Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[NH3+]CCCCCC[NH3+].C1(P(=O)(O)O)C=CC=CC=1.NCCCCCCN>O>[C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C([O-])CCCCC(=O)[O-]
Agent: NCCCCCCN
Agent: O=P(O)(O)c1ccccc1
Agent: [NH3+]CCCCCC[NH3+]
Solvent: O
Product: O=C(O)CCCCC(=O)O

Procedure:
A mixture of 100 parts of hexamethylene diammonium adipate, 0.65 part of phenylphosphonic acid, 0.48 part of hexamethylenediamine, 0.65 part of N:N'-bis(3-aminopropyl)piperazine, 0.46 part of adipic acid and 65.0 parts of water is polymerised using the conditions described in Example 1. The resulting polymer is then converted into fibres by known methods. The dye uptake of these fibres from dyebaths containing Solway Blue BN at pH's of 4.0, 7.0 and 9.0 are 8.4%, 4.7% and 1.5% respectively, compared with 4.2%, 0.6% and 0.1% for fibres prepared as described in this Example except that the phenylphosphonic acid and hexamethylenediamine were omitted from the mixture.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:19]3([CH3:26])[NH:23]C(=O)N[C:20]3=[O:25])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC[OH:29].[OH-].[Na+].Cl>O>[NH2:23][C:19]([C:14]1[CH:15]=[N:16][C:17]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:18]=2)([CH3:26])[C:20]([OH:25])=[O:29]
Reactant: CCO
Reactant: CCCCCCCOc1ccc2cc(C3(C)NC(=O)NC3=O)cnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCOc1ccc2cc(C(C)(N)C(=O)O)cnc2c1
Temperature: 110 °C
Reaction time: 96 h

Procedure:
A mixture of 5-(7-(heptyloxy)quinolin-3-yl)-5-methylimidazolidine-2,4-dione (1 g, 2.8 mmol), EtOH (2 mL), H2O (4 mL), and NaOH (2.24 g, 56 mmol, 20 eq.) was stirred for 4 day at 110° C. Then, to the reaction mixture was added HCl (40%) to adjust to pH=5 and then the desired compound was generated as yellow solid (740 mg, yield 80%), without further purification for next step. ESI-MS: 331 (M+H)+. 1H NMR (300 MHz, CD3OD) δ: 0.81-0.83 (t, 3H), 1.06-1.09 (t, 3H), 1.18-1.33 (m, 8H), 1.41-1.45 (m, 2H), 1.75-1.78 (m, 2H), 1.96 (s, 3H), 3.48-3.53 (m, 2H), 4.04 (m, 2H), 7.18-7.24 (m, 2H), 7.79-7.81 (d, 1H), 8.39 (s, 1H), 8.89 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]([NH2:7])=[NH:6].C([C:10](CC)([C:14]([O-])=[O:15])[C:11]([O-])=[O:12])C.[H-].[Na+]>CCO>[CH3:2][O:3][CH2:4][C:5]1[N:7]=[C:11]([OH:12])[CH:10]=[C:14]([OH:15])[N:6]=1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: COCC(=N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: COCc1nc(O)cc(O)n1
Reaction time: 16 h
Yield: 80.1 %

Procedure:
To a solution of 2-methoxy-acetamidine hydrochloride (20.18 g, 0.16 mol) and diethylmalonate (24.6 mL, 0.16 mol) in EtOH (150 mL) is added 60% dispersion of sodium hydride in oil (14.3 g, 0.36 mol). The mixture is heated to reflux and stirred for 16 hours. The mixture is concentrated in vacuo and the residue is diluted with water (100 mL) and extracted with EtOAc (75 mL). The aqueous layer is acidified to pH 3 with HCl and extracted thrice with EtOAc (75 mL). The organic extracts from acidic solution are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-methoxymethyl-pyrimidine-4,6-diol (20 g, 80%) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11](C2C=CC(F)=CC=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.[C:39](O)([C:41]([F:44])(F)F)=O>C(Cl)Cl>[F:44][C:41]1[CH:39]=[CH:10][C:9]([C:10]2[C:9]3[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH:35]=[N:34][N:33]=[N:32]5)[CH:26]=4)=[N:7][C:8]=3[CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cnnn2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3cnnn3)c2)=Nc2cccc(-c3ccc(F)cc3)c2N1

Procedure:
Prepared from {4′-fluoro-3-[3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K56) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (54 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[N:27][CH:28]=1>O1CCCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:28][N:27]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: N#CCC(=O)Nc1ccc(Cl)nc1
Yield: 76.7 %

