Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[O:22])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.Cl.C(OCC)C>O1CCOCC1>[ClH:29].[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[O:22])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reaction time: 0.08 h

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (1.86 g, 4.0 mmol) was treated with 4 N hydrochloric acid in dioxane (10 mL) at room temperature. After 5 minutes, the solids went into solution and the mixture was stirred for 1 h. Then, 25 mL of ethyl ether was added to precipitate the product. The solids were collected by filtration and washed with hexane. The resulting solid was very hydroscopic and became gummy. This material was dissolved in 50 mL of methanol and concentrated. After drying under high vacuum, 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride salt. (1.64 g, 97%) was obtained as a light yellow solid: mp 158-161° C.
Reaction SMILES: [CH3:1][C:2]1([CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH2:15]1)[C:3]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.P(Cl)(Cl)Cl>>[CH3:1][C:2]1([C:3]2[O:14][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:6][N:5]=2)[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH2:15]1
Reactant: CC1=CCC(C)(C(=O)NNC(=O)c2ccccc2)C=C1
Solvent: ClP(Cl)Cl
Product: CC1=CCC(C)(c2nnc(-c3ccccc3)o2)C=C1

Procedure:
Scheme III shows the reaction of 2,5-dimethylbenzoic acid chloride with benzoic hydrazide in the presence of triethylamine to give 1-(1,4-dimethylbenzoyl)-2-benzoylhydrazine. The resultant 1-(1,4-dimethylbenzoyl)-2-benzoylhydrazine is then allowed to cyclize in the presence of phosphorus chloride to give 2-(1,4-dimethylphenyl)-5-phenyl-1,3,4-oxadiazole, that then undergoes direct bromination or oxidation, as described above, to produce bis(bromomethyl) and bis(chloromethyl) monomers.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[CH:5][CH:4]=1)=[O:2].O.[BH4-].[Na+]>CN(C)C(=O)C>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: OCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1

Procedure:
5-(4'-formyl-1,1'-biphenyl-2-yl)-2-triphenylmethyl-2H-tetrazole was dissolved in N,N-dimethylacetamide and some water and reduced by sodium borohydride. The reaction mixture was then poured into water slowly to precipitate the title compound which is further purified by recrystallizations as described in Example 11.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@H](N=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@H](N)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 31.5 %

Procedure:
To a solution of trans-1-azido-4-(tert-butoxycarbonylamino)-2-cyclohexene (1.14 g, 4.79 mmol) in THF (50 mL) and water (5 mL) was added triphenylphosphine (2.60 g, 10 mmol) and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated and the thus obtained material was purified by column chromatography on silica gel (10:1:1 CH2Cl2—CH3OH—NH4OH) followed by radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) and provided 0.32 g (31%) of trans-1-amino-4-(tert-butoxycarbonylamino)-2-cyclohexene as a colorless oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.50-1.92 (m, 2H), 1.99-2.10 (m, 2H), 3.32 (br s, 1H), 4.10-4.19 (m, 1H), 4.47-4.60 (m, 1H), 5.57-5.77 (m, 2H);
Reaction SMILES: [ClH:1].[CH:2](=[C:9]1[C:14](=O)[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][N:11]([CH3:23])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:24][C:25]([F:30])([F:29])[CH2:26][NH:27][NH2:28]>CO>[ClH:1].[CH3:23][N:11]1[CH2:10][C:9](=[CH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:14]2=[N:28][N:27]([CH2:26][C:25]([F:30])([F:29])[F:24])[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]2[CH2:12]1
Reactant: NNCC(F)(F)F
Reactant: CN1CC(=Cc2ccccc2)C(=O)C(=Cc2ccccc2)C1
Agent: Cl
Solvent: CO
Product: CN1CC(=Cc2ccccc2)C2=NN(CC(F)(F)F)C(c3ccccc3)C2C1
Yield: 59.9 %

