Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[C:16]=3[N:17]=2)=[CH:4][C:3]=1[NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43])(=[O:35])=[O:34].Cl>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])(=[O:34])=[O:35])=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]=3[N:17]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccc(F)cc5F)c4)nc23)CC1
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(NC4CCNCC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(6-(6-chloro-5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (12.0 g, 19.0 mmol; prepared as in Example 1, Step B) in DCM (300 mL) was added HCl (4 M in 1,4-dioxane) at 0° C., and the reaction mixture was stirred for 4 h at room temperature. The solvent was removed by evaporation, and the obtained crude N-(2-chloro-5-(4-(piperidin-4-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide HCl salt was used for the next step without further purification. TEA (26.4 mL, 190 mmol) was added to a suspension of above obtained HCl salt in DCM (300 mL) at 0° C. The mixture was stirred for 1 h at room temperature and isopropyl carbonochloridate (19.0 mL, 19.0 mmol) was added to the reaction mixture at 0° C. The reaction mixture was stirred for 2 h at room temperature. DCM and water were poured into the residue, and the separated aqueous layer was extracted with DCM, the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:MeOH=20:1) to give isopropyl 4-(6-(6-chloro-5-(2,4-difluorophenylsulfonamido)pyridine-3-yl)pyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (9.87 g, 84%) as a pale yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 1.21 (6H, d, J=6.4 Hz), 1.62-1.78 (2H, m), 1.85-1.95 (2H, m), 2.82-3.08 (2H, m), 4.02-4.17 (2H, m), 4.40-4.54 (1H, m), 4.77-4.83 (1H, m), 7.22 (1H, dt, J=2.4, 8.8 Hz), 7.53-7.61 (1H, m), 7.74-7.83 (1H, m), 8.21 (1H, d, J=8.8 Hz), 8.42 (1H, d, J=10.8 Hz), 8.46 (1H, d, J=8.8 Hz), 8.54 (1H, s), 8.66 (1H, d, J=2.4 Hz), 9.39 (1H, d, J=2.4 Hz). NH peak was not observed. m/z=618.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15](OC)=[O:16])[CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[BH4-].[Na+].CO>O1CCCC1>[Br:1][C:2]1[CH:14]=[C:6]([CH:5]=[C:4]([CH2:15][OH:16])[CH:3]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc(Br)cc(CO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of tert-butyl methyl 5-bromoisophthalate (3.63 g, 11.5 mmol) in tetrahydrofuran (90 mL) at 0° C. was added portionwise sodium borohydride (1.53 g, 40.3 mmol). The mixture was stirred at 0° C. After 30 min, methanol (4.2 mL, 92.0 mmol) was added and the mixture was heated to 40° C. After 6 h, the mixture was cooled to ambient temperature and the mixture was quenched with methanol and concentrated. Ethyl acetate was added and the mixture was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (2.7 g).
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH:4]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=O.[CH2:20]([O:23][CH2:24][C:25]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:26])[CH2:21][CH3:22]>O1CCCC1>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:4]1[CH:3]([CH:1]=[CH:27][C:25](=[O:26])[CH2:24][O:23][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:10][C:5]21[O:9][CH2:8][CH2:7][O:6]2
Reactant: CCCOCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Solvent: C1CCOC1
Product: CCCOCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Yield: 150.2 %

Procedure:
A mixture of 7-formyl-6-(7 -hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (4.2 g.) and propoxyacetylmethylenetriphenylphosphorane (7.18 g.) in dry tetrahydrofuran (35 ml.) was heated at reflux under nitrogen for 18 hours. The solvent was removed in vacuo and the residue triturated with a mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate, allowed to stand at 0° C., filtered to remove triphenylphosphine oxide and the filtrate evaporated to dryness to give 6-(7-hydroxyheptyl)- 7-(3-oxo-4 -propoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane (8.6 g.), νmax 1620 cm-1, 1680 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[CH3:21][O:20][C:18]([CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1)=[O:19]
Reactant: COC(=O)CBr
Reactant: Cc1ccc(O)c[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C)[n+]([O-])c1
Reaction time: 0.5 h

