Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:17][CH2:18][CH2:19][CH3:20])=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[N:7][CH:8]=1)#[CH:2].[C:21]([O:25][C:26](=[O:33])[NH:27][CH2:28][CH2:29][N:30]=[N+:31]=[N-:32])([CH3:24])([CH3:23])[CH3:22].C(O)(C)(C)C.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].O.C(OCC)(=O)C.CN(C)C=O>[F:16][C:12]1[CH:11]=[C:10]([NH:9][C:6]2[N:5]=[C:4]([NH:17][CH2:18][CH2:19][CH3:20])[C:3]([C:1]3[N:32]=[N:31][N:30]([CH2:29][CH2:28][NH:27][C:26](=[O:33])[O:25][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:2]=3)=[CH:8][N:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1cnc(Nc2cccc(F)c2)nc1NCCC
Reactant: CC(C)(C)OC(=O)NCCN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1-c1cn(CCNC(=O)OC(C)(C)C)nn1
Reaction time: 12 h

Procedure:
To 5-ethynyl-N2-(3-fluorophenyl)-N4-propylpyrimidine-2,4-diamine (S2, 62.4 mg) and tert-butyl(2-azidoethyl)carbamate (S18, 51.6 mg), tert-butanol (0.6 mL), water (0.6 mL), N,N-dimethylformamide (1.2 mL), sodium ascorbate (9.15 mg) and copper sulfate (3.69 mg) were added at room temperature, and the mixture was stirred at the same temperature for 12 hours. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl (2-(4-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-1H-1,2,3-triazol-1-yl)ethyl)carbamate (S19, 32.5 mg).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O.[K+].[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19]C([O-])=O.C(N(CC)CC)C.[Mg+2].[Cl-].[Cl-]>C(#N)C>[CH3:5][O:6][C:7]1[C:8]([CH3:16])=[C:9]([C:10](=[O:12])[CH2:19][C:18]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COc1cccc(C(=O)O)c1C
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cccc(OC)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Thionyl chloride (118 mL) was added to 3-methoxy-2-methyl benzoic acid (98.8 g, 595 mmol) and heated to reflux. After 2 hr, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was azeotroped with toluene (2×300 mL) and the resultant solid set aside. A suspension of ethyl malonate potassium salt (208 g, 1.22 mol) in acetonitrile (1.50 L) cooled to 5° C., triethylamine (166 mL, 1.49 mol) were added followed by MgCl2 (142 g, 1.49 mol). The cooling bath was removed and the mixture stirred for 3.5 hr at ambient temperature. The mixture was re-cooled to 5° C. and a solution of the aforementioned acid chloride in acetonitrile (100 mL) was added over 10 min. The mixture was warmed to ambient temperature, stirred for 15 hr, concentrated in vacuo and azeotroped with toluene (2×mL). The residue was suspended in EtOAc (750 mL) and toluene (750 mL), cooled in an ice bath and 4 N HCl (750 mL) was added slowly. The cooling bath was removed and the biphasic mixture was stirred vigorously for 30 min. The layers were separated, and the organic layer was washed with sat NaHCO3 (2×1.0 L) and dried over MgSO4. The mixture was filtered, concentrated in vacuo, and purified by flash chromatography (5, 10% EtOAc/heptane) on SiO2 to afford 138 g of the title compound as a pale yellow liquid: 1H NMR (500 MHz, CDCl3) indicated a mixture of keto ester and enol in a 2.5 1 ratio. For keto ester: δ 1.23 (t, 3H, J=7.2 Hz), 2.34 (s, 3H), 3.85 (s, 3H), 3.89 (s, 2H), 4.17 (q, 2H, J=7.1 Hz), 6.97 (d, 1H, J=7.8 Hz), 7.14 (d, 1H, J=8.7 Hz), 7.22 (d, 1H, J=7.9 Hz).
Reaction SMILES: O1CCCOB1[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].Br[C:16]1[CH:22]=[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+].CCO>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>[CH2:23]([C:21]1[CH:22]=[CH:16][C:17]2[C:19](=[C:7]3[C:8](=[C:9]([NH2:10])[N:18]=2)[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:20]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCc1ccc(N)c(Br)c1
Reactant: N#Cc1ccccc1B1OCCCO1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCc1ccc2nc(N)c3ccccc3c2c1
Yield: 39.8 %

