Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H]1[C@@H](CO)O[C@@H](N2C=CC(N)=NC2=O)C1.C([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[CH:33][C:31](=O)[NH:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[N:35]=[N+:36]=[N-:37])(=O)C.ClC1C=CC([ClH]P(Cl)(=O)[O-])=CC=1.[NH:50]1C=NC=N1.N>N1C=CC=CC=1.O1CCOCC1>[NH3:1].[N:35]([C@@H:23]1[C@@H:22]([CH2:21][OH:20])[O:26][C@@H:25]([N:27]2[CH:34]=[CH:33][C:31]([NH2:50])=[N:30][C:28]2=[O:29])[CH2:24]1)=[N+:36]=[N-:37]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reactant: Nc1ccn([C@H]2C[C@H](N)[C@@H](CO)O2)c(=O)n1
Reactant: c1nc[nH]n1
Agent: N
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1CO

Procedure:
An alternate synthesis of compound (XIII) involves treatment of 3'-azido-5'-O-acetyl-2',3'-dideoxyuridine (X) with 4-chlorophenylphosphorodichloridate and 1,2,4-triazole in pyridine at room temperature for 3 days to give the 4-trizolylpyrimidinone derivative. Subsequent treatment with aqueous ammonia in dioxane (1:3 v/v) for 4 hours, then saturated methanolic ammonia overnight at room temperature, yields the 3'-azido analog (XII) Compound (XII) is then reduced under 50 psi of hydrogen in the presence of 10% palladium on charcoal at room temperature for 6 hours to obtain the desired 3'amino-2',3'-dideoxycytidine derivative (XIII).
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>O1CCCC1>[CH2:1]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 143.6 %

Procedure:
A solution of N-benzyl-4-methoxybenzenesulfonamide (15.00 g, 36.06 mmol) in tetrahydrofuran (90 ml) was added to a suspension of sodium hydride (60% oil suspension 1.47 g, 36.78 mmol) in tetrahydrofuran (90 ml) and stirred for 50 minutes at room temperature. Then the suspension, with ethyl bromoacetate (6.00 ml, 54.09 mmol) added thereto, was stirred for 14 hours at room temperature. After the reaction, the mixture, with water (100 ml) added thereto, was extracted with ethyl acetate (100 ml×3). The organic layer was dried over sodium sulfate, and then the solvent was evaporated out. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane), to give ethyl 2-{benzyl[(4-methoxyphenyl)sulfonyl]amino}acetate (18.82 g, 96%).
Reaction SMILES: [NH:1]([C:3]1[C:4]2[C:11](I)=[CH:10][N:9]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@@:14]3([CH3:22])[OH:15])[C:5]=2[N:6]=[CH:7][N:8]=1)[NH2:2].[C]=O.C([SnH](CCCC)CCCC)CCC.C1C[O:41][CH2:40]C1>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>[CH:40]([C:11]1[C:4]2[C:3]([NH:1][NH2:2])=[N:8][CH:7]=[N:6][C:5]=2[N:9]([C@@H:13]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@@:14]2([CH3:22])[OH:15])[CH:10]=1)=[O:41]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c2c(NN)ncnc21
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: [C]=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(C=O)c2c(NN)ncnc21

