Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20](OCC)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Product: CCOCc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Temperature: 110 °C
Yield: 92.3 %

Procedure:
A solution of ethyl 3-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (5.0 g, 15 mmol) and morpholine (10 mL, 100 mmol) was heated overnight in a high-pressure vessel at 90° C. An analysis by HPLC indicated the reaction was incomplete. The reaction was then heated overnight in a high-pressure vessel at 110° C., allowed to cool to ambient temperature, and concentrated under reduced pressure to provide 5.1 g of 2-(ethoxymethyl)-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16]>CCOCC>[C:15](=[O:16])([O:7][CH2:1][CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1)[O:17][CH2:18][Cl:19]
Reactant: O=C(Cl)OCCl
Reactant: OCC1CCCO1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCCl)OCC1CCCO1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.7 %

Procedure:
Tetrahydrofurfuryl alcohol (19.4 g) was dissolved in anhydrous ether (500 ml) and, after adding pyridine (15 g) under ice cooling, chloromethyl chloroformate (25 g) was added dropwise. After the reaction mixture was stirred at room temperature for 17 hours, the deposited pyridine hydrochloride was removed by filtration and the filtrate was washed with ether (50 ml×2). The washings and the filtrate were combined, washed with water (300 ml×2) and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain chloromethyl (2,3,4,5-tetrahydrofurfuryl) carbonate (33.9 g) as a colorless oily product.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([C:8]1[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=1)([CH3:7])([CH3:6])[CH3:5].NN>C(Cl)Cl>[CH3:1][N:2]([C:14]([NH:13][C:11]1[S:12][C:8]([C:4]([CH3:7])([CH3:6])[CH3:5])=[N:9][N:10]=1)=[O:15])[NH2:3]
Reactant: CNN
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Agent: NN
Solvent: ClCCl
Product: CN(N)C(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C

Procedure:
A solution of methylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-t-Butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-methyl-4-(5-t-butyl-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][CH2:22][CH:21]=[CH2:20])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.5 %

Procedure:
6-Methoxy-2-naphthol (22.1 g, 127.0 mmol) was dissolved in acetone (200 ml). Potassium carbonate (70.2 g, 508.0 mmol) and allyl bromide (16.5 ml, 191.0 mmol) were added to the resulting solution followed by stirring for 2 days at room temperature. After the reaction mixture was filtered, the organic solvent was distilled off under reduced pressure. Water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The organic solvent was distilled off again to give 6-methoxy-2-(2-propenyloxy)naphthalene (24.9 g, Yield 91%) as a crude product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:40][O:41][CH2:42][C:43]1[CH:63]=[C:62]([Cl:64])[C:46]2[O:47][C:48]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[O:49][C:45]=2[C:44]=1[Cl:65]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][CH2:42][C:43]2[CH:63]=[C:62]([Cl:64])[C:46]3[O:47][C:48]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:49][C:45]=3[C:44]=2[Cl:65])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Reactant: NOCc1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCc4cc(Cl)c5c(c4Cl)OC(c4ccccc4)(c4ccccc4)O5)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 104 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (52 mg) (0.088 mmol) and 47 mg (0.11 mmol) of 5-[(aminooxy)methyl]-4,7-dichloro-2,2-diphenyl-1,3-benzodioxol are dissolved in 1 ml of absolute dimethylacetamide. After stirring at room temperature for 20 hours the solvent is removed in a high vacuum at room temperature and the residue is crystallized by the addition of diethyl ether. The product is filtered off and washed in succession with diethyl ether and water. After drying in a high vacuum at room temperature there are obtained 88 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(4,7-dichloro-2,2-diphenyl-1,3-benzodioxol-5-yl)methoxy]imino]acetamido]-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid as a yellow powder.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:17]2[CH2:22][CH2:21][C@@H:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(OC(Cl)=O)C.O.[NH3:37]>C1COCC1>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:24](=[O:29])[C:25]([CH3:26])([CH3:28])[CH3:27])[C@H:17]2[CH2:22][CH2:21][C@@H:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10]([NH2:37])=[O:11])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N(C(=O)C(C)(C)C)[C@H]2CC[C@@H](C)CC2)C[C@H]1C(=O)O
Reactant: N
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](N(C(=O)C(C)(C)C)[C@H]2CC[C@@H](C)CC2)C[C@H]1C(N)=O
Reaction time: 1 h

