:16]=2)=[N:20][CH:21]=[N:22]1)([CH3:25])[CH3:26]
Reactant: CC1(C)CCN[C@@H]1C(N)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OS(=O)(=O)C(F)(F)F)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCC(C)(C)[C@H]3C(N)=O)cc1OCC2

Procedure:
Following the procedures of Example 388, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl trifluoromethanesulfonate and (S)-3,3-dimethylpyrrolidine-2-carboxamide were reacted to give 393. M/z 437.2, calc. 436.23. 1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.40 (s, 1H), 6.97 (s, 1H), 5.95 (dd, J=14.5, 7.9, 2H), 4.49 (dd, J=14.6, 5.6, 4H), 3.90 (s, 1H), 3.63 (t, J=8.5, 1H), 3.43 (d, J=7.8, 1H), 1.96 (dd, J=21.1, 9.3, 1H), 1.68 (dd, J=11.9, 5.8, 1H), 1.48 (dd, J=6.6, 3.6, 6H), 1.08 (d, J=6.9, 6H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[Cl:14].S(Cl)(Cl)=O.[CH3:19]O>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([O:13][CH3:19])=[O:12])[C:3]=1[Cl:14]
Reactant: CO
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 60 °C

Procedure:
To a solution of 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid (i.e. the product of Step D1 or D2 of Example 2) (8.5 g, 40 mmol) in methanol (120 mL) was added dropwise with cooling thionyl chloride (15 mL, 200 mmol). The mixture was heated at 60° C. for 24 h. The mixture was concentrated to 25% of the original volume and diluted with water (100 mL). Phenolphthalein pH indicator was added, and 10% aqueous sodium hydroxide was added dropwise with cooling at 10-20° C. to bring the pH to 8-10. The solid was isolated by filtration, washed with water and dried in a vacuum oven at 50-60° C. to afford the title product (7.3 g), a compound of the present invention.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][CH:21]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH3:22]>>[CH3:20][CH:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)[CH3:22]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)c1ccc(C=O)cc1
Product: CC(C)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-propan-2-ylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-propan-2-ylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])[CH:6]=1)(=O)C>[OH-].[Na+]>[OH:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=1)=[O:12]
Reactant: CC(=O)Oc1cccc(C(=O)Nc2cccc(C(F)(F)F)c2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(O)c1
Yield: 98.9 %

Procedure:
Using 3-({[3-(trifluoromethyl)phenyl]amino}carbonyl)phenyl acetate (16.2 g, 50 mmol) and 8N aqueous sodium hydroxide solution (10 mL), and in the same manner as in Example A25(ii), the title compound (13.9 g, 99%) was obtained as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([CH2:18][C:19]#[CH:20])[C:8](=[O:21])[C:7]=1[CH3:22])=[O:5])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:9]([CH2:18][C:19]#[CH:20])[C:8](=[O:21])[C:7]=1[CH3:22])([OH:5])=[O:3]
Reactant: C#CCn1c(-c2ccccc2)nc(C(=O)OCC)c(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C#CCn1c(-c2ccccc2)nc(C(=O)O)c(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.2 %