Procedure:
A stirred suspension of 12.5 g of 3,5-dibenzylidene-1-methyl-4-piperidone, hydrochloride in 225 ml of methanol is treated with 6.9 g of 70% aqueous 2,2,2-trifluoroethylhydrazine, heated, and the resulting solution refluxed for four hours. The solvent is removed on a rotary evaporator and the light yellow foamy residue (18 g) is dissolved in 90 ml of acetonitrile and treated with 7.5 ml of 5.1 N alcoholic hydrogen chloride; the solid salt rapidly separates after a few seconds. Following cooling for about 16 hours, the material is filtered under nitrogen, washed with cold acetonitrile and ether, and dried in vacuo yielding 9.7 g of material, melting point 185°-187° C (foaming); sintering at 181° C. Crystallization from 50 ml of methanol and 50 ml of ether yields 7.9 g of product, melting point 185°-187° C (foaming).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].O.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.[Cl-].[Na+].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>[NH2:19][C:20]1[CH:25]=[C:24]([C:2]2[C:3]([F:17])=[C:4]3[O:8][C:7]([CH:9]4[CH2:11][CH2:10]4)=[N:6][C:5]3=[C:12]([C:15]#[N:16])[C:13]=2[CH3:14])[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cccc(N)c2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 95 °C
Reaction time: 12 h

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (150 mg, 0.51 mmol) and 3-aminophenylboronic acid monohydrate (315 mg, 2.03 mmol) were dissolved in 1,4-dioxane (5 ml), then at room temperature, tripotassium phosphate (216 mg, 1.02 mmol) and then tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.10 mmol) were added. The suspension was stirred under nitrogen atmosphere at 95° C. for 12 hours. After cooling to room temperature, the solution was fractionated with ethyl acetate and saturated brine. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=2:1) to obtain the entitled compound (170 mg, quant.) as a white amorphous substance.
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1C(=O)C2=CC=CC=C2C1=O)[CH2:3][P:4]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=[O:8])[O:5][CH2:6][CH3:7].O.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C>[NH2:17][CH2:16][CH:2]([OH:1])[CH2:3][P:4]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=[O:8])[O:5][CH2:6][CH3:7]
Reactant: CCOC(OCC)P(=O)(CC(O)CN1C(=O)c2ccccc2C1=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCOC(OCC)P(=O)(CC(O)CN)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g of ethyl 2-hydroxy-3-phthalimido-propyl(diethoxymethyl)phosphinate in 23 ml of isopropanol is added 4 ml of water. To this mixture is added 0.47 g of sodium borohydride and this is stirred for a period of 24 hours at room temperature. After this time 2.6 ml of glacial acetic acid are carefully added and the reaction heated to 80° for a period of 2 hours. After this time, the reaction is cooled to room temperature, the solvent evaporated under reduced pressure and the residue passed down a silica column using a mixture of one part ethyl acetate to one part ethanol as eluant. Ethyl 3-amino-2-hydroxy-propyl(diethoxymethyl)phosphinate is obtained as colourless oil, 31P=+45.8 and +45.2 ppm (CDCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[CH2:18][CH2:17]4)=[N:12][N:11]3[C:27]=2[C:28]2[CH:33]=[CH:32][N:31]=[C:30]3[N:34](S(C4C=CC(C)=CC=4)(=O)=O)[CH:35]=[CH:36][C:29]=23)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[CH2:18][CH2:17]4)=[N:12][N:11]3[C:27]=2[C:28]2[CH:33]=[CH:32][N:31]=[C:30]3[NH:34][CH:35]=[CH:36][C:29]=23)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCC(N7CCCC7)CC6)nn45)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Fc1ccc(-c2nc3ccc(N4CCC(N5CCCC5)CC4)nn3c2-c2ccnc3[nH]ccc23)cc1

Procedure:
The 2-(4-fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine obtained in step 6.1 is dissolved in 3 ml of a mixture of methanol and tetrahydrofuran (2/1), then treated using 0.09 ml (0.54 mmol) of a 6N aqueous solution of sodium hydroxide at 60° C. for 1 and a half hours. The solvent is evaporated and the residue taken up in 3 ml of water. The product is extracted 2 times with 3 ml of dichloromethane. The organic phase is dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The residue obtained is then purified by chromatography over a silica gel column (4 g) by eluting with a gradient of dichloromethane, methanol and aqueous ammonia (of 95/5/05 to 90/10/1) in order to give 0.064 g of 2-(4-fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine after crystallization in 10 ml of acetonitrile, filtration and drying.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[NH:8][C:9](=[O:13])[N:10]([CH3:12])[CH:11]=1)=[O:5])[CH3:2].[CH3:21][Si](C)(C)N[Si](C)(C)C.[K].CI>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[N:8]([CH3:21])[C:9](=[O:13])[N:10]([CH3:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC(=O)C1=CN(C)C(=O)NC1c1ccc(F)cc1
Agent: [K]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CN(C)C(=O)N(C)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.5 %