Procedure:
To a solution of (4S)-1-BOC-4-[(2,2-dimethylpropanoyl)(cis-4-methyl-cyclohexyl)amino]-L-proline (0.83 g, 2.05 mmol) prepared in Step C in THF was added dropwise TEA (0.32 ml, 2.27 mmol). Then, ethylchloroformate (0.24 g, 2.27 mmol) was slowly added dropwise at 0° C., and the reaction solution was stirred at the same temperature for 1 h. 28% Ammonia water (1 equivalent) was slowly added dropwise at 0° C., and stirred at the same temperature for additional 1 h. After the reaction finished, the reaction mixture was concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with brine, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=2/1) to give the title compound (0.62 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[C:29]([Cl:36])[CH:28]=1.CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:35])=[C:29]([Cl:36])[CH:28]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 11.1) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 2 days under reflux conditions to give the title compound as brown solid. MS: m/e=537.1 [M+H+].
Reaction SMILES: [C:1]([N:5]([C:7]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)=[O:8])[NH2:6])([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH:22]([CH:26]([CH3:29])[CH2:27][CH3:28])[C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.[OH-].[Na+]>[C:1]([N:5]([C:7]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)=[O:8])[NH:6][C:23](=[O:24])[CH:22]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:26]([CH3:29])[CH2:27][CH3:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(=O)N(N)C(C)(C)C)c1
Reactant: CCC(C)C(C(=O)Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC(C)C(C(=O)NN(C(=O)c1cccc(C)c1)C(C)(C)C)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred suspension of N'-t-butyl-N'-(3-toluoyl)hydrazine (0.7 g) in toluene (10 ml) and aqueous sodium hydroxide (12 drops of 50% aqueous sodium hydroxide) was added dropwise 2-phenyl-3-methyl-pentanoyl chloride (1.0 g). The reaction mixture was stirred overnight, diluted with hexanes and the solids filtered. The solids were washed with hexane and air dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1)(=[O:19])[CH3:18]
Reactant: Oc1ccc(F)c(Br)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(F)c(Br)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
A solution of 3-bromo-4-fluorophenol (4.5 g, 23 mmol) [Ark Pharm, AK-26802] in dichloromethane (96 mL) at 0° C. was treated with triethylamine (4.9 mL, 35 mmol) followed by acetyl chloride (2.3 mL, 33 mmol) dropwise and stirred at 20° C. for 30 minutes. The reaction mixture was diluted with dichloromethane (100 mL), washed with 0.5 M hydrogen chloride in water (100 mL), saturated sodium bicarbonate (100 mL), and brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (5.5 g, quantitative) as a tan solid. This material, which did not ionize in the mass spectrometer, was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]3[C:21](=[O:22])[CH2:20][O:19][C:18]3=[O:23])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:24][NH2:25]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[O:19][CH2:20][C:21]([NH:25][CH3:24])=[O:22])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C1COC(=O)N1CCc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 79.3 %

Procedure:
0.46 g (1.39 mmol) of 3-(2-(4-[(4-chlorophenyl)oxy]phenyl)ethyl)-1,3-oxazolidine-2,4-dione, prepared in step 14.2., is redissolved in a mixture of 3 ml of tetrahydrofuran and 6 ml of methanol. 3 ml of a 2M solution of methylamine (6 mmol) in tetrahydrofuran are added. The mixture is left to react at ambient temperature overnight and then 2 g of silica are added and the mixture is evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 98/2 then 96/4 and 94/6 mixture of dichloromethane and methanol. The product is recrystallized from a mixture of ethyl acetate and diisopropyl ether, to give 0.40 g of product in the form of a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.CO[CH:23](OC)[CH2:24][NH:25][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][CH2:23][CH2:24][NH:25][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:27])=[O:28])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: COC(CNS(=O)(=O)NC(=O)OC(C)(C)C)OC
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 24.2 %

