Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: Oc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc2c(c1)Cc1cc(Br)ccc1-2
Yield: 87.6 %

Procedure:
A mixture of 2-bromo-7-hydroxyfluorene (18 g), pentyl bromide (15.1 g), potassium carbonate (26.6 g) and dimethylformamide (200 mL) was heated for 3 hours while refluxing. 6M-hydrochloric acid (100 mL) was added to the reaction solution, and the solution was extracted with toluene. The toluene layer was washed with water and then dried on anhydrous magnesium sulfate, and it was concentrated under reduced pressure. This concentrate was recrystallized from acetone to obtain 2-bromo-7-pentyloxyfluorene (20 g) of colorless needle crystal.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]([O:14][CH3:15])(=[O:13])/[CH:7]=[CH:8]\[C:9]([O:11][CH3:12])=[O:10]>>[CH3:12][O:11][C:9]([CH:8]1[CH2:1][CH:2]=[C:3]([CH3:5])[CH2:4][CH:7]1[C:6]([O:14][CH3:15])=[O:13])=[O:10]
Reactant: C=CC(=C)C
Reactant: COC(=O)/C=C\C(=O)OC
Product: COC(=O)C1CC=C(C)CC1C(=O)OC
Temperature: 150 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
Isoprene (350 g, 5.1 mol) and dimethyl maleate (741 g, 5.1 mol) were loaded into a stainless steel autoclave. The autoclave was sealed and heated to 150° C. The temperature of the autoclave increased to 195° C. due to the heat of the reaction. The temperature was held at 160° C. for 1 hour. Gas chromatography (GC) analysis indicated the completion of the reaction. The autoclave was then cooled to room temperature. Simple distillation of the resulting mixture provided 4-methyl-cyclohex-4-ene-1,2-dicarboxylic acid dimethyl ester (725 g, 3.4 mol, 66% yield) as a light yellow liquid.
Reaction SMILES: [OH:1][CH:2]([CH2:27][CH2:28][CH3:29])[CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C(Cl)Cl>C1(C)C=CC=CC=1>[O:1]=[C:2]([CH2:27][CH2:28][CH3:29])[CH2:3][CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1
Reactant: CCCC(O)CC1CCC(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC(=O)CC1CCC(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 60.2 %

Procedure:
4'-(4-(2-Hydroxypentyl)cyclohexyl)-4-trifluoromethoxybiphenyl (12.3 mmol) was added at 0 or below in the absence of a solvent to a mixture of PCC (13.5 mmol), 3 g of silica gel, and 70 ml of methylene chloride, and the mixture was stirred at room temperature for 7 hr to give a black suspension. 500 ml of toluene was added thereto, and the mixture was stirred. The precipitated insolubles were filtered off through Celite, and the solvent was distilled off from the resultant black solution under reduced pressure to give a dark brown crude product. The crude product was purified by silica gel column chromatography (eluting solution: toluene) to give 4'-(4-(2-oxopentyl)cyclohexyl)-4-trifluoromethoxybiphenyl (7.4 mmol, yield 66%) as a white crystal.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[CH2:6]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: NCCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCCNCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A solution of 3-aminopropan-1-ol (3 g, 39.9 mmol) and benzaldehyde (4.05 mL, 39.9 mmol) in methanol (200 mL) was stirred at room temperature overnight. The solution was cooled to 0° C., and sodium borohydride (1.813 g, 47.9 mmol) was added slowly in several portions. The resulting mixture was stirred at room temperature for three hours, and then it was partitioned between water and dichloromethane (3x). The organic extracts were combined and dried over Na2SO4, the drying agent was removed by filtration, and the solution was concentrated in vacuo to give the title compound as an oil (6.5 g, 98%).
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([OH:10])=[N:2]1.[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[O:1][N:2]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: Oc1noc2ncccc12
Reactant: CC1CCN(C(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1CCN(C(=O)Oc2noc3ncccc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
125 mg (0.918 mmol) of isoxazolo[5,4-b]pyridin-3-ol, 178 mg (1.1 mmol) of 4-methylpiperidine-1-carbonyl chloride and 255 μl (1.84 mmol) of triethylamine were dissolved in 10 ml of pyridine and stirred at room temperature for 4 h. A further 89 mg (0.55 mmol) of 4-methylpiperidine-1-carbonyl chloride and 128 μl (0.92 mmol) of triethylamine were added, and stirring was continued at room temperature for 6 h. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 101 mg (42%), M+H+: 262.1.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[C:10]1[CH:25]=[CH:24][C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].COCCO[Al+]OCCOC.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:17]([NH:16][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCNC(=O)c1ccc(C(=O)NCCCCCCC)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCNCc1ccc(CNCCCCCCC)cc1
Yield: 97.6 %