Procedure:
13.1 g (69.8 mmol) 2-(1,3,2-dioxaborinan-2-yl)benzonitrile, 16.3 g (63.4 mmol) 2-bromo-4-hexylaniline, 1.62 g (1.40 mmol) tetrakis(triphenylphosphine)palladium(0), and 23.6 g (171 mmol) potassium carbonate where refluxed in 250 ml toluene and 100 ml EtOH under N2 atmosphere for 20 hours. HPLC and TLC revealed almost complete consumption of the aniline. The reaction mixture was cooled and passed through a filter. The solids were washed with ethyl acetate to remove organics from the collected base. The filtrate was then evaporated down and dried on silica. The sample was purified using silica gel chromatography with 100% ethyl acetate as the eluent. The product fractions were then evaporated down to a minimal amount and hexanes added to crystallize the product as off white solids (7.05 g, 39.8% yield, GC-MS confirmed).
Reaction SMILES: [C:1]([Si:5]([CH3:34])([CH3:33])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20](Cl)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]2=[O:32])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1>CC(O)C>[C:1]([Si:5]([CH3:34])([CH3:33])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20]([NH:43][C:40]4[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=4)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]2=[O:32])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)cc1
Reactant: COc1ccc(N)cc1
Solvent: CC(C)O
Product: COc1ccc(Nc2ncc3c(n2)N([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)C(=O)N(c2ccc(OC)cc2)C3)cc1
Temperature: 160 °C

Procedure:
A mixture of 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.20 g, 0.40 mmol) (from Example 19a supra) and p-anisidine (63.6 mg, 0.52 mmol) (Aldrich) in 2-propanol (4 mL) was placed in a microwave reactor (SmithSynthesizer™). The reaction mixture was heated at 160° C. for 10 minutes. After cooling, it was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate-hexanes (3:7 then 2:3) to give 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(4-methoxy-phenyl)-7-(4-methoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.14 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[NH2:11].[C:12](Cl)(=O)C>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[NH2:11]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(Cl)c(N)c1
Temperature: 70 °C

Procedure:
To a solution of 4-chloro-3-amino-benzoic acid (10.0 g, 58.3 mmol) in methanol (50 mL) was added acetyl chloride (13.0 mL) dropwise at room temperature. After the addition, the reaction mixture was heated at 70° C. for 3 h and then cooled to room temperature. The solvent was removed under reduced pressure and water (100 mL) was added. The resulting solution was neutralized with NaHCO3 followed by extraction with EtOAc (3×100 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuum to afford a yellow oil (22, 10.5 g, 97%). 1H NMR (DMSO-d6, 300 MHz) δ 7.41 (??d, J=2.1 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.09 (dd, J=2.1, 8.4 Hz, 1H), 5.66 (br s, 2H), 3.80 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)([C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.C[Si]([N:46]=[N+:47]=[N-:48])(C)C.C([Sn](=O)CCCC)CCC>C(COC)OC>[CH:19]1([NH:18][C:17]([C:14]2([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]4[NH:34][N:48]=[N:47][N:46]=4)=[CH:31][CH:32]=3)[CH2:15][CH2:16][N:11]([C:9](=[O:10])[C@@H:8]([NH2:7])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[CH2:12][CH2:13]2)=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)N1CCC(Cc2ccc(C#N)cc2)(C(=O)NC2CCCCC2)CC1
Agent: CCCC[Sn](=O)CCCC
Solvent: COCCOC
Product: N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(-c3nnn[nH]3)cc2)(C(=O)NC2CCCCC2)CC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of {2-[4-(4-cyanobenzyl)-4-cyclohexylcarbamoyl-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester (9.77 mmol; 5.85 g) (prepared as in Example 1, substituting 4-cyanobenzylbromide for 4-biphenylmethyl bromide and cyclohexylamine for cyclohexylmethylamine), in dimethoxyethane (3 mL) was added trimethylsilyl azide (0.67 mmol; 0.088 mL) and dibutyltin oxide (0.201 mmol; 53.15 mg). The resulting mixture was heated at 100° C. for 18 hours and then purified via reverse phase HPLC. The desired fractions were collected and lyophilized, and the residue was dissolved in THF (2 mL) and a 4N HCl solution in 1,4-dioxane (4 mL) was added. The resulting solution was stirred for 5 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 1-(2-(S)-amino-3-thiophen-2-yl-propionyl)-4-[4-(1H-tetrazol-5-yl)-benzyl]-piperidine-4-carboxylic acid cyclohexylamide as a hydrochloride salt.
Reaction SMILES: [Na].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1.[CH3:10][OH:11]>>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([O:11][CH3:10])=[N:4][CH:5]=1
Reactant: CO
Reactant: Brc1ccc(Br)nc1
Agent: [Na]
Product: COc1ccc(Br)cn1
Yield: 83 %