Procedure:
The compound from Step 1 is dissolved as a 0.1M solution in THF and 0.2 eq. of tetrakis(triphenylphosphine)palladium (0) are added. While bubbling carbon monoxide gas into the solution, 1 eq. of tributyltin hydride is added over the period of 6 hours. The reaction is then evaporated and subjected to silica gel chromatography, to give the target compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.C(N(CC)CC)C.Cl[CH2:34][CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38].O>ClCCl>[O:38]=[S:37]1(=[O:39])[CH2:36][CH2:35][CH2:34][N:1]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3cnc(N)cc3C)CC2)c(C)c1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cnc(N2CCN(C(=O)c3cnc(N4CCCS4(=O)=O)cc3C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (320 mg) described in Preparation Example 176 was added 4-methoxybenzylamine (1 mL), and the mixture was stirred at 160° C. for 6 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (330 mg). The obtained [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (330 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give (6-amino-4-methylpyridin-3-yl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone. The obtained (6-amino-4-methylpyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone and triethylamine (0.30 mL) were dissolved in dichloromethane (10 mL), 3-chloropropane-1-sulfonyl chloride (0.18 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give the title compound (220 mg).
Reaction SMILES: ClC(Cl)(Cl)C([N:5]1[CH:12]2[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2)=O.C(O)(C)C.[OH-].[Na+].O>C1(C)C=CC=CC=1>[CH:6]12[CH2:14][CH:10]3[CH2:9][CH:8]([CH2:13][CH:12]([CH2:11]3)[NH:5]1)[CH2:7]2
Reactant: O=C(N1C2CC3CC(C2)CC1C3)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: C1C2CC3CC1CC(C2)N3
Temperature: 80 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution containing 23.4 g (83 mmol) of N-trichloroacetyl-2-azaadamantane and 70.1 g of isopropanol, was heated to 80° C., and 99.4 g of a 20 wt % NaOH aqueous solution was added, followed by stirring for one hour. 47 g of water and 47 g of toluene were added, followed by liquid separation, to obtain a toluene solution of 2-azaadamantane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.N1(CCN[C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])C=CN=N1.C([OH:39])C>N1CCCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11](=[CH:35][C:30]2[NH:31][C:32]([CH3:34])=[CH:33][C:29]=2[C:27]([OH:28])=[O:39])[C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: CCO
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)O)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3-triazol-1-yl-ethyl)-amide as a yellow solid (61 mg, 52%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([Cl:15])[C:7]=1Cl)(=[O:5])=[O:4])[CH3:2].Cl.[OH-:18].[Na+]>>[Cl:15][C:8]1[C:7]([OH:18])=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: [OH-]
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Product: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1O

Procedure:
A solution of the 4-ethylsulfonyl-2,3-dichlorobenzoic acid prepared in Example 3 (0.35 mole) in 500 ml of 20% sodium hydroxide was heated at reflux for 7 hours. After cooling, the aqueous solution was acidified with concentrated hydrochloric acid and extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulfate, and concentrated in vacuo to afford the crude acid. Recrystallization of the crude acid from ethyl acetate afforded the desired pure acid as white crystals. m.p. 188°-192° C.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:28])[N:3]1[CH2:29][CH2:30][CH3:31]>C1COCC1.CO.[Pd]>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:28])[N:3]1[CH2:29][CH2:30][CH3:31]
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C=CC(=O)O)(CCC3)C4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CCC(=O)O)(CCC3)C4)nc2n(CCC)c1=O