Procedure:
To a mixture of 3.6 g N,N'-diheptylterephthalamide obtained in Example 1 and 60 ml toluene, was added dropwise 15.6 ml of a 70% solution of bis(2-methoxyethoxy)aluminum hydride in toluene. After heating under reflux for three hours, the reaction mixture was treated with 30 ml of 2.5N aqueous caustic soda solution under ice cooling, and the toluene layer separated was washed with saturated aqueous solution of sodium chloride and dried over a drying agent. Distilling off the solvent from the dried solution gave 3.24 g of N,N'-diheptyl-p-xylylenediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:10][C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:17]C(=O)C(F)(F)F.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:10][C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:17]
Reactant: CN(Cc1ccc(Cl)s1)c1ccc(NC(=O)C(F)(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(Cc1ccc(Cl)s1)c1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To a solution of N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2,2,2-trifluoroacetamide (3.118 g) in methanol (MeOH) (50 mL) solution of potassium carbonate (K2CO3) (6.4 g) in water (25 mL) was added and the reaction mixture was stirred until reaction completion (24 hours) at room temperature. The obtained reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (NaHCO3) and evaporated to give 2.26 g of dark brown oil which was used in the next step without further purification. 1H NMR (DMSO-d6): 2.71 (s, 3H, NMe), 4.47 (s, 2H), 4.71 (br. s, 2H, NH2), 6.67-6.75 (m, 3H), 6.82 (d, 1H), 6.93 (d, 1H). LC/MS (m/z) 288.0 ([M+H]+); RT=2.07, (UV, ELSD) 85%, 98%.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:7]=[CH:6][C:5]=1[CH:19]=[CH:20]OCC.C(O)(C(F)(F)F)=O.[CH:32]1([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=[CH2:44])[N:38]=2)[NH2:36])[CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH:32]1([C@H:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=[CH2:44])[N:38]=2)[N:36]2[CH2:20][CH2:19][C:5]3[C:4](=[CH:9][C:8]([O:10][C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=4[F:18])=[CH:7][CH:6]=3)[C:3]2=[O:24])[CH2:33][CH2:34]1
Reactant: CCOC=Cc1ccc(Oc2ccc(F)cc2F)cc1C(=O)OC
Reactant: C=Cc1cccc(C(N)C2CC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: C=Cc1cccc([C@@H](C2CC2)N2CCc3ccc(Oc4ccc(F)cc4F)cc3C2=O)n1
Temperature: 25 °C