Procedure:
To a solution of 1.81 g (6.1 mmol) of 6-ethoxycarbonyl-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone in 100 mL of ethanol and 50 mL of THF was added 50 mL of 5% aqueous sodium hydroxide. The mixture was stirred at room temperature for 24 h and rotovapped to remove the bulk of the organic solvents. The residue was diluted with 50 mL of 5% aqueous sodium hydroxide and washed with 100 mL of ether. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with two 100 mL portions of ethyl acetate. The combined ethyl acetate extracts were washed with 50 mL of brine, dried over MgSO4 and concentrated to leave 0.87 g (53%) of crude 6-carboxy-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone as a brown oil.
Reaction SMILES: C(N(CC)CC)C.C1(=O)NC(=O)CC1.Cl[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17].[F:22][C:23]([F:34])([F:33])[C@H:24]([CH3:32])[C@@H:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH2:26]>C(OCC)(=O)C.C1COCC1>[CH2:19]([O:18][C:16]([NH:26][C@H:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C@H:24]([C:23]([F:34])([F:33])[F:22])[CH3:32])=[O:17])[CH:20]=[CH2:21]
Reactant: C=CCOC(=O)Cl
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)C(F)(F)F
Agent: O=C1CCC(=O)N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N[C@H](C(=O)OCC)[C@@H](C)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.7 ml (69.3 mmol) of triethylamine were added dropwise to a solution of 6.38 g (55.4 mmol) of succinimide in 90 ml of abs. THF. The resulting suspension was cooled to 0° C., and a solution of 6.68 g (55.4 mmol) of allyl chloroformate in 10 ml of abs. THF was added dropwise. The mixture was stirred at 0° C. for 1 h, and three portions of in total 9.2 g (about 46 mmol) of ethyl (3R)-4,4,4-trifluorovalinate (diastereomer mixture, crude product) were added. The reaction mixture was warmed to RT overnight, then diluted with ethyl acetate, washed with sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1). This gave 6.50 g of the target product (about 50% of theory, diastereomer ratio about 2:1).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:14][C:15]([OH:17])=[O:16])[C:8]=2[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+].[CH2:29](O)[CH3:30]>>[CH:1]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:14][C:15]([O:17][CH2:29][CH3:30])=[O:16])[C:8]=2[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)c1nccc2c(CC(=O)O)cccc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)Cc1cccc2c(C(C)C)nccc12
Temperature: 0 °C

Procedure:
1-iso-Propylisoquinoline-5-acetic acid (0.5 g) was dissolved in 20 ml of ethanol, and 3 ml of conc. sulfuric acid was added. The mixture was heated under reflux for 3 hours. The reaction mixture was poured into ice water, made weakly alkaline with potassium carbonate, extracted with benzene, washed in water, and dried. The solvent was distilled off under reduced pressure to afford 0.5 g of ethyl 1-isopropylisoquinoline-5-acetate as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.S(Cl)(Cl)=O.[CH2:25](Cl)Cl>>[CH3:25][O:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2
Reactant: ClCCl
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(OC)c1ccccc1CO2
Reaction time: 2 h

Procedure:
In 300 ml of methylene chloride was dissolved 30.0 g of Compound b obtained in Reference Example 2. Under ice cooling, 10 ml of thionyl chloride was dropwise added to the solution. After stirring for further 2 hours under ice cooling, the reaction mixture was concentrated under reduced pressure. To the resulting residue, 500 ml of methanol and 20 ml of triethylamine were added and the mixture was stirred at room temperature for an hour. The solvent was distilled off under reduced pressure and the residue was extracted with 1 liter of ethyl acetate. The extract was washed in sequence with saturated aqueous sodium bicarbonate solution and then saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from isopropyl ether to give 19.0 g of white crystalline methyl 11-methoxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.
Reaction SMILES: [Na].[CH3:2][OH:3].[C:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[N:11][CH:12]=1)([OH:6])=[O:5].Cl>O>[C:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13](=[NH:14])[O:3][CH3:2])=[N:11][CH:12]=1)([OH:6])=[O:5]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: CO
Agent: Cl
Agent: [Na]
Solvent: O
Product: COC(=N)c1ccc(C(=O)O)cn1