Procedure:
3-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]non-1-yl]-acrylic acid (150 mg) was hydrogenated in the presence of 10% Pd/C in THF:MeOH (2:1, 5 ml) @60 psi overnight. Catalyst was filtered through celite and the solvent was concentrated. Solid was purified by crystallizing from ether Yield 105 mg. Mass (ES+ 431)
Reaction SMILES: [NH2:1]OS(=O)(=O)O.C(=O)([O-])O.[Na+].[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:25]3[CH:42]=[CH:41][C:28]([O:29][CH2:30][C@@H:31]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])=[CH:27][CH:26]=3)=[N:21][CH:22]=2)[CH2:14][CH2:13]1>O.CO>[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[N:21]([N:1]=[C:24]([C:25]4[CH:42]=[CH:41][C:28]([O:29][CH2:30][C@@H:31]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH3:32])=[CH:27][CH:26]=4)[CH:23]=3)[CH:22]=2)[CH2:14][CH2:13]1
Reactant: C[C@@H](COc1ccc(C#Cc2ccc(OCC3CC3)cn2)cc1)NC(=O)OC(C)(C)C
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H](COc1ccc(-c2cc3ccc(OCC4CC4)cn3n2)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
(Aminooxy)(hydroxy)sulfane dioxide (679 mg) was dissolved in water (3 mL), and saturated aqueous sodium hydrogen carbonate solution was added dropwise thereto at 0° C. to neutralize the solution. To the obtained mixture was added a solution of tert-butyl [(1S)-2-(4-{[5-(cyclopropylmethoxy)pyridin-2-yl]ethynyl}phenoxy)-1-methylethyl]carbamate (845 mg) in methanol (5 mL) at room temperature, and the mixture was stirred at 60° C. overnight, and concentrated under reduced pressure. To the residue were added DMF (8 mL) and potassium carbonate (829 mg), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and water, and the aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless solid (134 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[CH2:14](Br)[CH:15]=[CH2:16]>O1CCCC1>[CH2:16]([O:13][C:10]([C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1)([CH3:11])[CH3:12])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: CC(C)(O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a stirred solution of sodium hydride (1.47 g) in dry tetrahydrofuran (60 ml) was added dropwise under an argon atmosphere a solution of 2-(4-fluorophenyl)-2-propanol (4.35 g) in dry tetrahydrofuran (10 ml). The resulting yellow suspension was stirred at room temperature for 10 min. A solution of allyl bromide (3.1 ml) diluted in dry tetrahydrofuran (10 ml) was added slowly. The reaction mixture was stirred for 30 min and quenched by addition of water. The solution was extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4) and evaporated. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0->90:10) to give 1-(1-allyloxy-1-methyl-ethyl)-4-fluoro-benzene (3.30 g, 60%) as a light yellow liquid. MS (EI): 179.0 ([M-CH3]).
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]1([CH3:25])[CH2:11][C:10]2[C:12]([CH3:24])=[C:13]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:14]([CH3:17])=[C:15]([CH3:16])[C:9]=2[O:8]1.[Cl:26][C:27]1[N:32]=[C:31]([Cl:33])[CH:30]=[CH:29][N:28]=1.C(N(CC)CC)C>O>[Cl:26][C:27]1[N:32]=[C:31]([N:21]2[CH2:20][CH2:19][N:18]([C:13]3[C:14]([CH3:17])=[C:15]([CH3:16])[C:9]4[O:8][C:7]([CH3:25])([CH3:6])[CH2:11][C:10]=4[C:12]=3[CH3:24])[CH2:23][CH2:22]2)[CH:30]=[CH:29][N:28]=1.[Cl:33][C:31]1[CH:30]=[CH:29][N:28]=[C:27]([N:21]2[CH2:20][CH2:19][N:18]([C:13]3[C:14]([CH3:17])=[C:15]([CH3:16])[C:9]4[O:8][C:7]([CH3:25])([CH3:6])[CH2:11][C:10]=4[C:12]=3[CH3:24])[CH2:23][CH2:22]2)[N:32]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(C)c(N2CCN(c3ccnc(Cl)n3)CC2)c(C)c2c1OC(C)(C)C2
Product: Cc1c(C)c(N2CCN(c3nccc(Cl)n3)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %
Yield: 4 %

Procedure:
To the DMF (10 mL) solution of 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (1.92 g, 7.00 mmol) synthesized in Reference example 61, 2,4-dichloropyrimidine (1.04 g, 7.00 mmol) and triethylamine (1.07 mL, 7.70 mmol) were added and the mixture was stirred at room temperature for 1 hour. To the mixture solution, water was added. The extraction was carried out by using ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 95:5-85:15) to obtain 2-chloro-4-[4-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazin-1-yl]pyrimidine 1.68 g (ethyl acetate/hexane=4:1, Rf=0.1, yield 62%) and 4-chloro-2-[4-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazin-1-yl]pyrimidine 100 mg (ethyl acetate/hexane=4:1, Rf=0.5, yield 4%).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:24]=[CH:23][C:10]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=3[CH3:22])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:12]([CH2:11][C:10]1[CH:23]=[CH:24][C:7]([O:6][C:5]2[CH:25]=[CH:26][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[CH3:22])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(NCc2ccc(Oc3ccc(Br)cc3)cc2)cccc1[N+](=O)[O-]
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3ccc(Br)cc3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 64B and benzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[H-].[Li+].Cl[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:17][CH2:16][N:7]1[C:6]2[CH:12]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1COc2ccc(Br)cc2N1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1COc2ccc(Br)cc2N1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
In N,N-dimethylformamide (4 ml) was dissolved 6-bromo-2H-1,4-benzoxazin-3(4H)-one (200 mg, 0.88 mmol). The solution was cooled in an ice bath, the reaction vessel was charged with nitrogen gas, lithium hydride (purity 90%, 11.7 mg, 1.32 mmol) was then added thereto and the mixture was stirred at room temperature for 10 minutes. Thereafter, benzyl chloromethyl ether (0.20 ml, 1.44 mmol) was added dropwise to the reaction solution at the same temperature and the mixture was stirred at the same temperature for 1.5 hours. Thereafter, lithium hydride (purity 90%, 2.3 mg, 0.26 mmol) and benzyl chloromethyl ether (0.04 ml, 0.29 mmol) were added while continuing stirring, whereby the reaction was quenched. The reaction solution was diluted with dichloromethane, washed with water (×4), dried over anhydrous magnesium sulfate and filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 278 mg (91%) of the title compound in the form of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH:23]1([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: IC1CCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(C3CCCC3)CC2)cc1

