Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:6]([C:16]2[N:17]=[C:18]([NH2:24])[NH:19][C:20](=[O:23])[C:21]=2[N:22]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])[CH:2]=[CH2:3].[CH2:25](Br)C=C>>[CH2:1]([S:4][C:5]1[N:6]([C:16]2[N:17]=[C:18]([NH2:24])[NH:19][C:20](=[O:23])[C:21]=2[N:22]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])[CH:2]=[CH:3][CH3:25]
Reactant: C=CCSc1nc2c(=O)[nH]c(N)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C=CCBr
Product: CC=CCSc1nc2c(=O)[nH]c(N)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 48 %

Procedure:
Following the first procedure for the preparation of 8-(2-propenylmercapto)guanosine (Example 9), but substituting 2-butenyl chloride for allyl bromide, the title compound was obtained in 48 percent yield as a white powder, mp 210° C. (decomp.). NMR (DMSO-d6): δ 6.3 (bs, 2H); 5.6 (d, J=5 Hz, 1H); 1.6 (d, J=6 Hz, 3H). IR (KBr): 1690, 1630, 1600, 1510 and 1365 cm-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.S(Cl)([Cl:19])(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:12]1[CH:13]=[C:8]([CH:5]2[CH2:6][CH2:7][C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4]2)[CH:9]=[CH:10][C:11]=1[OH:14]
Reactant: CC1(C)CCC(c2ccc(O)cc2)CC1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(c2ccc(O)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of 4-(4,4-dimethylcyclohexyl)phenol (2.16 g, 10.6 mmol), disiobutylamine (0.14 mL) and sulfuryl chloride (0.59 mL, 7.4 mmol) in toluene was stirred at 70° C. for 2 h. The reaction mixture was cooled to room temperature, treated with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was subjected to chromatography on silica gel, using hexane/ethyl acetate (20:1), to afford the title compound (1.7 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][O:5][C:6](=[O:30])[C@H:7]([CH2:26][CH2:27][S:28][CH3:29])[NH:8][C:9](=[O:25])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:32][Si:2]([CH3:1])([CH3:31])[CH2:3][CH2:4][O:5][C:6](=[O:30])[C@H:7]([CH2:26][CH2:27][S:28][CH3:29])[NH:8][C:9](=[O:25])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CSCC[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1)C(=O)OCC[Si](C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CSCC[C@H](NC(=O)c1ccc(N)cc1-c1ccccc1)C(=O)OCC[Si](C)(C)C

Procedure:
A mixture of the product of Example 283A (8.85 g, 25.8 mmol), ammonium formate (4.88 g, 77.4 mmol) and palladium (10%) on carbon (1 g) in methanol was refluxed for 5 hours. The mixture was then filtered through Celite and rinsed with ethyl acetate. The filtrate was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:15].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH3:15])[N:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2cn[nH]c2c1
Reactant: CC(Cl)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccccn1)n1ncc2ncc(Br)cc21
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To an ice-cooled solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (0.60 g, 3.0 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (60%, 488 mg, 12.2 mmol). After 30 min, 2-(1-chloroethyl)pyridine (1.73 g, 12.2 mmol) was added to reaction mixture, and the resulting suspension was warmed to 27° C. After 17 h, the reaction mixture was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (3×30 mL). The organic extracts were concentrated in vacuo. Purification by flash column chromatography (6→15% ethyl acetate in petroleum ether) afforded 6-bromo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[4,3-b]pyridine (450 mg, 49% yield). LRMS (ESI): [MH]+=304.6.
Reaction SMILES: Br[CH2:2][CH2:3]Br.C([O-])([O-])=O.[K+].[K+].[SH:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=1[OH:19]>CC(C)=O>[O:19]1[C:13]2[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=2[S:11][CH2:3][CH2:2]1
Reactant: BrCCBr
Reactant: Oc1ccc(O)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1ccc2c(c1)SCCO2
Reaction time: 10 h
Yield: 55.2 %