Procedure:
A solution of the pyridine N-oxide (a) (21.12 g) in DMF (450 ml) was treated with potassium carbonate (26.2 g) then, after 30 minutes, with methyl bromoacetate (16 ml), and stirred overnight. Solvent was evaporated, saturated brine (500 ml) added and the mixture extracted with chloroform (6×200 ml). The combined organic solution was dried and evaporated and the residue chromatographed (20% EtOH in EtOAc) to give a solid (18.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:26]3[CH:27]=[C:28]([N+:33]([O-])=O)[C:29]([NH2:32])=[N:30][CH:31]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:26]3[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[N:30][CH:31]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: COc1cc2nccc(N3CCOc4ccc(-c5cnc(N)c([N+](=O)[O-])c5)cc4C3)c2cc1OC
Agent: [Pd]
Solvent: CO
Product: COc1cc2nccc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2cc1OC
Reaction time: 18 h
Yield: 92.6 %

Procedure:
A mixture of 5-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-3-nitropyridin-2-amine (135 mg, 0.28 mmol), palladium (10% on charcoal, 135 mg) and methanol (15 mL) was hydrogenated in a Parr apparatus at 45 psi for 18 hours. The mixture was filtered then concentrated to give 5-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyridine-2,3-diamine (115 mg, 91% yield), MS (EI) for C25H25N5O3: 444 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17](O)=[O:18])=[CH:8]1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C(OCC)C>[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][OH:18])=[CH:8]1
Reactant: O=C(O)CC1=CCc2ccccc21
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCCC1=CCc2ccccc21
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A suspension is prepared from 3.4 g (0.09 mol) of lithium aluminium hydride in 200 ml of dry diethyl ether. A solution of 7.7 g (0.044 mol) of 1H-indene-3-acetic acid in 150 ml of diethyl ether is added dropwise, and the mixture is stirred and heated at reflux for 20 h. The mixture is cooled, hydrolysed with approximately 8 ml of 10% aqueous sodium potassium tartrate solution, heated at boiling for 1 h and filtered. The residue is rinsed with diethyl ether, and the filtrate is evaporated under reduced pressure. The residue is purified by distillation. 5.2 g of a product are obtained which is used as it is in the following step.
Reaction SMILES: [CH2:1]([OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(N(CCCC)CCCC)CCC.C1(C)C(S(NN)(=O)=O)=CC=CC=1>>[CH2:20]([OH:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:22]
Reactant: OCCCCCCCCCC=CCCCCCCCCCO
Agent: Cc1ccccc1S(=O)(=O)NN
Solvent: CCCCN(CCCC)CCCC
Product: OCCCCCCCCCCCCCCCCCCCCO
Temperature: 25 °C

Procedure:
Hydrogenation of 10-eicosene-1,20-diol: Two hundred fifty grams of the 10-eicosene-1,20-diol were placed in a twelve liter flask outfitted with a heating mantle, mechanical stirrer, condenser, and nitrogen inlet. Three liters of xylenes were added. Two equivalents each tributylamine and toluenesulfonhydrazide were added. Stirring and nitrogen flow were initiated and the solution slowly heated until the reaction was at reflux. The reaction was refluxed overnight, and then cooled to room temperature. The product, 1,20-eicosanediol, precipitated from solution and was filtered, washing with methanol. The crude product was recrystallized once from methanol, yielding white crystals with a melting point of about 101° C. The product was 99% pure by gas chromatography. IR(KBr): 3419, 3357, 2919, 2848, 1469, 1355, 1321, 1124, 1055, 1034, 999, 969, 722, 610, 502 cm−1; 1H NMR(300 MHz, toluene-d8, elevated temperature): * 3.3 (t, 4H), 1.3 (bd, 36H), 0.5 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17]C)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: Br
Product: Oc1ccc2c(c1)CN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 48.3 %