Procedure:
A mixture of 1-(4-nitrophenyl)piperazine (12 g, 57.9 mmol) (Acros Organics), powdered potassium carbonate (5.4 g, 39 mmol), iodocyclopentane (7 mL, 60.8 mmol) (Aldrich) and a catalytic amount of 18-crown-6 in acetonitrile (90 mL) was heated at reflux overnight. The mixture was filtered, and the filter cake was washed with acetonitrile. The solvent was evaporated from the combined filtrates and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, evaporated to a yellow solid and dried under vacuum to give 1-cyclopentyl-4-(4-nitrophenyl)piperazine) (6.6 g, 41%.)
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=[O:5].[N-:15]=[N+:16]=[N-:17].[Na+].CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:15]([CH2:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=[O:5])=[N+:16]=[N-:17]
Reactant: N=C(N)Nc1nc(C(=O)CBr)cs1
Reactant: [N-]=[N+]=[N-]
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A mixture of 50 g (0.14 mol) of 2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide, 23.6 g (0.36 mol) of sodium azide, and 250 ml of dimethylformamide was stirred at room temperature for 1.5 hours. The mixture was poured into 1.5 liters of water, and the aqueous solution was made basic with solid sodium carbonate. The resulting precipitate was filtered, washed well with water, and dried, thereby affording 30.6 g (93%) of 2-azido-1-(2-guanidino-4-thiazolyl)ethanone as a light brown crystalline solid, mp 177° (dec). Analytically pure material can be prepared by recrystallization from absolute ethanol: Calcd. for C6H7N7OS: C, 32.00; H, 3.13; N, 43.53; S. 14.24; found: C, 32.22; H, 3.43; N, 41.93; S, 13.97.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[NH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N(CC)CC)C>>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([NH:22][S:2]([C:5]1[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=1)(=[O:3])=[O:4])[CH2:24]2.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Solvent: CCN(CC)CC
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)NC3CN4CCC3CC4)cc2c2cc[nH]c12
Yield: 8.2 %

Procedure:
This compound is prepared according to synthesis 25, from 200 mg (0.6 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2), 100 mg (0.8 mmol) of 3-aminoquinuclidine (in free form) and 170 μL (1.22 mmol) of triethylamine. After purification by chromatography on silica (eluent chloroform/methanol/ammonia 85/13/2), 11 mg (4%) of 8-(1-azabicyclo[2.2.2]oct-3-ylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
To a stirred suspension of 4-chlorophenylacetic acid (85.3 g) in 500 ml of toluene, 45 ml of thionyl chloride (74.4 g) are added. The resulting mixture is stirred at RT, heated slowly to boiling, and stirred overnight under reflux. After cooling the reaction mixture to RT, the solvent is evaporated in vacuo. Distillation of the residue affords 38.15 g of a red liquid.
Reaction SMILES: [CH:1](/[P:4](=[O:15])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:2]\[CH3:3].[O-2].[Al+3].[O-2].[O-2].[Al+3].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:3]/[CH:2]=[CH:1]/[P:4](=[O:15])([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C/P(=O)(OC(C)(C)C)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [O-2]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OP(=O)(/C=C/CBr)OC(C)(C)C
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
(1)-2 To a solution of di-tert.-butyl trans-1-propenylphosphonate (12.0 g.) in carbon tetrachloride (120 ml.) were added basic aluminum oxide (24.0 g.), N-bromosuccinimide (10.95 g.) and then dibenzoylperoxide (1.4 g.) The mixture was heated to reflux for an hour and then stirred for 30 minutes under ice-cooling. The resultant mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give oily di-tert.-butyl 3-bromo-trans-1-propenylphosphonate (17.2 g.).