Procedure:
4-(4-Fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (1.0 g, 3.6 mmol) was dissolved in 10 mL DMF and cooled to 0°. Potassium hexamethyldisilazane (8 mL, 4 mmol of 0.5M toluene solution) was added and the reaction mixture was stirred at 0° for 5 minutes. CH3I (0.3 mL, 4.8 mmol) was added and the mixture was allowed to warm to room temperature and stir for 2 hours. The solution was poured into cold aqueous pH 2 buffer and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was chromatographed in 0-30% ethyl acetate/hexane to yield 700 mg of 4-(4-fluoro-phenyl)-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]>CO.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:3]([N:2]([CH3:15])[CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: CN(C)c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc(N)cc1C(=O)O
Yield: 64.3 %

Procedure:
A solution of 2-dimethylamino-5-nitro-benzoic acid (200 mg, 0.95 mmol) in methanol (15 ml) was hydrogenated over 10% Pd/C (20 mg) at 30 psi until no further gas uptake was observed. The reaction mixture was then filtered over celite and the filtrate evaporated to yield the crude product. Recrystallisation using pet. ether yielded 5-amino-2-dimethylamino-benzoic acid (110 mg, 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25](O)=[O:26])=[O:14])=[CH:11][CH:10]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH3:7].[NH3:34]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25]([NH2:34])=[O:26])=[O:14])=[CH:11][CH:10]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCC/C=C/COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C(=O)O)cc1
Reactant: N
Solvent: c1ccccc1
Product: CCCC/C=C/COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 40 ml of benzene was suspended 2.8 g of (E)-2-[2-[4-(2-heptenyloxy)benzoylamino]phenylthio]benzoic acid followed by addition of 1.2 g of N,N'-carbonyldiimidazole, and the mixture was stirred at room temperature for 2 hours. Ammonia gas was introduced into the mixture with ice-cooling and stirring for 20 minutes and the mixture was then allowed to stand at room temperature for 2 hours. The crystals separated out therefrom were collected by filtration and washed with ethyl acetate to give 2.6 g of the title compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:15][N:16]([CH3:21])[C:17](=[O:20])[CH:18]=[CH2:19].Cl>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:19][CH2:18][C:17]([N:16]([CH3:21])[CH3:15])=[O:20])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: C=CC(=O)N(C)C
Reactant: CC1=C2CCNCC2c2ccccc21
Agent: Cl
Product: CC1=C2CCN(CCC(=O)N(C)C)CC2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and N,N-dimethyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 7 hours. M.P. of the hydrochloride of the title compound 219°-221° from ethanol.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[OH-].[Na+].[CH2:29]([OH:32])[CH2:30][CH3:31]>>[N:21]1([NH:20][C:4]2[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=[C:2]([O:32][CH2:29][CH2:30][CH3:31])[N:3]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CCCO
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1nc(NN2CCCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Yield: 37 %