Procedure:
After sodium (10 g, 0.435 mol) was dissolved in methanol (500 ml), 2,5-dibromopyridine (50 g, 0.211 mol) was added thereto and the mixture was heated for 2 days under reflux. The reaction solution was cooled as it was, and then concentrated. Then, the residue was diluted with ethyl acetate and an aqueous saturated solution of ammonium chloride. The organic layer was washed with an aqueous saturated solution of ammonium chloride and brine, and then dried over anhydrous sodium sulfate and concentrated, to give the title compound (33 g, 83%) as a pale brown oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[CH:12][O:13][C:14]=2[CH3:15])=[CH:4][C:3]=1[O:16][CH3:17].CON(C)[C:21](=[O:37])[CH:22]([O:35][CH3:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[C:12]([C:21](=[O:37])[CH:22]([O:35][CH3:36])[C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:27][CH:28]=3)[O:13][C:14]=2[CH3:15])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2ncoc2C)cc(OC)c1Br
Product: COc1cc(-c2nc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)oc2C)cc(OC)c1Br

Procedure:
1-(4-(4-Bromo-3,5-dimethoxyphenyl)-5-methyloxazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was prepared from 4-(4-bromo-3,5-dimethoxyphenyl)-5-methyloxazole and N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (40% EtOAc-hexanes) gave the product as a yellow solid (0.048 g, 13% yield). MS: m/z 531.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:19]([NH2:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([Cl:21])[CH:3]=1.N([C@H]1C[C@H]2C[C@@H]1CC2)=[C:23]=S>C(Cl)CCl>[NH:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:5]3[C:4]([Cl:21])=[CH:3][C:2]4[NH:1][CH:23]=[N:20][C:19]=4[CH:18]=3)=[O:7])[CH:17]=2)[CH:13]=[N:14]1
Reactant: S=C=N[C@H]1C[C@@H]2CC[C@H]1C2
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1N
Solvent: ClCCCl
Product: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc[nH]c2cc1Cl

Procedure:
4,5-Diamino-2-chloro-N-(1H-indazol-6-yl)benzamide (0.3 mmol; see Example 171) was reacted with (1S,2S,4R)-2-Isothiocyanato-bicyclo[2.2.1]heptane (0.3 mmol) followed by cyclization in situ using EDC as described in general procedure B to provide 2-((1S,2S,4R))-bicyclo[2.2.1]hept-2-ylamino)-6-chloro-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)amide. MS: m/z 421 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH:17]([CH2:23][NH:24]C(=O)CC)[CH2:18]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(O)CCC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH:17]([CH2:23][NH2:24])[CH2:18]3)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)NCC1Cc2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2C1
Solvent: CCCCO
Product: CC(C)c1ccc(S(=O)(=O)Nc2cccc3c2CC(CN)C3)cc1
Yield: 18.6 %