Procedure:
Sodium (12 mmol) is added to a flask containing 20 ml of methanol. After the sodium has dissolved, 5 mmol of 5-carboxy-2-cyano-pyridine is added. The mixture is heated at 50° for 6 h. After cooling, the reaction mixture is diluted with water and acidified (pH=5)with 2N HCl. The solid is collected and dried, and corresponds to the title compound, m.p. 284°-286°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:34]([NH:33][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[O:16])[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 70 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.47 (m, 2H), 7.43–7.39 (m, 2H), 7.30–7.27 (m, 2H), 7.04–7.00 (m, 2H), 6.96 (d, 1H, J=7.2 Hz), 6.77 (br s, 1H), 3.30 (dd, 2H, J=5.6, 11.6 Hz), 2.95 (d, 2H, J=11.6 Hz), 2.49 (m, 1H), 2.34 (t, 4H, J=6.4 Hz), 2.19 (s, 3H), 1.99–1.80 (m, 6H), 1.73–1.60 (m, 10H); ESMS m/e: 480.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[N:21]([CH3:22])[C:20]3[C:19](=[O:23])[N:18]([CH2:24][C:25]#[CH:26])[C:17](=[O:27])[NH:16][C:15]=3[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(C#CC2N(C)C3C(=O)N(CC#C)C(=O)N(C)C=3N=2)C=CC=1OC.C(=O)([O-])[O-].[K+].[K+].[C:62]([O:68][CH2:69]Cl)(=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64]>CN(C=O)C>[C:62]([O:68][CH2:69][N:16]1[C:15]2[N:14]=[C:13]([C:12]#[C:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:21]([CH3:22])[C:20]=2[C:19](=[O:23])[N:18]([CH2:24][C:25]#[CH:26])[C:17]1=[O:27])(=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: C#CCn1c(=O)[nH]c2nc(C#Cc3ccc(OC)c(OC)c3)n(C)c2c1=O
Agent: C#CCn1c(=O)c2c(nc(C#Cc3ccc(OC)c(OC)c3)n2C)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCn1c(=O)c2c(nc(C#Cc3ccc(OC)c(OC)c3)n2C)n(COC(=O)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
The crude 8-[(3,4-dimethoxyphenyl)ethynyl]-7-methyl-1-prop-2-ynyl-3,7-dihydro-1H-purine-2,6-dione (ca. 452 mg, 1.24 mmol), contaminated with the starting material and with the dimethylated derivative (8-[(3,4-dimethoxyphenyl)ethynyl]-3,7-dimethyl-1-prop-2-ynyl-3,7-dihydro-1H-purine-2,6-dione), was suspended in dry DMF (7 mL). Subsequently dry potassium carbonate (514 mg, 3.72 mmol) and chloromethyl pivalate (654 mg, 4.34 mmol) was added. The mixture was stirred at room temperature for 3 h (TLC-control: dichloromethane/methanol, 9.5:0.5, Rf=0.60 for the main product) and the product was precipitated by adding water (30 mL), filtered under reduced pressure and dried at 70° C. The crude product was dissolved in a minimum of ethyl acetate (by slightly heating) and purified by column chromatography (eluent: petroleum ether/ethyl acetate, 1:1) affording 471 mg (79% yield over two steps) of {8-[(3,4-dimethoxyphenyl)ethynyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydro-3H-purin-3-yl}methyl pivalate as a colorless solid.
Reaction SMILES: S[C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.S[C:11]1C2C=CC=CC=2C=CC(=O)[CH:12]=1.NC1C2C=NC=CC=2C=CC(=O)C=1>>[CH:11]1[C:8]2[CH2:7][CH2:6][CH:5]=[CH:4][C:3](=[O:9])[C:2]=2[CH:12]=1
Reactant: O=c1ccc2ccccc2c(S)c1
Reactant: O=c1cccccc1S
Agent: Nc1cc(=O)ccc2ccncc12
Product: O=C1C=CCCC2=C1C=C2

Procedure:
By following serially the procedures of Examples 1 and 2 but replacing 2-mercapto-2,4,6-cycloheptatrien-1-one with an equivalent amount of 5-mercapto-7H-benzocyclohepten-7-one, 9-amino-7H-cyclohepta[c]pyridin-7-one, 5-mercapto-3H,-6,7-dihydrocyclobutacyclohepten-3-one, 1-ethylamino-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-3-one and 5-mercapto-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-3-one, the following compounds are obtained respectively: [(7-oxo-7H-benzocyclohepten-5-yl)thio]oxoacetic acid ethyl ester (l; R1, R5, and R6 = H; R2 = S--CO--COOC2H5 ; and R3 and R4 together form a --CH=CH--CH=CH-- chain), [(7-oxo-7H-cyclohepta[c]pyridin-9-yl)-amino]oxo-acetic acid ethyl ester (I; R1, R5 and R6 = H; R2 = NC2H5 --CO--COOC2H5 ; and R3 and R4 together form a --CH=CH--N=CH-- chain). [(3-oxo-3H-6,7-dihydrocyclobutacyclohepten-5-yl)thio]oxo-acetic acid ethyl ester (I; R1, R5 and R6 = H; R2 = S--CO--COOC2H5 ; and R3 and R4 together form a --CH2CH2 -- chain), [N-(3-oxo-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-1-yl)ethylamino]oxo-acetic acid ethyl ester (I; R1, R2 and R6 = H; R3 and R4 together form a --(CH2)6 chain; and R5 = NC2H5 --CO--COOC2H 5) and [(3-oxo-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-5-yl)thio]oxo-acetic acid ethyl ester (I; R1, R5 and R6 = H; R2 = S--CO--COOC2H5 ; and R3 and R4 together form a --(CH2)8 -- chain).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH2:11][N:12]2[C:16]1[C:17]2[C:24]([CH:25]([CH3:27])[CH3:26])=[CH:23][S:22][C:18]=2[N:19]=[CH:20][N:21]=1)(=O)=O.Cl.[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][O:30]2.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(C(C)=O)C.C(Cl)Cl>[CH:25]([C:24]1[C:17]2[C:16]([N:12]3[CH2:11][CH:10]4[CH2:15][CH:13]3[CH2:14][CH:9]4[O:8][CH2:7][CH2:6][N:33]3[CH2:34][CH:29]4[CH2:35][CH:32]3[CH2:31][O:30]4)=[N:21][CH:20]=[N:19][C:18]=2[S:22][CH:23]=1)([CH3:27])[CH3:26]
Reactant: C1OC2CNC1C2
Reactant: CC(C)c1csc2ncnc(N3CC4CC3CC4OCCOS(C)(=O)=O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1csc2ncnc(N3CC4CC3CC4OCCN3CC4CC3CO4)c12
Temperature: 180 °C
Yield: 17.9 %

