Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[CH2:11][CH3:12].C(OC(N1CCC(CC(Br)=O)CC1)=O)(C)(C)C>>[CH2:11]([C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1)[CH3:12]
Reactant: CCC(=O)CBr
Reactant: Nc1ccccn1
Agent: CC(C)(C)OC(=O)N1CCC(CC(=O)Br)CC1
Product: CCc1cn2ccccc2n1

Procedure:
The title compound was prepared from 2-aminopyridine and 1-bromo-2-butanone, employing procedures analogous to those described for Piperidine 1. 1H NMR (500 MHz, CDCl3) δ 1.34 (t, J=7.3 Hz, 3H), 2.82 (q, J=7.6 Hz, 2H), 6.70 (t, J=6.6 Hz, 1H), 7.10 (m, 1H), 7.32 (s, 3H), 7.51 (d, J=8.9 Hz, 1H), 8.03 (dd, J=6.6, 0.9 Hz, 1H).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][O:13]C2=O)=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]>CO.O>[OH:13][CH2:14][CH2:15][NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[C:6]([N+:17]([O-:19])=[O:18])[CH:7]=1
Reactant: COc1ccc(N2CCOC2=O)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(NCCO)cc1[N+](=O)[O-]

Procedure:
Solid potassium hydroxide (3.5 g) is dissolved in methanol (100 ml). To the obtained solution the 3-(4-methoxy-3-nitrophenyl)-1,3-oxazolidin-2-one of step 1.1 (5 g) is added whereupon a yellow suspension is formed. Then the reaction mixture is heated under reflux for 5 hours and a red solution is obtained. With stirring, diluted acetc acid (3.7 g in 20 ml water) is added dropwise to the warm solution and the reaction mixture is cooled down to from about 0° C. to about 5° C. An orange suspension is obtained, which is filtered. The resulting solid is dried.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[N:23][CH:24]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[N:23][CH:24]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: Nc1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(Cl)nc3)cccc12
Reaction time: 72 h
Yield: 42.7 %

Procedure:
A solution of 5-dimethylamino-1-naphthalenesulphonyl chloride (1.35 g), 5-amino-2-chloropyridine (0.64 g), pyridine (0.4 g) and 4-dimethylaminopyridine (0.02 g) in dichloromethane (20 ml) was allowed to stand for three days. The solution was divided into two equal portions and each portion was applied to a separate silica gel Mega Bond Elut column. The columns were eluted with dichloromethane and the product-containing fractions were concentrated by evaporation. The residue was triturated with ether to give 5-(dimethylamino)-N-(2-chloro-5-pyridyl)-1-naphthalenesulphonamide (0.77 g); m.p. 145-146° C.; mass spectrum (+ve FAB, methanol/NBA): 362(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].CO[C:15]1C(OC)=C[C:18]2[NH:19][C:20](CCCNC)=N[C:17]=2[CH:16]=1>>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:11]=[C:15]([CH2:16][CH2:17][CH2:18][NH:19][CH3:20])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Product: CNCCCc1nc2c(C(=O)OC)cccc2[nH]1