Procedure:
5.95 g (70.0 mmol) of cyanoacetic acid and 14.44 g (70.0 mmol) of dicyclohexylcarbodiimide were added to a stirred solution of 9.00 g (70.0 mmol) of 5-amino-2-chloropyridine in 150 ml of anhydrous tetrahydrofuran at 0° C. The reaction was monitored by thin layer chromatography and when complete, the reaction mixture was filtered and the filtrate was evaporated to dryness. The resulting solid was triturated with anhydrous dichloromethane, filtered and dried in vacuo to obtain 10.5 g of N-(2-chloropyrid-5-yl)-2-cyanoacetamide (77% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)[CH:7]=1.[NH4+].[Cl-]>CCO.[Fe]>[NH2:20][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2cc(Br)ccc2[N+](=O)[O-])C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(Nc2cc(Br)ccc2N)C1
Reaction time: 4 h
Yield: 78 %

Procedure:
To a solution of crude tert-butyl 3-((5-bromo-2-nitrophenyl)amino)azetidine-1-carboxylate (550 mg, 1.5 mmol) in EtOH (10 mL) was added Fe powder (1.27 mg, 22.7 mmol) and NH4Cl (1.20 g, 0.227 mmol, in 10 ml water). After stirring for 4 h at refluxing temperature, the solution cooled and filtered through a Celite pad and the filtrate concentrated. The residue used directly for next step (400 mg, Yield 78%) without further purification. LCMS (m/z): 342.1 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH3:9].Br[C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2>C1(C)C=CC=CC=1.CCOCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:8]([O:10][P:11]([C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([C:27]([F:29])([F:30])[F:28])=[CH:22][CH:21]=2)(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9]
Reactant: FC(F)(F)c1ccc2ncc(Br)cc2c1
Reactant: CCOP([O-])OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOP(=O)(OCC)c1cnc2ccc(C(F)(F)F)cc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1.44 g of tetrakis-(triphenylphosphine)-palladium(O) are introduced in 16 ml of toluene, 3.8 ml of triethylamine and 3.6 ml of diethylphosphite at room temperature under nitrogen and mixed with 6.90 g of 3-bromo-6-trifluoromethyl-quinoline. It is stirred for two hours at 90° C. bath temperature. The mixture is diluted with ether, suctioned off and the filtrate is concentrated by evaporation. After column chromatography, 8.3 g of 6-trifluoromethyl-quinoline-3-phosphonic acid diethyl ester of melting point 69° C. is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:35])=[N:9][CH:10]=1)=[O:4].[Li+].[OH-]>CO>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:27]=[CH:26][C:25]([C:20]2[N:19]=[N:18][C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:8]4[CH:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=4)[C@H:12]([CH3:35])[CH2:13]3)=[C:22]([CH3:23])[C:21]=2[CH3:24])=[CH:30][CH:29]=1
Reactant: COC(=O)c1cnc(N2CCN(c3nnc(-c4ccc(C(F)(F)F)cc4)c(C)c3C)C[C@H]2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(-c2ccc(C(F)(F)F)cc2)nnc(N2CCN(c3cnc(C(=O)O)cn3)[C@H](C)C2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of example 7 (0.26 g, 0.53 mmol) and methanol (10 mL) is added 50% aqueous LiOH aqueous (10 mL). The mixture is stirred at room temperature overnight. Solvent is removed. The residue is dissolved in water and acidified with 3N HCl to pH about 7 and extracted with ethyl acetate. The ethyl acetate layer is concentrated to afford the title compound (0.25 g, 98%) as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[N:16]([CH3:17])[C:15]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:14]=2[N:13]=1)[CH2:9][C:10]#[CH:11]>>[F:22][C:20]1[CH:19]=[CH:18][C:15]2[N:16]([CH3:17])[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:13][C:14]=2[CH:21]=1
Reactant: Ic1ccccn1
Reactant: C#CCCc1nc2cc(F)ccc2n1C
Product: Cn1c(CCC#Cc2ccccn2)nc2cc(F)ccc21
Yield: 27.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (74 mg, 0.36 mmol) and 2-(but-3-ynyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole (73 mg, 0.36 mmol). The crude residue was purified over silicagel chromatography (prepacked 2 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 28 mg of 5-fluoro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole as a orange oily solid (Yield: 27%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.C[Sn](C)C.C[Sn](C)C.Br[C:35]1[N:36]=[CH:37][CH:38]=[C:39]2[CH:43]=[CH:42][N:41]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:40]=12>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:35]3[N:36]=[CH:37][CH:38]=[C:39]4[CH:43]=[CH:42][N:41]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:40]=34)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: C[Si](C)(C)CCOCn1ccc2ccnc(Br)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nccc4ccn(COCC[Si](C)(C)C)c34)nc12
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
To a solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.2 g, 468 μmol) and hexamethylditin (215 mg, 655 mmol) in toluene (2.5 mL) was added Pd(Ph3P)4 (54 mg). After bubbling nitrogen through the reaction mixture for 15 min, it was heated to 95° C. After 1.5 h, 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine and Pd(Ph3P)4 (108 mg, 93.6 μmol) were added. After 72 h the reaction mixture was cooled, filtered through celite, and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.13 g, 47%). 1H NMR (CDCl3) δ: 9.01 (s, 1H), 8.46 (d, J=5.3 Hz, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 7.68 (d, J=5.3 Hz, 1H), 7.41 (d, J=3.0 Hz, 1H), 6.69 (d, J=3.3 Hz, 1H), 5.74 (s, 2H), 5.51 (s, 2H), 3.59 (dd, J=8.9, 7.7 Hz, 2H), 2.82-2.89 (m, 2H), 1.42 (s, 9H), 0.92-0.99 (m, 2H), 0.41-0.47 (m, 2H), −0.02 (s, 9H), −0.27 (s, 9H).
Reaction SMILES: [CH:1]1([C:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1>C(O)(=O)C.[Zn]>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C=C(c1ccnc(OC)c1)C1CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)CC(c1ccnc(OC)c1)C1CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(2-methoxypyridin-4-yl)acrylate in acetic acid (100 mL) was added a zinc powder (16.3 g), and the mixture was stirred at room temperature for 5 min. The reaction mixture was filtered, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (4.17 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17]([C:26]4[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[C:28]([O:29][CH3:30])[CH:27]=4)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1
Reactant: COc1ccnc(CCc2nc3cc(Br)cnc3[nH]2)c1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(OC)c(OC)c4)cnc3[nH]2)c1
Yield: 30.7 %