Procedure:
Combine 2-Benzyl-5-methoxy-2,3-dihydro-1H-isoindol (580.0 mg, 2.42 mmol) and 48% HBr (aq) (20 mL). Reflux the reaction for 5 hours and then cool to room temperature. Concentrate the reaction mixture under reduced pressure then add to 5 g a SCX column. Wash the column with MeOH and elute with 1N NH3-MeOH to afford 265.4 mg, 1.17 mmol (49% yield) of the title compound as a brown solid: 1H NMR (500 MHz, d-Methanol); 3.8-3.9 (4H, m), 3.91 (2H, s), 6.6-6.7 (2H, m), 7.0 (1H, d), 7.2-7.5 (4H, m); MS m/z 226 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH3:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([CH3:25])[S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccccc1
Product: Cc1cc2c(NCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[C:33]([F:39])[CH:32]=1.[Cl-].[NH4+]>CN(C)C=O.O>[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[C:2]([CH3:4])[CH3:3])=[C:33]([F:39])[CH:32]=1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=Cc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of isopropyltriphenylphosphonium iodide (0.65 g, 1.5 mmol) in N,N-dimethylformamide (6 ml) was added slowly a solution of potassium t-butoxide (0.18 g, 1.6 mmol) in N,N-dimethylformamide (2 ml) at 0° C. with stirring, and the resulting mixture was stirred for 30 minutes. Furthermore, to the reaction mixture was added a solution of 4-bromo-2-fluorobenzaldehyde (0.20 g, 1.0 mmol) in N,N-dimethylformamide (2 ml) at the same temperature with stirring, and after raising the reaction temperature to room temperature, the resulting mixture was furthermore stirred for 1 hour. After stirring, a saturated aqueous solution of ammonium chloride (5 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 5:95) as the eluent to afford the title compound (0.19 g) in a yield of 82% as a colourless oily product.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[CH3:27][OH:28]>>[C:1]([O:4][C@@H:5]1[C@H:10]([NH:11][C:12]([O:28][CH3:27])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: COC(=S)N[C@H]1[C@@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (1.0 g, 2.57 mmol) in anhydrous methanol (10 mL) was heated to reflux. The reaction was complete after 1 h as determined by TLC. The solvent was removed in vacuo. The product was then purified by flash column silica chromatography using a solvent system of 3:1 hexanes/EtOAc, which provided (2R,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(methoxycarbonothioylamino)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (1.0 g, 92% yield) as a slightly yellow syrup. 1H NMR (500 MHz, CDCl3) δ 2.11 (s, 3H), 2.12 (s, 6H), 3.81 (ddd, 1H), 3.95 (s, 3H), 4.1 (m, 2H), 4.31 (m, 1H), 5.17 (m, 2H), 5.73 (d, 1H, J=8.6 Hz), 6.21 (d, 1H, J=10.0 Hz).
Reaction SMILES: [CH2:1]([NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:16](=O)(O)[O-:17].[K+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C(Cl)Cl.O>[CH2:1]([N:15]=[C:16]=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C([O-])O
Reactant: CCCCCCCCCCCCCCN
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN=C=O
Reaction time: 0.5 h

Procedure:
To a vigorously-stirred, biphasic mixture of 1-tetradecylamine (9.44 g, 44.2 mmol) in CH2Cl2 (300 mL) and potassium bicarbonate (21.8 g, 158 mmol) in H2O (200 mL) was added (dropwise) a 1.93 M solution of phosgene in toluene (30.0 mL, 57.9 mmol) at 0° C. After 30 min, the organic layer was separated and dried over MgSO4. The volatile components were removed with a rotary evaporator to afford crude tetradecyl isocyanate which was immediately taken up in THF (15 mL) and added to a heterogeneous mixture of 5,6-dichlorobenzotriazole (5.94 g, 31.6 mmol) and THF (125 mL). The reaction mixture was stirred at ambient temperature for 14 h, and the volatile components were then removed with a rotary evaporator. The crude product was first purified by silica gel column chromatography (heptane: ethyl acetate=7:3) and then recrystallized from ethanol to afford 12.2 g (90%) of D12.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[OH-].[Na+].S([O-])(O[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O>>[CH2:26]([O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: CCN(CC)CCO
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCOCCN(CC)CC
Temperature: 20 °C