Procedure:
Prepared from 2,3-diamino-benzoic acid methyl ester (J. Med. Chem. 2000, 43(22), 4084-4097) in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:32]2[N:36]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:35]=[N:34][N:33]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:8]=2)[CH:6]=1.C([Li])CCC.Cl[C:62]([O:64][CH2:65][CH3:66])=[O:63]>O1CCCC1.CN(C)CCN(C)C>[Si:15]([O:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH:3]=[C:4]2[C:32]2[N:36]([C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:35]=[N:34][N:33]=2)=[CH:8][CH:9]=1)([C:28]([CH3:29])([CH3:31])[CH3:30])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)[Si](OCc1ccc(-n2cc(Br)cc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)(c1ccccc1)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)n(-c2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)c1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-bromo-1-(4-tert-butyldiphenylsilyloxymethylphenyl)-2-(1-trityl-1H-tetrazol-5-yl)pyrrole (500 mg) in a mixture of tetrahydrofuran (5 ml) and N,N,N',N'-tetramethylethylenediamine (0.19 ml) was added n-butyl lithium (0.41 ml; 1.6M in n-hexane) at -78° C. under nitrogen atmosphere and the mixture was stirred at the same temperature for half an hour. Ethyl chloroformate (0.3 ml) was added to the mixture at the same temperature and the resulting mixture was stirred at -78° C. for half an hour, at 0° C. for one hour and then at ambient temperature for two hours. The reaction was quenched with aqueous saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated and the residue was purified by flash chromatography eluted with a mixture of ethyl acetate-n-hexane 1:9 (V/V) to give 1-(4-tert-butyldiphenylsilyloxymethylphenyl)-4-ethoxycarbonyl-2-(1-trityl-1H-tetrazol-5-yl)pyrrole (311 mg) as a colorless viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[H-].[Na+].Br[CH2:26][C:27]1[CH:35]=[CH:34][C:30]2=[N:31][S:32][N:33]=[C:29]2[CH:28]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]3=[N:31][S:32][N:33]=[C:29]3[CH:28]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: BrCc1ccc2nsnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2nsnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (600 mg) in DMF (6 ml) was added sodium hydride (60% in oil, 74 mg) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 1 hr. To the reaction mixture was added 5-bromomethylbenzo[2,1,3]thiadiazole (460 mg) at room temperature, and the mixture was stirred for 2 hrs. Water was added to the reaction mixture and crystals were collected by filtration, washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate. The crystals were collected by filtration, combined with the crystals obtained earlier, and subjected to silica gel column chromatography (THF) and further to recrystallization (THF-ethyl acetate) to give the title compound (450 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH3:20])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:27][CH3:28])=[C:5]([CH3:29])[O:4][N:3]=1.CC1C([C:36]2C=C3C(C(NCC4SC(C)=NC=4C)=C(C(N)=O)C=N3)=C[C:37]=2[O:58][CH3:59])=C(C)ON=1.COCC(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:27][CH3:28])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH3:20])[C:36]([CH2:37][O:58][CH3:59])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: COc1cc2c(NCc3sc(C)nc3C)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Reactant: COc1cc2c(NC(C)c3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1C(C)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-N4-[1-(2-pyridinyl)ethyl]-3,4-quinolinediamine (for a preparation see Intermediate 65, 250 mg) in DCM (20 ml) was added (methyloxy)acetic acid (116 mg) followed by HATU (1.2 equiv) and triethylamine (1.5 equiv). The reaction mixture was stirred at room temperature for 1 h, and was then hydrolysed using a saturated solution of sodium hydrogen carbonate. The mixture was extracted with DCM and the organic dried over Na2SO4, filtered and concentrated to dryness. The resulting product was dissolved in ethanol (60 ml) and a solution of sodium hydroxide (1N, 15 ml) was added. The reaction mixture was heated to 90° C. for 16 h and was then allowed to cool to room temperature. DCM (150 ml) and water (100 ml) were added. The phases were separated and the organic phase was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography eluting with DCM/methanol (95:5). The resulting residue was taken-up in acetonitrile, washed with diethyl ether and dried in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-2-[(methyloxy)methyl]-1-[1-(2-pyridinyl)ethyl]-1H-imidazo[4,5-c]quinoline (90 mg) as a beige powder.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11]CC2C=CC=CC=2)=[CH:7][N:6]=1)([CH3:4])[CH3:3]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:4][C:2]([C:5]1[N:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(OCc2ccccc2)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(O)cn1

Procedure:
To a stirred solution of 2-(1,1-dimethylethyl)-5-[(phenylmethyl)oxy]pyridine, (5.3 g) in ethanol (150 ml) was added 20% Pd(OH)2 (12.3 g) at 25-30 C. The above mixture was purged with hydrogen for 3 h until it had gone to completion by tlc. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo and purified to give the title compound, 3.9 g
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C@@H:20]2[C@H:21]([C:23]([OH:25])=O)[CH2:22][C@@:16]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:17]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[CH2:18][CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClCCl.[NH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>>[CH2:8]([N:15]1[C@@H:20]2[C@H:21]([C:23]([N:51]3[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)=[O:25])[CH2:22][C@@:16]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:17]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[CH2:18][CH2:19]2)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A 0.07M solution of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate (Example 53) in dichloromethane (2.5 ml, 0.18 mmol) was added to a mixture of piperidine (0.25 ml, 2.5 mmol), triethylamine (0.1 ml, 0.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.34 mmol), and 4-N,N-dimethylaminopyridine (12 mg, 0.1 mmol). The mixture was stirred at room temperature overnight and purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (100 mg, 88%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[CH:18]>>[C:19]1([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1ccccc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(C#Cc3ccccc3)c2c2ccccc12
Yield: 68.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and ethynyl benzene (66 mg, 0.65 mmol) to provide 161 (87 mg, 67% yield) as a light-yellow solid. LC-MS (M+H=297, obsd.=297).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][NH2:7].C([O-])(=O)C.[Na+].Cl.[CH:14]([C@@H:16]1[C@:24]2([CH3:25])[C@@:19]([OH:32])([CH2:20][C@@H:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:23]2)[CH2:18][CH2:17]1)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[NH2:3][CH2:4][CH2:5][O:6]/[N:7]=[CH:14]/[C@@H:16]1[C@:24]2([CH3:25])[C@@:19]([OH:32])([CH2:20][C@@H:21]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:23]2)[CH2:18][CH2:17]1
Reactant: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2C=O
Reactant: NCCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2/C=N/OCCN
Yield: 69.4 %