Procedure:
To the solution of 5-(2,4-difluoro-phenoxy)-2-(2-ethoxy-vinyl)-benzoic acid methyl ester 9 (2.09 g, 6.3 mmol) in dichloromethane (20 mL) was added 2 mL of TFA and five drops of water. The reaction was stirred at room temperature for ten minutes, at which time the solvent was removed. The crude reaction mixture was re-suspended in 100 ml of dichloromethane, extracted twice with 50 ml of saturated NaHCO3. The organic layer was dried with sodium sulfate and the solvent removed. The crude intermediate was re-suspended in 100 ml of dichloroethane and added drop wise to a 100 ml solution of dichloroethane containing cyclopropyl(6-vinylpyridin-2-yl)methanamine A20 (1.2 g, 6.9 mmol) and sodium triacetoxyborohydride (3.3 g, 15.7 mmol). The mixture was stirred at 70° C. during the drop wise addition and for additional 2 hours. The reaction was diluted with 500 mL dichloromethane and extracted with saturated brine (300 mL). The organic layer was concentrated and loaded onto a silica gel column and eluted with dichloromethane followed by separation of the enatiomers (AD-H column, 10% IPA/Hex) to give 115 mg of (R)-2-(cyclopropyl(6-vinylpyridin-2-yl)methyl)-7-(2,4-difluorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 74 as clear oil. The sterochemical configuration was assigned based on the compound 11 TLC, Rf=0.25 (CH2Cl2); Rt=20.2 min (45 min. run, AD-H chiral analalytical column, 1 ml/min, 5% IPA/Hex); 1H NMR (Methanol-D4) δ 7.69 (t, J=7.6, 1H), 7.42 (s, 1H), 7.35 (d, J=7.5, 1H), 7.29 (d, J=7.6, 1H), 7.25 (d, J=8.3, 1H), 7.09 (m, 3H), 6.97 (m, 1H), 6.78 (dd, J=10.7, 17.4, 1H), 6.18 (d, J=17.4, 1H), 5.39 (d, J=10.7, 1H), 4.99 (d, J=10.1, 1H), 3.8 (m, 2H), 2.9 (m, 2H), 1.63 (m, 1H), 0.81 (m, 1H), 0.66 (m, 1H), 0.56 (m, 1H), 0.46 (m, 1H), M+1 found 433.1; C26H22F2N2O2 requires 432.2
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([NH:20][C:21]([N:23]3C=CN=C3)=[O:22])[CH:16]=[CH:17][C:18]=2[CH3:19])[C:3]1=[O:28].[CH3:29][CH:30]([CH3:36])[CH2:31][C:32]([NH:34]N)=[O:33]>C1COCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([NH:20][C:21]([NH:23][NH:34][C:32](=[O:33])[CH2:31][CH:30]([CH3:36])[CH3:29])=[O:22])[CH:16]=[CH:17][C:18]=2[CH3:19])[C:3]1=[O:28]
Reactant: Cc1cc2c(cn1)cc(-c1cc(NC(=O)n3ccnc3)ccc1C)c(=O)n2C
Reactant: CC(C)CC(=O)NN
Solvent: C1CCOC1
Product: Cc1cc2c(cn1)cc(-c1cc(NC(=O)NNC(=O)CC(C)C)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 18 (0.08 mmol) was dissolved in THF (0.5 mL) and 3-methylbutanehydrazide (12 mg, 0.1 mmol) was added at rt. The reaction mixture was stirred at rt for 1 h to yield the crude N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)-2-(3-methylbutanoyl)hydrazinecarboxamide 26, which was used without purification after removal of THF. MS m/z 422.2 (M+1).
Reaction SMILES: [C:1]1([OH:9])[CH:8]=[C:6]([CH3:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:4][C:3]1[CH:2]=[C:1]([OH:9])[CH:8]=[C:6]([CH3:7])[CH:5]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.4 %

Procedure:
A 0° C. mixture of orcinol (10.0 g, 80.6 mmol) and 325 mesh potassium carbonate (12.25 g, 88.6 mmol) in DMF (100 mL) is treated dropwise with benzyl bromide (6.91 g, 40.4 mmol). The mixture was then warmed to rt and stirred for 20 hours under N2. The reaction is filtered, and the filtrate is acidified with 1 N HCl. The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 5/1 hexanes/ethyl acetate to afford 4.88 g (57%) of the title compound. Rf=0.40 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C14H14O2 214, found 215 (M+1, 100%).
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].[C:6]([C:8]([C:20]#[N:21])=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)#[N:7]>C(O)C>[NH2:21][C:20]1[C:8]([C:6]#[N:7])=[C:9]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)[NH:2][CH:3]([SH:4])[N:5]=1
Reactant: NC(N)=S
Reactant: CC(=O)Nc1ccc(C=C(C#N)C#N)cc1
Agent: [Na]
Solvent: CCO
Product: CC(=O)Nc1ccc(C2=C(C#N)C(N)=NC(S)N2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To 20 mL of absolute ethanol, 250 mg of metallic sodium was added in small portions. After dissolved completely, 760 mg of thiourea was added to the above solution, and the mixture was stirred at room temperature for 1 hour. To the reaction, 2.11 g of N-[4-(2,2-dicyanovinyl)phenyl]acetamide was added, and the mixture was heated to reflux for 3 hours. Then, the solvent was removed under reduced pressure from the reaction mixture, the residue was dissolved in 30 mL of water. In addition, the mixture was acidified by adding acetic acid in small portions, thereto 30 mL of ethyl acetate was added and then the solution was stirred overnight. Filtration of the precipitated material gave 1.2 g of N-[4-(6-amino-5-cyano-2-mercapto-2,3-dihydropyrimidin-4-yl)phenyl]acetamide as a white powder.
Reaction SMILES: CN1CC[N:5]([C:8]2[C:14]3=[CH:15][CH:16]=[CH:17][N:13]3[CH2:12][C:11]3[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=3[N:9]=2)CC1.C(O)(=O)C>[Zn].C(O)C>[NH2:5][C:8]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[CH2:12][C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[N:9]=1
Reactant: CN1CCN(C2=Nc3ccccc3Cn3cccc32)CC1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: NC1=Nc2ccccc2Cn2cccc21
Temperature: 0 °C