Procedure:
1,2-Dibromoethane (2.3 mL, 26.7 mmol) and K2CO3 (8.21 g, 59.4 mmol) were slurried in acetone (250 mL) and a solution of 2-sulfanyl-1,4-benzenediol (prepared according to J. Org. Chem. 1990, 55, 2736) (4.22 g, 29.7 mmol) in acetone (50 mL) was added over 4 h to the stirred mixture. Once the addition was complete stirring was continued for a further 10 h before the solvent was removed in vacuo. The residue was partitioned between water (50 mL) and EtOAc (50 mL), the aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were dried (MgSO4) and evaporated. Purification of the residue by column chromatography [SiO2; 9:1 (pentane/EtOAc)] gave the title compound (2.48 g, 55%) as a pale orange oil; δH (CDCl3, 400 MHz) 3.08 (2H, m), 4.31 (2H, m), 4.44 (1H, s), 6.42 (1H, d), 6.49 (1H, s), 6.66 (1H, d); MS m/z (ES−) 167 (M−H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14]Cl)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH2:23]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[CH3:24]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][NH:28][CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:29])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)N1CCN(C(=O)CCl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNCC(=O)N1CCN(C(=O)OCC)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a solution of 1-ethoxycarbonyl-4-chloromethylcarbonylpiperazine (520 mg, 2.21 mmol) in DMF (40 mL) was added cesium carbonate (2.0 g, 6.20 mmol) and glycine ethyl ester hydrochloride (310 mg, 2.21 mmol). The resulting reaction mixture was stirred at 50° C. After 1 hour, the reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3×150 mL) and brine, and concentrated in vacuo to afford 1-ethoxycarbonyl-4-(ethoxycarbonylmethyl)aminomethylcarbonylpiperazine as an oil (520 mg), which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:3]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cc1Oc1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1Oc1cccc(C(F)(F)F)c1

Procedure:
136 G. of 4-chloro-2-(3-trifluoromethyl-phenoxy)-benzoic acid are boiled at reflux for 2.5 hours in a mixture of 1000 ml. of methanol and 100 ml. of concentrated sulfuric acid. After concentration of the mixture under vacuum, the residue is poured on to ice and extracted with benzene. The benzene extracts are washed with water, aqueous sodium bicarbonate solution and again with water. After evaporation of the benzene, there is obtained 4-chloro-2-(3-trifluoromethyl-phenoxy)-benzoic acid methyl ester in the form of an oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].O.[O:40]1CCOCC1>>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([OH:40])[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: C1COCCO1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Solvent: O
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(O)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
A solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-[2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-amine (18 mg, 0.044 mmol) from Example 84, step 1, in water/dioxane was heated to 105° C. for 16 hr. Solvent was evaporated and the product purified by super critical chromatography (SFC) to give 4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-ol. MS (ES+): 390.
Reaction SMILES: [O:1]([CH2:8][C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[NH2:12][C:9]([CH3:10])=[CH:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(=O)COc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC(N)=COc1ccccc1
Reaction time: 24 h