Procedure:
To a solution of 6.30 g of 0.12 g of 2-aminoethoxyamine dihydrochloride, 0.28 g of sodium acetate in 2 ml of dioxane and 1 ml of water was made aid to pH 4.5 with 3N HCl. A solution of 0.20 g of (1S,3aS,5S,7aR)-1-formyl-5-phenyl -7a-methylperhydroinden-3a-ol in 1 ml of dioxane and 0.5 ml of water was added dropwise at room temperature. After 1 hr the solution was alkalinized with 10% aqueous Na2CO3 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was ground with diethyl ether to give 0.17 g of the title compound (I-am) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7])[CH3:3].[CH2:10](O)[CH3:11]>S(=O)(=O)(O)O>[CH3:1][N:2]([CH2:4][C:5](=[CH2:9])[C:6]([O:8][CH2:10][CH3:11])=[O:7])[CH3:3]
Reactant: CCO
Reactant: C=C(CN(C)C)C(=O)O
Agent: O=S(=O)(O)O
Product: C=C(CN(C)C)C(=O)OCC
Reaction time: 3 h
Yield: 55 %

Procedure:
A solution of 2-dimethylaminomethylacrylic acid (129g) in concentrated sulphuric acid (105 ml, 98%) and ethanol (500 ml) was boiled under reflux for 3 hours. After evaporating to half volume and pouring the residue into water (1 liter), anhydrous sodium carbonate (212g) was added and the solution was allowed to stand for 3 hours, when it gave a neutral reaction. The aqueous mixture was extracted with ether (3 × 250 ml), after drying over anhydrous sodium sulphate, the ether extract was evaporated at atmospheric pressure. The residual pale yellow oil was distilled under reduced pressure to give ethyl 2-dimethylaminomethylacrylate (86g, 55% boiling point 84° C/20 mm).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:12])[CH2:10][C:9](=O)[O:8][C:6](=[O:7])[CH2:5]1>O1CCCC1>[CH3:3][C:4]1([CH3:12])[CH2:10][CH2:9][O:8][C:6](=[O:7])[CH2:5]1
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCOC(=O)C1
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A suspension of 5.8 g (0.15 mole) of sodium borohydride in 30 ml of dry tetrahydrofuran was stirred and cooled in an ice bath under nitrogen while 21.32 g (0.15 mole) of 3,3-dimethyl glutaric anhydride in 120 ml of dry tetrahydrofuran was added in 5 minutes. The ice bath was then removed and stirring was continued for 2 hours. Hydrochloric acid (6N, 60 ml) was added cautiously and the mixture was then concentrated in vacuo. Water (300 ml) was added and the mixture was extracted with ethyl ether. The ethyl ether extract was dried over anhydrous Na2SO4, concentrated in vacuo and distilled (60°, 1 mm Hg) giving 13.1 g (68.2%) of 3,3-dimethyl valerolactone with consistent 1H-NMR spectral data. This lactone (5 g, 39.04 mmole) and triphenyl phosphine hydrobromide (13.56 g, 39.04 mmole) were heated neat under nitrogen at 175° (oil bath temperature) for 3.5 hours. The reaction mixture was cooled to room temperature, diluted with 100 ml of water-ethyl acetate (1:1) and the phases were separated. The aqueous phase was washed again with ethyl acetate, treated with charcoal, filtered and lyophilized to yield 12 g (65.2%) of 4-carboxy-3,3-dimethylbutyltriphenylphosphonium bromide with consistent 1H-NMR spectral data. This was dried (65°, 0.3 mm Hg, 18 hours) prior to use.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]([CH:18]4[CH2:22][CH2:21][N:20]([CH2:23][C:24](=[O:43])[N:25]5[CH2:30][CH2:29][N:28]([C:31]6[CH:36]=[CH:35][C:34]([C:37]7[N:42]=[CH:41][CH:40]=[CH:39][N:38]=7)=[CH:33][CH:32]=6)[CH2:27][CH2:26]5)[CH2:19]4)=[O:17])[CH:13]=3)[N:8](COCC[Si](C)(C)C)[N:7]=2)=[N:4][N:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:4]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]([CH:18]4[CH2:22][CH2:21][N:20]([CH2:23][C:24](=[O:43])[N:25]5[CH2:30][CH2:29][N:28]([C:31]6[CH:32]=[CH:33][C:34]([C:37]7[N:38]=[CH:39][CH:40]=[CH:41][N:42]=7)=[CH:35][CH:36]=6)[CH2:27][CH2:26]5)[CH2:19]4)=[O:17])[CH:13]=3)[NH:8][N:7]=2)=[N:1][N:2]=[N:3]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2nnn[nH]2)c2cc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3nnn[nH]3)c2c1)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.6 %