Procedure:
A mixture of 20 g. of 1-(o-nitrobenzyl)-2-pyrrolecarbonitrile [M. Artico et al.; See Example 1], 50 g. of zinc dust, 40 ml. of glacial acetic acid and 200 ml. of ethanol is stirred at room temperature for about 24 hr. The reaction mixture is filtered to remove unreacted zinc dust and the precipitate is washed with alcohol. The filtrate is chilled to 0° C. and the precipitated zinc salts are removed by filtration; this filtrate is then evaporated to a solid residue which is dissolved in methylene chloride and filtered again. The solvent is removed by evaporation and the residue crystallized by the addition of ether; the product is collected and 11-amino-5H-pyrrolo[2,1-c]-[1,4]benzodiazepine, m.p. 179°-181° C., is thereby obtained.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2C(OC(C)(C)C)=O)[NH:5][CH:6]=1.Cl>CO.O1CCOCC1>[I:1][C:2]1[N:3]=[C:4]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][NH:8]2)[NH:5][CH:6]=1
Reactant: C[C@H]1C[C@@H](c2nc(I)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H]1CN[C@H](c2nc(I)c[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.5 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(4-iodo-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (1.6 g, 4.242 mmol) in MeOH (16 mL) is added a 4M HCl in dioxane solution (16 ml) at 0° C. The reaction mixture is stirred at RT overnight and evaporated to dryness to afford 4-iodo-2-[(2S,4S)-4-methylpyrrolidin-2-yl]-1H-imidazole (1.37 g, 92.5%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH3:14])[N:13]=1.[C:15]([Cu])#[N:16]>CN(C)C=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[C:3]([C:9]2[N:10]=[N:11][N:12]([CH3:14])[N:13]=2)[CH:4]=1
Reactant: Cn1nnc(-c2cc(F)ccc2Br)n1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2cc(F)ccc2C#N)n1
Temperature: 105 °C
Yield: 73.8 %

Procedure:
A mixture of intermediate 57, 5-(2-bromo-5-fluoro-phenyl)-2-methyl-2H-tetrazole (650 mg, 2.53 mmol) and CuCN (224 mg, 2.5 mmol) in dimethylformamide (4 mL) was placed in a sealed tube and heated at 100-110° C. for 20 hrs. After cooling, the insoluble material was filtered, and the filtrate concentrated in vacuo. The residue was dissolved in CH2Cl2, washed with aq. 4N HCl and dil. NH4OH, then dried (MgSO4), filtered, and concentrated. The residual solid was purified by column chromatography (SiO2, CH2Cl2) to obtain 375 mg (Yield 73%) of the title compound as an off-white solid; 1H NMR (500 MHz, CDCl3) δ ppm: 4.48 (3 H, s) 7.29 (1 H, dd, J=7.6, 2.8 Hz) 7.85 (1 H, dd, J=8.6, 5.2 Hz) 8.00 (1 H, dd, J=9.0, 2.6 Hz); LC/MS m/z 204.
Reaction SMILES: [OH-].[Na+:2].C(O)(=O)C(O)=O.[CH:9]([C:11]1[CH:24]=[C:23]([C:25]2[S:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[C:26]=2[CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[CH:37][CH:36]=2)[CH:22]=[CH:21][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:10].CO>C1COCC1>[Na+:2].[CH:9]([C:11]1[CH:24]=[C:23]([C:25]2[S:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[C:26]=2[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][N:44]3[CH2:45][CH2:46][CH2:47][CH2:48]3)=[CH:39][CH:40]=2)[CH:22]=[CH:21][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[O:10]
Reactant: COC(=O)CCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1C=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=Cc1cc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)ccc1OCCCC(=O)[O-]
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The title compound was prepared by adding 179 μL (0.179 mmol) of 1 N NaOH to a solution of 100 mg (0.179 mmol) methyl 4-[2-formyl-[3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophen-2-yl]phenoxy]]butyrate (Example 19, Part B) dissolved in 1.0 mL of 1:1 THF:MeOH mixture. The solution was stirred at room temperature for 22 h. The reaction mixture was then evaporated in vacuo and dried in a vacuum oven at 55° C. over P2O5 to yield the title compound (101.4 mg, 0.179 mmol, quantitative yield) as a light yellow solid.
Reaction SMILES: C([O:4][P:5](/[CH:11]=[CH:12]/[CH:13]([CH2:26][OH:27])[CH2:14][O:15][N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25])([O:7]C(C)C)=[O:6])(C)C.C[Si](Br)(C)C>CN(C)C=O>[OH:27][CH2:26][CH:13](/[CH:12]=[CH:11]/[P:5]([OH:6])([OH:7])=[O:4])[CH2:14][O:15][N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25]
Reactant: CC(C)OP(=O)(/C=C/C(CO)COn1cnc2c(N)ncnc21)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2OCC(/C=C/P(=O)(O)O)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 15106.5 %