Procedure:
A mixture of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (103 mg, 0.302 mmol, 1.5 equiv.; Step D) and tert-butyl N-(2,2-dimethoxyethyl)sulfamoylcarbamate (57.2 mg, 0.201 mmol) in dichloromethane (1.0 mL) was stirred under N2 at room temperature. To this mixture was added trifluoroacetic acid (0.50 mL, 6.5 mmol) and triethylsilane (80.2 μL, 0.502 mmol, 2.5 equiv.) drop-wise. This reaction mixture was stirred at room temperature for 2 h. HPLC indicated approximately 30% conversion. The reaction mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate to pH ˜8. The mixture was extracted in ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (50% ethyl acetate/hexane) to give the desired product (27.5 mg, 29.5%) as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.90 (s, 1H), 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.59 (t, J=8.6 Hz, 1H), 6.58 (t, J=5.7 Hz, 1H), 3.38 (dd, J=12.7, 6.2 Hz, 2H), 3.10 (dd, J=12.1, 5.9 Hz, 2H), 1.41 (s, 9H). C17H19BrFN7O7S (MW 564.34), LCMS (EI) m/e 485.8/487.8 (M+-C5H8O2+Na).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O[N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16]>CN(C=O)C>[C:1]([O:8][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 5 h
Yield: 74.3 %

Procedure:
To a solution of 4.64 g (0.04 mol) of hexanoic acid and 5.75 g (0.05 mol) of N-hydroxy succinimide in 100 mL distilled DMF, 10.3 g (0.05 mol) of DCCl was added. The mixture was cooled with an ice-water bath and stirred for 5 h. The dicyclohexyl urea (DCU) precipitate was removed by filtration, and the DMF solvent was removed by vacuum rotary evaporation. The yellow oil residue was washed with water and hexane to yield a white solid, which was vacuum dried at 78° C. to give 6.34 g (74%) of N-hexanoyloxy succinimide. IR (KBr): 1816 cm−1 (ν(C═O) of ester), 1745-1786 cm−1 (ν(C═O) of imide). 1H-NMR (DMSO-d6, ppm): 0.86 (3H, —CH3), 1.31 (4H, —(CH2)2CH3), 1.62 (2H, CH2CH2COO—), 2.64 (2H, —CH2COO—), 2.80 (4H, —COCH2CH2CO—).
Reaction SMILES: Cl.C([O:5][CH2:6][N:7]([N+:23]([O-:25])=[O:24])[CH2:8][N:9]([N+:20]([O-:22])=[O:21])[CH2:10][N:11]([N+:17]([O-:19])=[O:18])[CH2:12][O:13]C(=O)C)(=O)C>>[OH:13][CH2:12][N:11]([N+:17]([O-:19])=[O:18])[CH2:10][N:9]([N+:20]([O-:22])=[O:21])[CH2:8][N:7]([N+:23]([O-:25])=[O:24])[CH2:6][OH:5]
Reactant: CC(=O)OCN(CN(CN(COC(C)=O)[N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Agent: Cl
Product: O=[N+]([O-])N(CO)CN(CN(CO)[N+](=O)[O-])[N+](=O)[O-]
Yield: 75 %