Procedure:
0.2 mol of phenoxyacetone in 200 ml of tetrahydrofuran is saturated at reflux temperature with ammonia gas with the addition of 0.2 g of p-toluene sulphonic acid. The mixture is allowed to stand at room temperature for 24 hours and the solvent is then removed by evaporation in vacuo. The evaporation residue is employed crude in the reaction of Example 5B.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[N:8][CH:9]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC.C([O-])([O-])=O.[Na+].[Na+]>>[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2([CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[CH:5]=1
Reactant: OCCO
Reactant: CC(=O)c1cncc(Br)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cncc(Br)c2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(5-bromo-pyridin-3-yl)-ethanone (1800 mg, 9.00 mmol) in ethylene glycol (9.57 mL, 171.69 mmol) was treated with trimethylorthoformate (2.01 mL, 18.34 mmol) followed by LiBF4 (172 mg, 1.80 mmol). The reaction mixture was heated at 95° C. overnight. Sat. aq. Na2CO3 was added and the mixture was extracted twice with ether. The combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (50:50 hept-EA)=0.57. LC-MS-conditions 02: tR=0.87 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36].[CH3:37][N:38]([CH3:44])[CH2:39][CH2:40][CH2:41][NH:42][CH3:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:42]([CH2:41][CH2:40][CH2:39][N:38]([CH3:44])[CH3:37])[CH3:43])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36]
Reactant: CNCCCN(C)C
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N(C)CCCN(C)C)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (0.04 g, 0.078 mmol), N,N,N′-trimethyl-1,3-propanediamine (0.134 g, 0.115 mmol), and TEA (0.016 g, 0.156 mmol) were combined in CH2Cl2 (5 mL) and stirred under argon at room temperature. The solvents were pumped off in vacuo. The residue was flash chromatographed on silica gel (10 g) eluted with CH2Cl2 to 6:1:0.1, CH2Cl2:ethanol:NH4OH. The compound had an impurity which was removed by filtering through a silica gel plug with 3% MeOH/CH2Cl2 to give the title compound as an off-white amorphous solid. mp 104-109° C. LC-MS m/z 549 (M+H)+, 1.65 min (ret time).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:32])[C:20]([C:26]4[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:22]=3)[C:17]2=[O:33])=[C:13]([CH3:34])[CH:12]=[C:11]([CH3:35])[N:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:32][C:19]1[C:20]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:21][CH:22]=[C:23]2[C:18]=1[C:17](=[O:33])[N:16]([CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:35])=[CH:12][C:13]=1[CH3:34])[CH2:25][CH2:24]2
Reactant: Cc1cc(C)c(CN2CCc3ccc(-c4ccnn4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CN2CCc3ccc(-c4ccnn4C)c(Cl)c3C2=O)c(=O)[nH]1
Yield: 17.8 %

Procedure:
A solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (66c, 60 mg, 0.12 mmol) in TFA (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue purified by prep chromatography to give the title compound (Example 66, 8.5 mg, 17%) as a white solid. 1H NMR (700 MHz, DMSO-d6) δ 11.56 (br. s, 1H) 7.44 (d, J=7.70 Hz, 1H) 7.35 (d, J=7.70 Hz, 1H) 7.50 (d, J=1.76 Hz, 1H) 6.29 (d, J=1.76 Hz, 1H) 5.90 (s, 1H) 4.60 (s, 2H) 3.61 (s, 3H) 3.46-3.50 (m, 2H) 2.91 (t, J=5.83 Hz, 2H) 2.19 (s, 3H) 2.14 (s, 3H); MS 397.0 [M+1].
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH2:16]([O:32][C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:16]([O:32][C:33]1[S:34][C:35]([CH:9]=[O:10])=[CH:36][CH:37]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCOc1cccs1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCOc1ccc(C=O)s1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To a cooled mixture of 27 g of N-methylformanilide and 27 g (0.176 mole) of phosphorus oxychloride is added 32.5 g (0.1 mole) of 2-hexadecyloxythiophene. The mixture is warmed to 70° C under vacuum (10 mm Hg). The mixture is allowed to stand at 60°-70° C for 7 hours, then overnight at room temperature after which the mixture is stirred into 100 g of ice. The mixture is extracted into benzene, washed with water, dried over sodium sulfate and distilled in vacuo to give 5-hexadecyloxy-2-thiophenecarboxaldehyde. The carboxaldehyde (7.1 g, 0.02 mole) is stirred vigorously with 4 g of potassium hydroxide in 2.6 ml of water for 24 hours. The mixture is diluted with water and extracted into ether. The aqueous layer is separated and acidified with hydrochloric acid precipitating 5-(hexadecyloxy)-2 -thiophenecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:20])=[C:4]([F:23])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:30][O:31][C:32](Cl)=[O:33].O>C1COCC1>[C:32](=[O:33])([O:31][CH3:30])[O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[CH:9][C:8](=[O:20])[N:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][C:4]=3[F:23])[CH:12]=2)=[CH:14][CH:15]=1
Reactant: O=c1ccc(-c2ccc(O)cc2)cn1Cc1ccc(Cl)cc1F
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Oc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
According to Scheme 14 Method B: A suspension of 1-(4-chloro-2-fluorobenzyl)-5-(4-hydroxyphenyl)pyridin-2(1H)-one (1 eq, 0.61 mmol, 0.20 g, Example 20 Step 2), K2CO3 (10 eq, 6.10 mmol, 0.84 g) and methylchloroformate (4 eq, 2.43 mmol, 0.19 mL) in THF (10 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, then the aqueous phase was extracted with AcOEt. The organic phase was dried over MgSO4, filtered and evaporated. The resulting crude oil was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 109 SiO2) using CH2Cl2/AcOEt 90/10 then washed with Et2O and was dried to afford 4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl methyl carbonate (0.36 mmol, 139 mg, 59%) as a white solid.
Reaction SMILES: [Na].[CH2:2]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)[CH3:3].Br[CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>CO>[CH2:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCc1ccc(S)cc1
Reactant: CC(C)=CCCC(C)=CCBr
Agent: [Na]
Solvent: CO
Product: CCc1ccc(SCC=C(C)CCC=C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2 g. of sodium in 50 ml. of methanol at about 0° is added 35 g. of p-ethylphenylmercaptan. After about 0.5 hour, 15 g. of 1-bromo-3,7-dimethylocta-2,6-diene is added and then the mixture is refluxed for about two hours. Then the solvent is evaporated and the concentrate taken up in petroleum ether which is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to yield 1-(p-ethylphenyl)thio-3,7-dimethylocta-2,6-diene which can be purified by chromatography. ##STR11##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:40]4[CH2:41][CH2:42][N:37]([C:33]5[S:32][CH:36]=[CH:35][N:34]=5)[CH2:38][CH2:39]4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: c1csc(N2CCNCC2)n1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2nccs2)CC1
Yield: 61 %