Procedure:
A solution of (E)-9-[4-(diisopropoxyphosphoryl) -2(hydroxymethyl)but-3-enyloxy]adenine (0.25 g, 0.63 mmol) in anhydrous N,N-dimethylformamide (5 ml) under nitrogen was treated with trimethylsilylbromide (1.24 ml, 9.4 mmol) at 0° C. and the solution stirred for 18 h at room temperature. The solvent was removed in vacuo coevaporatng several times with methanol and toluene and the residue chromatographed on C18 reverse phase silica gel eluting with water to give (E)-9-(2-hydroxymethyl-4-phosphonobut-3-enyloxy) adenine as a solid (30 g, 17%); λmax (H2O) 260 nm (13711); υmax (KBr) 3434, 1717, 1690, 1653, 1640, 1472, and 1414 cm-1 ; δH [(CD3)2SO] 2.78 (1H, m, CH), 3.38 (3H, br.s, 3×OH, H2O), 3.60 (2H, m, CH2OH) , 4.48 (2H, m, CH2ON), 5.99 (1H, m, PCH=CH), 6.48 (1H, m, PCH=CH), 7.37 (2H, br.s, D2O exchangeable NH2), 8.14 (1H, s, H-2/H-8), 8.34 (1H, s, H-2/H-8) (Found: C, 36.50; H, 4.45; N, 20.49%. C10H14N5O5P.0.9H2O requires C, 36.24; H, 4.77; N, 21.13%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[C:20](=O)[CH2:19]1)=[O:17].[CH3:34][NH2:35]>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[CH:20]([NH:35][CH3:34])[CH2:19]1)=[O:17]
Reactant: O=C(NCC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Reactant: CN
Product: CNC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1CNC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 25 5-chloro-thiophene-2-carboxylic acid {(1RS,4SR)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-oxo-cyclopentylmethyl}-amide (example 32A) was reacted with methylamine (solution in THF) to give 5-chloro-thiophene-2-carboxylic acid {4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methylamino-cyclopentylmethyl}-amide. Light yellow solid. 503.3 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:24]=4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.NC1C=C(C2N=C3N(C=2C2C=CN=C(NC4C=CC=C(OCCCN5CCOCC5)C=4)N=2)C=CS3)C=CC=1.[C:75]1([CH2:81][C:82](Cl)=[O:83])[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1.FC1C=CC=C(F)C=1C(Cl)=O>>[N:31]1([CH2:30][CH2:29][C:25]2[CH:24]=[C:23]([NH:22][C:18]3[N:17]=[C:16]([C:15]4[N:14]5[C:10]([S:11][CH:12]=[CH:13]5)=[N:9][C:8]=4[C:4]4[CH:3]=[C:2]([NH:1][C:82](=[O:83])[CH2:81][C:75]5[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=5)[CH:7]=[CH:6][CH:5]=4)[CH:21]=[CH:20][N:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Agent: O=C(Cl)c1c(F)cccc1F
Product: O=C(Cc1ccccc1)Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1

Procedure:
The title compound was prepared as described in EXAMPLE 297, with the following substitutions: 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(2-morpholinoethyl)phenyl)pyrimidin-2-amine for 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(3-morpholinopropoxy)phenyl)pyrimidin-2-amine and 2-phenylacetyl chloride for 2,6-difluorobenzoyl chloride. (ESI(+)) m/e 616 (M+H)+; (ESI(−)) m/e 614 (M−H)−; 1H-NMR (300 MHz, DMSO-d6) □ 10.29 (s, 1H), 9.62 (s, 1H), 8.80 (d, 1H), 8.26 (d, 1H), 7.88 (t, 1H), 7.68-7.74 (m, 1H), 7.54-7.61 (m, 2H), 7.49 (d, 1H), 7.40 (t, 1H), 7.18-7.36 (m, 6H), 6.86 (d, 1H), 6.59 (d, 1H), 3.65 (s, 2H), 3.53-3.60 (m, 4H), 3.17 (d, 1H), 2.68-2.76 (m, 2H), 2.52-2.56 (m, 1H), 2.38-2.43 (m, 4H).