Procedure:
2-[[2-(5-Isopropylthieno[2,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-5-yl]oxy]ethyl methanesulfonate (0.11 g, 0.27 mmol), 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (0.072 g, 0.53 mmol) and potassium carbonate (0.11 g, 0.80 mmol) were combined in methyl ethyl ketone (2 mL)/DMF (1 mL, 12.8) and heated in the microwave for 30 minutes at 180° C. The reaction mixture was diluted with DCM, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by basic prep HPLC (method 2) to afford 5-[2-[[2-(5-isopropylthieno[2,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-5-yl]oxy]ethyl]-2-oxa-5-azabicyclo[2.2.1]heptane as a colourless gum (20 mg). LCMS RT=4.33 min. M+1=415.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:30])[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[C:17]([OH:24])=[C:16]([C:25](OC)=[O:26])[C:15]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl-].[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH3+:49])=[C:44]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:43]=1>CO>[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH:49][C:25]([C:16]2[C:15](=[O:29])[N:14]([CH2:13][CH2:12][N:11]([CH3:30])[C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:23]3[C:18]([C:17]=2[OH:24])=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:26])=[C:44]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:43]=1
Reactant: COC(=O)c1c(O)c2ncccc2n(CCN(C)C(=O)OCc2ccccc2)c1=O
Reactant: CS(=O)(=O)c1cc(F)ccc1C[NH3+]
Agent: [Cl-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCn1c(=O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)c(O)c2ncccc21)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of methyl 1-{2-[[(benzyloxy)carbonyl](methyl)amino]ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.5 g, 1.21 mmol) in MeOH (6 mL) was treated with Hunig's base (0.33 mL, 1.82 mmol) and 1-[4-fluoro-2-(methylsulfonyl)phenyl]methanaminium chloride (0.35 g, 1.46 mmol) and heated in a sealed reaction vessel at 80 degrees C. After overnight, an additional 0.5 equivalents of the amine and 1.5 equivalents of Hunig's base was added and the reaction heated until HPLC showed the starting material gone. The reaction was cooled and the solids that percipitated were collected by filtration to give pure product.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11])(=[O:5])=[O:4])[CH3:2].[C:12](Cl)([Cl:14])=[O:13].N1C=CC=CC=1>ClCCl>[CH2:1]([S:3]([N:6]1[CH2:10][CH2:9][N:8]([C:12]([Cl:14])=[O:13])[C:7]1=[O:11])(=[O:5])=[O:4])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCS(=O)(=O)N1CCNC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Reaction time: 8 h

Procedure:
The N-ethanesulphonyl-imidazolidin-2-one was then suspended in dichloromethane, a large excess of phosgene was introduced at 0° C, a little pyridine was added and the mixture was left to stand overnight. The excess phosgene was then largely removed by passing in dry air and the product (3-ethanesulphonyl-imidazolidin-2-on-1-carbonyl chloride) was suspended in dichloromethane and filtered off.