Procedure:
N-[4-(4-Isopropyl-benzenesulfonylamino)-indan-2-ylmethyl]-propionamide (1.00 g, 2.50 mmol, synthesized as described in Example 8) was dissolved in 25 mL of n-butanol and 10 mL of concentrated (6N) hydrochloric acid was added. The resulting mixture was stirred at reflux for 5 h. The solution was cooled, added to water and extracted with ethyl acetate. The aqueous solution was treated with NaOH (2N) and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and the filtrate was evaporated in vacuo to give product as a white solid which was further purified by column chromatography using (dichloromethane-MeOH, 5-50%) to give a yellow oil (160 mg, 18%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:7].[CH2:12]([N:19]1[C:23]2[C:24]([Cl:28])=[N:25][CH:26]=[CH:27][C:22]=2[NH:21][C:20]1=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[C:23]2[C:24]([Cl:28])=[N:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]1[Cl:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]c2ccnc(Cl)c2n1Cc1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nccc2c1N(Cc1ccccc1)C(Cl)N2
Yield: 31.5 %

Procedure:
5 ml of phosphorus oxychloride and 0.338 g of phosphorus pentachloride were added to 0.383 g of 3-benzyl-4-chloro-1,3-dihydroimidazo[4,5-c]pyridin-2-one, and the mixture was heated under reflux for 24 hours. The solvent was concentrated under reduced pressure, and the residue was poured into 50 g of ice/water. The mixture was extracted with 100 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.13 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([OH:11])[CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][C:23]([NH2:25])=[O:24]>>[C:23]([CH2:22][O:11][C:9]1[CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=1[N+:12]([O-:14])=[O:13])(=[O:24])[NH2:25]
Reactant: NC(=O)CI
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc([N+](=O)[O-])c(OCC(N)=O)c1

Procedure:
Reaction of 1.08 g of 5-methoxycarbonyl-2-nitrophenol, 1.82 g of potassium carbonate and 2.02 g of iodoacetamide gives 2-carbamoylmethoxy-4-(methoxycarbonyl)nitrobenzene of mp 138°-9° C.; Rf (O)=0.63; FAB-MS: (M+H)+ 255; anal. calc. for C10H10N2O6 : C47.25%, H3.97%, N11.02%; found C47.08%, H4.04%, N10.79%. Starting from 1.16 g of 2-carbamoylmethoxy-4-(methoxycarbonyl)nitrobenzene, 2-carbamoylmethoxy-4-(methoxycarbonyl)aniline of mp 178°-80° C.; Rf (O)=0.37; MS: M+ =224; anal, calc. for C10H12 N2O4 : C53.57%, H5.39%, N12.49%; found C53.41%. H5.32%, N12.53%.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[N-:12]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CN(C=O)C.CCOC(C)=O>[Cl:11][C:4]1[C:5]([C:6]#[N:7])=[CH:8][CH:9]=[CH:10][C:3]=1[CH2:2][NH2:12]
Reactant: N#Cc1cccc(CBr)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(CN)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a soln. of 3-(bromomethyl)-2-chlorobenzonitrile (0.87 mmol) in 9 mL DMF was added NaN3 (1.3 mmol) and the resulting brown solution was stirred at RT for 20 min. The reaction mixture was diluted with EtOAc, washed twice with water and brine, dried over MgSO4 and concentrated in vacuo. The crude azide was redissolved in 4.3 mL THF and 0.1 mL water. Triphenylphosphine (1.04 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was acidified with 0.1; N HCl soln. until pH 3 and it was extracted 3 times with Et2O. The aq. phase was basified with 1M NaOH soln. and extracted 3 times with DCM. The comb. org. layers were dried over MgSO4 and conc. in vacuo to give the desired product as yellowish oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[CH2:22][OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[CH2:22][O:23][C:24](=[O:26])[CH3:25])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN1CCC(CO)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCN1CCC(COC(C)=O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21