Procedure:
0.50 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine (example 6) and 0.41 g of 3,4-dimethoxyphenylboronic acid are dissolved in 25 ml of degassed dioxane. Then a solution of 0.415 g of potassium carbonate and 0.127 g of lithium chloride in 19 ml of degassed water and 0.173 g of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is heated to reflux under N2 for 48 hours and, after cooling and addition of water, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30–26:1). Concentration of the chromatographically pure fractions and crystallisation from ethyl acetate gives 0.18 g of the title compound as a yellowish solid of m.p. 185–186° C. The mass spectrum shows the molecular peaks MH+ and 2MNa+ at 391.3 and 803.0 Da.
Reaction SMILES: CO[C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([NH:19][C:20](=[O:26])[CH2:21][O:22]C(=O)C)[C@@H:16]([OH:27])[C@H:15]2[OH:28])=[C:7]([NH:29][C@H:30]([CH2:38][OH:39])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:6]=1)=[O:4].[CH2:40]([NH2:43])[CH2:41][NH2:42]>>[NH2:42][CH2:41][CH2:40][NH:43][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([NH:19][C:20](=[O:26])[CH2:21][OH:22])[C@@H:16]([OH:27])[C@H:15]2[OH:28])=[C:7]([NH:29][C@H:30]([CH2:38][OH:39])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:6]=1)=[O:4]
Reactant: NCCN
Reactant: COC(=O)c1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@@H]3C[C@H](NC(=O)COC(C)=O)[C@@H](O)[C@H]3O)c2n1
Product: NCCNC(=O)c1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@@H]3C[C@H](NC(=O)CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
9-[(1R,2S,3R,4S)-4-(2-Acetoxy-acetylamino)-2,3-dihydroxy-cyclopentyl]-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (Intermediate WF) is dissolved in ethylenediamine (>10 eq.). The reaction mixture is stirred at 90° C. for 1 hour. The reaction mixture is cooled and reduced in vacuo. The title compound is obtained by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH:9](O)[CH:8]([CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(C)C2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc2cc(C)sc2c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
A solution of 3.7 g of 6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxy-2-methylbenzo[b]thiophene in 20 ml of glacial acetic acid containing 5 ml of boron trifluoride etherate is warmed on a steam bath for 5 min. to form a clear solution. After stirring at room temperature for 1 hour, the solution is poured into an ice-cold solution of 10% sodium hydroxide. The organic materials are extracted 3 times with ether, dried and concentrated under vacuum. The reddish brown residue is purified by dissolving it in ether and passing it through an alumina column packed with ether. Elution with ether gives 2.1 g of 6,7-dichloro-5-methoxy-2-methylbenzo[b]thiophene as off-white crystals, mp 113°-114°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:26][O:27][CH2:28][CH2:29][CH3:30]>>[CH3:26][O:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1
Reactant: CCCOCBr
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Product: COCCCOc1ccc(CCc2ccc3cc(C(C)NC(C)=O)oc3c2)cc1
Yield: 27 %