Procedure:
2-Chloro-N-(1-piperidinyl)adenosine (0.50 g, 1.3 mmol) (Example 5) was dissolved in a solution of sodium hydroxide (0.51 g, 1.3 mmol) in 1-propanol (15 ml), and the solution was heated at reflux for 4.5 hours, after which time TLC investigation showed that the starting material had been consumed. The reaction mixture was evaporated and the resultant residue was dissolved in water. The solution was neutralized with 4N aqueous hydrochloric acid and extracted with dichloromethane (3×50 ml). The combined extracts were dried (MgSO4) and evaporated to an oil which was triturated with diethyl ether to afford a fawn foam. This foam was purified by column chromatography on silica gel (2×20 cm); elution with a mixture of dichloromethane/ethanol 25% aqueous ammonia solution (60/10/1) provided the title compound (0.20 g, 37%) as a semi-solid foam; 1H NMR (400 MHz, Me2SO-d6) δ 3.54, 3.65 (2H, ABX, H-5'a and H-5'b), 3.92 (1H, q, H-4'), 4.15 (1H, q, H-3'), 4.60 (1H, q, H-2'), 5.80 (1H, d, H-1'), 8.16 (1H, s, H-8).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]1([Na])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Na].ClC1C=CC=CC=1.[CH3:23][Si:24]([CH3:27])([CH3:26])Cl>O.C1(C)C=CC=CC=1>[C:8]1([Si:24]([CH3:27])([CH3:26])[CH3:23])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [Na]c1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: [Na]
Solvent: Clc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: O
Product: C[Si](C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A toluene (5 g) solution containing 0.87 g (8.60 mmol, 2 mol %) of diisopropylamine was added to phenyl sodium, which had been prepared by reacting 20.0 g (0.870 mol) of sodium dispersion and 48.0 g (0.426 mol) of chlorobenzene in 160 g of tolunene, at room temperature, and then the reaction mixture was stirred for 2 hours. To the resultant greenish brown slurry, 46.3 g (0.426 mol) of trimethylchlorosilane was added, dropwise, keeping the reaction temperature in the range of from 15 to 20° C., and then the reaction mixture was subjected to hydrolysis with 100 ml of water. After the separated organic layer was washed with water three times, the thus-obtained organic solution was subjected to gas chromatography analysis. As a result, it was found that benzyltrimethylsilane was produced, at the yield of 98.5%, while the yield of phenyltrimethylsilane was not more than 0.5%. This fact indicates that phenyl sodium was almost quantitatively converted to benzyl sodium. Further, a solvent was distilled off from the obtained organic layer, and then the remaining slightly yellowish oil was distilled under reduced pressure, to give 65.5 g of benzyltrimethylsilane (0.399 mol, 93.7%, b.p. 120 to 122° C./100 mmHg).
Reaction SMILES: CC1C=CC([O:8][S:9]([C:12]2[CH:13]=[C:14]([NH:18][S:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][C:28]([NH:32][C:33]([NH:35][C:36]5[CH:45]=[C:44]6[C:39]([CH:40]=[CH:41][C:42]([S:46]([NH:49][C:50]7[CH:51]=[C:52]([S:56]([O:59]C8C=CC(C)=CC=8)(=[O:58])=[O:57])[CH:53]=[CH:54][CH:55]=7)(=[O:48])=[O:47])=[CH:43]6)=[CH:38][CH:37]=5)=[O:34])=[CH:29]4)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=CC=1.[OH-].[Na+:68].Cl>>[Na+:68].[Na+:68].[S:56]([C:52]1[CH:51]=[C:50]([NH:49][S:46]([C:42]2[CH:43]=[C:44]3[C:39]([CH:38]=[CH:37][C:36]([NH:35][C:33]([NH:32][C:28]4[CH:29]=[C:30]5[C:25]([CH:24]=[CH:23][C:22]([S:19]([NH:18][C:14]6[CH:13]=[C:12]([S:9]([O-:11])(=[O:8])=[O:10])[CH:17]=[CH:16][CH:15]=6)(=[O:21])=[O:20])=[CH:31]5)=[CH:26][CH:27]=4)=[O:34])=[CH:45]3)=[CH:40][CH:41]=2)(=[O:48])=[O:47])[CH:55]=[CH:54][CH:53]=1)([OH:59])(=[O:57])=[O:58].[S:56]([C:52]1[CH:51]=[C:50]([NH:49][S:46]([C:42]2[CH:43]=[C:44]3[C:39]([CH:38]=[CH:37][C:36]([NH:35][C:33]([NH:32][C:28]4[CH:29]=[C:30]5[C:25]([CH:24]=[CH:23][C:22]([S:19]([NH:18][C:14]6[CH:13]=[C:12]([S:9]([O-:11])(=[O:8])=[O:10])[CH:17]=[CH:16][CH:15]=6)(=[O:21])=[O:20])=[CH:31]5)=[CH:26][CH:27]=4)=[O:34])=[CH:45]3)=[CH:40][CH:41]=2)(=[O:48])=[O:47])[CH:55]=[CH:54][CH:53]=1)([OH:59])(=[O:57])=[O:58]
Reactant: Cc1ccc(OS(=O)(=O)c2cccc(NS(=O)(=O)c3ccc4ccc(NC(=O)Nc5ccc6ccc(S(=O)(=O)Nc7cccc(S(=O)(=O)Oc8ccc(C)cc8)c7)cc6c5)cc4c3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc2ccc(S(=O)(=O)Nc3cccc(S(=O)(=O)[O-])c3)cc2c1)Nc1ccc2ccc(S(=O)(=O)Nc3cccc(S(=O)(=O)O)c3)cc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 35 mg (0.036 mmol) of compound 9 was added 2 mL of 5 N NaOH. The reaction was allowed to stir at ambient temperature for 6 hours. The reaction was acidified with 6 N HCl and the solution was added to a small reverse-phase (C18) solid phase extraction column. The column was washed with H2O followed by 50:50 (v:v) CH3CN:H2O to elute the product. This provided 26 mg of compound 13.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].[Cu][C:14]#[N:15]>CN1CCCC1=O>[C:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12])#[N:15]
Reactant: N#C[Cu]
Reactant: O=c1[nH]cnc2ccc(I)cc12
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2nc[nH]c(=O)c2c1
Temperature: 170 °C
Reaction time: 1.5 h
Yield: 36.4 %