Procedure:
To a solution of 8-(t-butyldimethylsilyloxymethyl)-4-hydroxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (1.98 g) in pyridine (5 ml), acetic anhydride was added dropwise with stirring under ice-cooling and the mixture was stirred for 2 hours at room temperature. Pyridine was distilled off under reduced pressure, and the resultant residue was extracted with dichloromethane. After washing with a saturated aqueous solution of copper sulfate and with water in this order, the mixture was dried and the solvent was distilled off under reduced pressure to give 8-t-butyldimethylsilyloxymethyl-4-acetyloxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (2.23 g).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[CH:20]([NH2:23])([CH3:22])[CH3:21]>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH:23][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)N
Reactant: Clc1cccc(Cl)c1Cn1cnc2c(Cl)ncnc21
Solvent: CO
Product: CC(C)Nc1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Yield: 82 %

Procedure:
6-Chloro-9-(2,6-dichlorobenzyl)purine (314 mg), 296 mg of isopropylamine and 25 ml of methanol were treated in the same manner as Example 2 and recrystallized from aqueous ethanol to obtain 276 mg (yield 79%) of 9-(2,6-dichlorobenzyl)-6-isopropylaminopurine as colorless needles melting at 109°-110° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([O:21][C:22]([C:24]1[N:25]2[CH:28]([O:29][CH2:30][C:31]=1[CH2:32][CH:33]=[O:34])[CH:27]([NH:35][C:36](=[O:66])[C:37](=[N:63][O:64][CH3:65])[C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[S:41][CH:42]=1)[C:26]2=[O:67])=[O:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[S:68](Cl)([C:71]1[CH:77]=[CH:76][C:74]([CH3:75])=[CH:73][CH:72]=1)(=[O:70])=[O:69].CCOCC>C(Cl)Cl>[CH:8]([O:21][C:22]([C:24]1[N:25]2[CH:28]([O:29][CH2:30][C:31]=1[CH:32]=[CH:33][O:34][S:68]([C:71]1[CH:77]=[CH:76][C:74]([CH3:75])=[CH:73][CH:72]=1)(=[O:70])=[O:69])[CH:27]([NH:35][C:36](=[O:66])[C:37](=[N:63][O:64][CH3:65])[C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[S:41][CH:42]=1)[C:26]2=[O:67])=[O:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC=O)COC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)COC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
Triethylamine (0.27 cc) is added, in the course of 10 minutes, to a solution, cooled to -5° C., of the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-(2-oxoethyl)-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (1.00 g) and tosyl chloride (0.35 g) in methylene chloride (20 cc). The mixture is stirred at -5° C. for 10 minutes and then left to return to 20° C. The mixture is then stirred for 30 minutes. The solvent is evaporated off under reduced pressure (350 mm Hg; 47 kPa). This yields a chestnut-coloured oil, which solidifies on stirring with ether (100 cc). The solid is filtered off and dried. This yields the E form of the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-8-oxo-3-(2-tosyloxyvinyl)-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.38 g) in the form of a cream-coloured powder. The filtrate is concentrated to a residual volume of 5 cc and isopropyl ether (100 cc) is added. A pale yellow solid separates out. It is isolated on a filter and a second fraction of the E form of the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-(2-tosyloxyvinyl)-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.11 g) is obtained.
Reaction SMILES: [Br:1]Br.P(Br)(Br)Br.[C:7]1([CH2:13][CH2:14][CH2:15][CH:16](O)[CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C(Cl)Cl>[Br:1][CH:16]([CH2:15][CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:17]
Reactant: CC(O)CCCc1ccccc1
Reactant: BrBr
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(Br)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To phosphorous pentabromide, prepared by addition of bromine (9.0 g.) in methylene chloride (10 ml.) to phosphorous tribromide (15.0 g.) in methylene chloride (15 ml.) at 0° C., is added 5-phenyl-2-pentanol (812 g.) in methylene chloride at 0° C. The mixture is stirred for 2.5 hours at 0° C. and is then allowed to warm to room temperature. Water (50 ml.) is added, the mixture stirred for one hour and the methylene chloride layer separated. The extraction is repeated and the combined extracts washed with water, saturated sodium bicarbonate solution, brine and then dried over magnesium sulfate. Concentration of the dried extracts gives 12.4 g. of title product as a light yellow oil.