Procedure:
4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}benzoic acid (70 mg) was reacted with 1-thiazol-2-yl-piperazine as in General Procedure 8 to give the title compound as a yellow solid (61% yield). M.p. 243-244, LCMS: m/z=598.92 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.49-3.92 (m, 12H), 4.63 (s, 2H), 5.06 (bs, 1H), 6.57-6.64 (m, 2H), 7.21 (d, J=3.52 Hz, 1H), 7.35-7.43 (m, 5H), 7.51 (s, 1H), 7.65 (d, J=8.4 Hz, 1H) 7.76 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13].[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13])=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(F)c1C
Product: COC(=O)c1nc(C)sc1-c1cccc(F)c1C

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-2-methyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.93 min; [M+H]+=266.3.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([Cl:52])[CH:48]=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([Cl:53])=[CH:47][CH:48]=[C:49]([Cl:52])[C:50]=3[Cl:51])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(Cl)ccc(Cl)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3,4-trichlorobenzene and isolated as light red solid. MS (m/e): 475.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17](=[O:18])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]3=[O:14])=[CH:4][C:3]=2[F:15])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: Nc1ccc(-n2ccncc2=O)cc1F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc(-n2ccncc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1

Procedure:
71.1 Using general method G, 1-(4-amino-3-fluoro-phenyl)-1H-pyrazin-2-one (prepared according to WO 2003045912) was activated with 4-nitrophenyl chloroformate to give [2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester. Pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:24][N:25]([CH:32]([CH3:34])[CH3:33])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH3:24])[CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CNCC4)cc1Cl
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c3c2C1

Procedure:
The title compound was synthesized in analogy to Example 89 from N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydropyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 76A (100 mg, 0.29 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (77 mg, 0.40 mmol) to yield 56 mg (40%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)[C:7]1[NH:8][CH:9]=[CH:10][N:11]=1)[CH3:3].O.[NH2:23][NH2:24]>C(O)C>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:23][NH2:24])=[O:17])=[CH:14][CH:13]=1)[C:7]1[NH:8][CH:9]=[CH:10][N:11]=1)[CH3:3]
Reactant: COC(=O)c1ccc(C(CCN(C)C)c2ncc[nH]2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN(C)CCC(c1ccc(C(=O)NN)cc1)c1ncc[nH]1

Procedure:
A solution of 4-[3-(N,N-dimethylamino)-1-(imidazol-2-yl)propyl]benzoic acid, methyl ester (3.0 g) and hydrazine hydrate (12.5 ml) in ethanol (50 ml) was boiled under reflux for 1 day. Removal of the solvent gave a white solid which was recrystallised from isopropanol-ether to give the title compound, m.p. 168°-170° (2.46 g).