Procedure:
6-Iodoquinazolin-4-one (10 g) in 1-methyl-2-pyrrolidinone (50 ml) was treated with copper (I) cyanide (4.28 g) at 206° C. under N2 for 16 hours. The resulting mixture was cooled to 170° C. and the methyl-2-pyrrolidinone removed by vacuum distillation. Potassium cyanide (2.4 g) in water (30 ml) and ethyl acetate (150 ml) were added to the cooled residue and heating continued at 110° C. for 1.5 hours. This mixture was then filtered hot through a pad of celite and the filter cake washed thoroughly with ethyl acetate. Subsequent separation, drying and concentration in vacuo gave the title compound (2.29 g) as a beige solid; δH [2H6]DMSO 12.65(1H, bs), 8.53(1H, d), 8.28(1H, s), 8.19(1H, dd), 7.82(1H, d); m/z (M−1+) 171.
Reaction SMILES: FC(F)(F)C1C=C[C:6]([C:7](O)=[O:8])=[CH:5]C=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25](C(O)C)=[CH:24][CH:23]=2)=[N:19][CH:20]=1>>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:27]=2[CH2:5][CH2:6][C:7]3=[O:8])=[N:19][CH:20]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(O)c1ccc(Oc2ccc(N)cn2)cc1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 4-(trifluoromethyl)benzoic acid in place of 3,4-dichloro benzoic acid and using an equimolar amount of 1-{4-[(5-amino-2-pyridinyl)oxy]phenyl)-1-ethanol obtained in Reference Example 37 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: [P:1]([O:16]C1C=CC=CC=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO.[C:25]1(O)C=CC=CC=1.C1(OC)C=CC=CC=1>CI>[CH3:25][P:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: Oc1ccccc1
Solvent: COc1ccccc1
Solvent: CI
Solvent: CO
Product: CP(=O)(Oc1ccccc1)Oc1ccccc1
Yield: 92 %

Procedure:
A reactor fitted with an efficient condenser, thermometer, mechanical stirrer and side-arm addition funnel was charged with 1552 g (5.0 mol) of triphenyl phosphite. The reactant was placed under a nitrogen blanket and heated to reflux. A solution of 5.0 g of methyl iodide in 160 g (5.1 mol) of methanol was then slowly added over a two hour period. Throughout the addition, the temperature of the reactor contents was maintained within the 200°-250° C. range. One further hour at 215° C. proved sufficient for the reaction to reach completion. Subsequently, as aspirator vacuum distillation removed 468 g (5.0 mol) of phenol containing a small amount of anisole. Thereafter, a high vacuum distillation recovered 1150 g (4.6 mol, 92% yield) of diphenyl methylphosphonate. Glc analysis using a 6 foot column packed with 10% OV-101 on chromosorb W, was employed to monitor the progress of both the reaction and distillation. The s:p signal for the product appeared at -24.0 ppm. Proton nmr signals were seen at τ8.36 (3H, doublet, J=18 HZ, CH3P) and τ2.9-2.5 (10H, multiplet, phenyl).