Procedure:
Using N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (32.3 mg, 0.100 mmol) obtained in Example 165 and 1-bromomethoxypropane (0.0306 mL, 0.200 mmol) and in the same manner as in Example 158, the title compound was obtained (10.5 mg, yield 27%) as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C1(OC)C=CC=CC=1.N(CC1C=CC(OC)=CC=1)=[N+]=[N-].[F:25][C:26]1[C:27](=[O:46])[NH:28][C:29](=[O:45])[N:30]([C@H:32]2[C@@H:35]([CH2:36][O:37]CC3C=CC=CC=3)[CH2:34][CH2:33]2)[CH:31]=1>CO>[F:25][C:26]1[C:27](=[O:46])[NH:28][C:29](=[O:45])[N:30]([C@H:32]2[C@@H:35]([CH2:36][OH:37])[CH2:34][CH2:33]2)[CH:31]=1
Reactant: O=c1[nH]c(=O)n([C@@H]2CC[C@@H]2COCc2ccccc2)cc1F
Agent: COc1ccc(CN=[N+]=[N-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: COc1ccccc1
Product: O=c1[nH]c(=O)n([C@@H]2CC[C@@H]2CO)cc1F
Temperature: 0 °C

Procedure:
In a 25 mL flask with AlCl3 (1.93 g, 14.4 mmol) inside, dry anisole 5 mL was added under argon to give a light yellow solution. In another flask with N3-PMB -5-fluoro-1-[cis-4-(benzyloxymethyl)cyclobutyl]uracil (0.66 g, 1.44 mmol) inside, dry anisole 5 mL was added, after which time AlCl3 solution was added to it very slowly at room temperature. After addition finishes, the mixture was cooled to 0° C. and dry MeOH was added slowly to give a colorless solution at the end. Then the solvents were removed and the product was purified by silica gel flash chromatography (CH2Cl2:MeOH=20:1 to CH2Cl2:MeOH=10:1) to give a white solid (0.26 g, 74%, Rf=0.11 (CH2Cl2:MeOH=20:1)). 1H NMR (CD3OD, 400 MHz): δ IR (neat) νmax 3402, 3064, 2934, 1694, 1473, 1369, 1244, 1041, 1005, 913, 784, 706.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]#[C:11][CH2:12][N:13]1[C:21]2[C:20](Cl)=[N:19][CH:18]=[N:17][C:16]=2[CH:15]=[CH:14]1)(C(C)(C)C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[NH2:27].O>C(O)(C)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:20]2[C:21]3[N:13]([CH2:12][C:11]#[C:10][CH2:9][OH:8])[CH:14]=[CH:15][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCC#CCn1ccc2ncnc(Cl)c21
Solvent: O
Solvent: CC(C)O
Product: OCC#CCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 80 °C
Reaction time: 6 h
Yield: 73.9 %

Procedure:
5-(4-{[Tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-yl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (408.3 mg) was dissolved in isopropyl alcohol (7 mL), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (421.0 mg) was added, and the mixture was stirred at 80° C. for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofuran (6 mL), a 1.0 M solution (2 mL) of tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33→20:80) and crystallized from hexane/ethyl acetate to give the title compound (425 mg) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](Br)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:12]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1
Yield: 90.1 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (7.61 g) in acetone (80 ml) were added geranyl bromide (10.9 g) and potassium carbonate (13.8 g). The mixture was refluxed with heating for 6 hours. The reaction solution, after water (150 ml) were added thereto, was extracted with chloroform. The extract was dried over sodium sulfite anhydride and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1), thereby yielding 13.00 g (90%) of methyl 4-geranyloxybenzoate.
Reaction SMILES: [CH:1]([N:4]1[C@@H:9]([CH3:10])[C:8](=[O:11])[NH:7][C:6]2[CH:12]=[C:13]([C:16](OC)=[O:17])[CH:14]=[N:15][C:5]1=2)([CH3:3])[CH3:2].[H-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:17][CH2:16][C:13]1[CH:14]=[N:15][C:5]2[N:4]([CH:1]([CH3:2])[CH3:3])[C@@H:9]([CH3:10])[C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)[C@H](C)N2C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N1c2ncc(CO)cc2NC(=O)[C@@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
(S)-methyl 4-isopropyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-b]pyrazine-7-carboxylate (0.649 g, 2.46 mmol) was dissolved in THF (8 mL) and cooled to 0° C. under nitrogen atmosphere. Sodium hydride (60% susp. in mineral oil, 0.112 g, 2.80 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. It was then cooled to −50° C. and LiAlH4 (1M in THF, 9.80 mL, 9.80 mmol) was added dropwise over 10 min. The reaction mixture was kept at −30-(−20)° C. for 1 h, cooled to below −50° C. and slowly quenched with MeOH (5 mL). The resulting solution was warmed to room temperature and subjected to preparative HPLC (1-30% acetonitrile in water, TFA buffered) to afford the title compound as a grey solid (TFA salt, 450 mg, 52%). [M+H] calc'd for C12H17N3O2, 236; found, 236.