Procedure:
The weight percentage ranges for hydrogen chloride in the concentrated aqueous hydrochloric acid are critical. Concentrated hydrochloric acid (37 weight percent hydrogen chloride) failed to hydrolyze 1,7-diacetoxy-2,4,6-trinitro-2,4,6-triazaheptane to 1,7-dihydroxy-2,4,6-trinitro-2,4,6-triazaheptane. Aqueous hydrochloric acid solutions containing 20 and 25 weight percent of hydrogen chloride produced 1,7-dihydroxy-2,4,6-trinitro-2,4,6-triazaheptane in low yield with undesirable impurities. However, concentrated aqueous hydrochloric acid containing 30 weight percent hydrogen chloride was used to hydrolyze 1,7-diacetoxy-2,4,6-trinitro-2,4,6-triazaheptane to produce 1,7-dihydroxy-2,4,6-trinitro-2,4,6-triazaheptane in 75 percent yield. The product was sufficiently pure to be used as a monomer for energetic polymers without a purification step.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1COCC1>[CH3:15][S:16]([O:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1)(=[O:18])=[O:17]
Reactant: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Temperature: 3 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
In a 4 neck 5 L flask was added (R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 719 mmol) in 2.5 L of THF. The material was cooled to 3° C. and methanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portions over 10 minutes. N-ethyl-N-iospropylpropan-2-amine (126 ml, 719 mmol) was added through an addition funnel over 12 minutes. The reaction was stirred in an ice bath for 30 minutes and then at ambient temperature for 1 hour. The reaction was filtered and the solids washed with MTBE (3 L). The filtrate was concentrated and the residue was purified over silica gel (3 kg silica, 7:1 to 3:1 Hexane/EtOAc) to afford an oil that slowly solidified under vacuum. The solids were ground using a mortar and pestle, washed with hexanes (about 1000 mL) and dried to afford (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 531 mmol, 73.8% yield) as a white solid.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:49][NH:50][O:51][CH3:52].O>C(Cl)Cl>[C:17]([O:16][C:14](=[O:15])[NH:1][CH:2]([C:11](=[O:13])[N:50]([O:51][CH3:52])[CH3:49])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of Boc-Phe(4-F)-OH (5.0 g, 17.7 mmol) in methylene chloride (89 ml), BOP reagent (9.39 g, 21.2 mmol), N,O-dimethylhydroxylamine hydrochloride (2.07 g, 21.2 mmol) and TEA (5.92 ml, 42.5 mmol) were added under cooling with ice and stirred for 30 min. The reaction mixture was mixed with water and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving the titled compound (5.76 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N+:11]([O-:13])=[O:12].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]2=[N:10][N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])Nc1ccccn1
Reactant: ClCc1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])N=c1ccccn1Cc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
2-Chloro-5-chloromethylpyridine (3.24 g) and 2-nitraminopyridine (2.78 g) were dissolved in anhydrous ethanol (50 ml), and triethylamine (4.04 g) was added to the solution. The mixture was stirred at room temperature for a while. Then, it was heated under reflux conditions for 8 hours. The reaction mixture was cooled to room temperature, and poured into ice water. The precipitated crystals were collected by filtration, and recrystallized from ethanol to give pale yellow 1-(2-chloro-5-pyridylmethyl)-2-nitroimino-1,2-dihydropyridine (2.3 g) as the desired compound. mp. 209°-212° C.
Reaction SMILES: CN(C)[C:3](=[CH2:11])[C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5].Cl.[NH2:14]O>CO>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4]1[O:5][N:14]=[CH:11][CH:3]=1
Reactant: NO
Reactant: C=C(C(=O)c1cccs1)N(C)C
Agent: Cl
Solvent: CO
Product: c1csc(-c2ccno2)c1
Yield: 93.3 %

Procedure:
A mixture of Compound 3 (18.1 g, 100 mmol) and hydroxylamine hydrochloride (7.0 g, 101 mmol) in 100 mL of anhydrous methanol was refluxed under nitrogen for 2 hours. The reaction mixture was cooled, concentrated and partitioned between water and dichloromethane. The dichloromethane layer was dried with anhydrous sodium sulfate, filtered and concentrated as to yield compound 4 as a dark yellow-orange oil (14.1 g, 93.3 mmol, 93%). GC/MS, m/z=151 at tR=8.30 min (100%). LC/MS,[M+H]=152.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:21][C:22]([C:25]1[CH:26]=[CH:27][C:28]([O:33][C:34]([F:37])([F:36])[F:35])=[C:29]([CH:32]=1)[CH:30]=O)([F:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:30][C:29]2[CH:32]=[C:25]([C:22]([F:24])([F:21])[CH3:23])[CH:26]=[CH:27][C:28]=2[O:33][C:34]([F:35])([F:37])[F:36])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(F)(F)c1ccc(OC(F)(F)F)c(C=O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 156.8 %

Procedure:
To a stirred solution of Compound 12 (500 mg, 1.81 mmol) and Compound 25 (552 mg, 2.17 mmol) in dry CH2Cl2 (10 ml) was added sodium triacetoxyborohydride (1.15 g, 5.43 mmol) portionwise at room temperature. Then to this was added acetic acid (109 mg, 1.81 mmol) at same temperature. The reaction mixture was stirred at room temperature for 66 h. The reaction mixture was basified to pH10-11 with 10% NaOH aq. with ice-cooling. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with brine, dried (MgSO4), and concentrated in vacuo to give crude product (1.46 g) as a pale yellow oil. This was employed for the next step without further purification.