Procedure:
To a solution of 31 from Step 1 (31 mg, 0.054 mmol, 2 isomers) in CH2Cl2 (2 mL) was added TFA (2 mL) at rt. The crude was stirred at rt for 5 hrs. The crude was evaporated and quenched with sat. NaHCO3 at rt. The crude was evaporated and filtered through a plug of silica gel and evaporated. The crude was purified via preparation plate to give 13 mg of the product.
Reaction SMILES: CN(C)C=O.[C:6](=[O:26])([O:22][CH:23](Cl)[CH3:24])[O:7][CH2:8][CH2:9][CH2:10][C@@H:11]([O:18][N+:19]([O-:21])=[O:20])[C@H:12]([O:14][N+:15]([O-:17])=[O:16])[CH3:13].[CH2:27]([C:31]1[N:32]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]3[N:57]([C:58]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[N:56]=[N:55][N:54]=3)=[CH:43][CH:42]=2)[C:33]([C:37]([OH:39])=[O:38])=[C:34]([Cl:36])[N:35]=1)[CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH2:27]([C:31]1[N:32]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]3[N:57]([C:58]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)([C:71]4[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[N:56]=[N:55][N:54]=3)=[CH:45][CH:46]=2)[C:33]([C:37]([O:39][CH:23]([O:22][C:6]([O:7][CH2:8][CH2:9][CH2:10][C@@H:11]([O:18][N+:19]([O-:21])=[O:20])[C@H:12]([O:14][N+:15]([O-:17])=[O:16])[CH3:13])=[O:26])[CH3:24])=[O:38])=[C:34]([Cl:36])[N:35]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Cl)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A N,N-dimethylformamide (20 mL) solution of (4R,5R)-4,5-bis(nitrooxy)hexyl 1-chloroethyl carbonate (1.15 g, 3.48 mmol) was added to a stirred N,N-dimethylformamide (20 mL) suspension of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (2.54 g, 3.74 mmol) and cesium carbonate (1.25 g, 3.84 mmol). The solution was stirred at 70° C. for 2 hours. Water (100 mL) was added, and the solution was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 20-60% ethyl acetate/hexanes to give the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J=7.4 Hz, 1H), 7.49 (dt, J=1.4, 7.6 Hz, 1H), 7.45 (dt, J=1.1, 7.5 Hz, 1H), 7.31-7.36 (m, 4H), 7.26 (t, J=7.8 Hz, 6H), 7.10 (d, J=8.0 Hz, 6H), 6.93 (d, J=7.8 Hz, 2H), 6.86 (q, J=5.5 Hz, 1H), 6.79 (d, J=8.0 Hz, 2H), 5.54 (d, J=15.4 Hz, 1H), 5.32 (d, J=16.2 Hz, 1H), 5.14-5.24 (m, 2H), 4.10-4.20 (m, 2H), 2.50 (t, J=7.8 Hz, 2H), 1.7-1.9 (m, 4H), 1.62 (quintet, J=7.7 Hz, 2H), 1.54 (d, J=5.5 Hz, 3H), 1.37 (d, J=6.1 Hz, 3H), 1.27 (sextet, J=7.4 Hz, 2H), 0.85 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[C:3](=[N:4][O:5][N+:6]=2[O-:10])[CH:2]=1.C1CC[N:19]2[C:14](=[N:15]CCC2)CC1.N#CN.C(O)(=O)C>CC(C)=O>[CH:1]1[CH:9]=[CH:8][C:7]2[N+:6]([O-:10])=[N:15][C:14]([NH2:19])=[N+:4]([O-:5])[C:3]=2[CH:2]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: [O-][n+]1onc2ccccc21
Agent: N#CN
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: Nc1n[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 42.4 %

Procedure:
To a solution containing 3.77 g (27.7 mmoles) of benzofuroxan in 8.44 g (55.4 mmoles) of DBU was added portionwise with cooling 2.33 g (55.5 mmoles) of cyanamide. The reaction mixture was stirred at room temperature for 5 days and then diluted with 26 ml of acetone and treated with 4.16 g (69.3 mmoles) of acetic acid. After stirring at room temperature overnight the mixture was further diluted with 30.2 ml of acetone and stirred at room temperature an additional 2.5 hours. The resulting precipitate was collected and washed with 50 ml of acetone and 15 ml of water and then dried under vacuum overnight to give 2.09 g of tirapazamine.