Procedure:
140.6 grams (1.2 moles) of diethyl ethanolamine, 48 grams (1.2 moles) of sodium hydroxide and 288.4 grams (1 mole) of lauryl sulfate, Na salt were reacted under a nitrogen atmosphere using the procedure of Example 9. Approx. 20 grams of the diethyl ethanolamine evaporated from the reaction with water during the reaction and was immediately replaced. After a reaction time of 2 hours at 190° C., followed by cooling to 20° C., the reaction mixture was purified using the procedure of Example 2. 168 grams of an oily liquid having an amine number of 151 were obtained.
Reaction SMILES: [F:1][C:2]([N+:21]([O-:23])=[O:22])([N+:18]([O-:20])=[O:19])[CH2:3][N:4]([CH2:9][C:10]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[F:11])[C:5]([NH:7][NH2:8])=[O:6].[F:24][C:25]([N+:31]([O-:33])=[O:32])([N+:28]([O-:30])=[O:29])[C:26]#[N:27]>>[F:1][C:2]([N+:21]([O-:23])=[O:22])([N+:18]([O-:20])=[O:19])[CH2:3][N:4]([CH2:9][C:10]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[F:11])[C:5]([NH:7][N:8]=[N:27][CH2:26][C:25]([F:24])([N+:31]([O-:33])=[O:32])[N+:28]([O-:30])=[O:29])=[O:6]
Reactant: N#CC(F)([N+](=O)[O-])[N+](=O)[O-]
Reactant: NNC(=O)N(CC(F)([N+](=O)[O-])[N+](=O)[O-])CC(F)([N+](=O)[O-])[N+](=O)[O-]
Product: O=C(NN=NCC(F)([N+](=O)[O-])[N+](=O)[O-])N(CC(F)([N+](=O)[O-])[N+](=O)[O-])CC(F)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
The initial derivatives prepared from I can also be useful intermediates for the synthesis of other explosive materials. For example [N,N-bis(2-fluoro-2,2-dinitroethyl)carbamyl]hydrazine (VI) was added to fluorodinitroacetonitrile to give 1-[N,N-bis(2-fluoro-2,2-dinitroethyl)carbamyl]-2-(2-fluoro-2,2-dinitroethylimino)hydrazine (IX). Compound IX was hydrolyzed to give 1-[N,N-bis(2-fluoro-2,2-dinitroethyl)carbamyl]-2-fluorodinitroacetyl hydrazine (X) and cyclized with trifluoroacetic anhydride to yield trifluoroacetyl-3-[bis(2-fluoro-2,2-dinitroethyl)amino]-5-fluorodinitromethyl-1,2,4-triazole (XI).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)([Cl:16])=O.CN(C=O)C>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ccc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 53a from 4-amino-3-nitro-benzoic acid with thionyl chloride and DMF in dichloromethane at reflux.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:5][N:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.C([Li])CCC>O1CCCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[C:2]([B:16]([OH:21])[OH:17])=[C:3]2[CH2:15][CH2:14][CH2:13][N:4]2[N:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1c(-c2ccccn2)nn2c1CCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 54.8 %

Procedure:
Place tetrahydrofuran (60.0 mL) in a 100 mL round-bottom flask equipped with a temperature probe, a magnetic stirrer, and a septum and put under a nitrogen atmosphere. Add 3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Preparation 3, Part D; 3.00 g, 11.4 mmol) and triisopropyl borate (6.80 mL, 29.5 mmol). Cool the mixture to −78° C. using a dry ice/acetone bath. Add 1.41M n-butyllithium in hexanes (19.3 mL, 27.3 mmol) dropwise via a syringe pump over 10 min keeping the temperature below −40° C. Remove the dry ice/acetone bath and allow the reaction mixture to warm to room temperature. Add saturated aqueous ammonium chloride (20 mL) and extract with chloroform (2×150 mL). Combine the organic layers, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to afford an oil. Purify by normal phase flash chromatography (120 g Biotage KP-Sil 40L: ethyl acetate for 25 min, 0-10% methanol in ethyl acetate in ramp over 15 min, then 10% methanol in ethyl acetate) to obtain 1.43 g (55%) of the title product. MS (ES) m/z=230 (M+H).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[CH:16]=O>CO.C(O)C>[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[CH:16]=[CH:16][C:9]1[C:10]([Cl:15])=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[CH:6][C:5]([Cl:4])=[CH:14]2
Reactant: O=Cc1c(Cl)ccc2cc(Cl)cnc12
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Clc1cnc2c(C=Cc3c(Cl)ccc4cc(Cl)cnc34)c(Cl)ccc2c1
Reaction time: 2 h

Procedure:
18 ml of a 15% strength solution of sodium methylate in methanol were added dropwise, at room temperature, to a suspension of 25.4 g of 3,7-dichloro-8-triphenylphosphoniummethylquinoline chloride and 11.3 g of 3,7-dichloro-8-formylquinoline in 150 ml of ethanol. The mixture was stirred for 2 hours, after which the yellow precipitate was filtered off under suction, treated with water and again filtered off under suction.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][C:14]3([CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][C:14]([CH2:16][O:19][C:20]3[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=3)([OH:15])[CH2:13][CH2:12]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CCN2CCC3(CC2)CO3)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCN2CCC(O)(COc3ccc(C=O)cc3)CC2)cc1
Temperature: 100 °C
Yield: 84.4 %

Procedure:
The compound (10.0 g) obtained in Step 3 of Example 1 and 4-hydroxybenzaldehyde (5.04 g) were dissolved in anhydrous dimethylformamide (55 mL), and to the mixture was added potassium carbonate (28.5 g) and 18-crown-6 (1.09 g) at room temperature under nitrogen atmosphere and the mixture was heated at 100° C. for five hours. After allowing to cool, insoluble matter was removed by filtration and washed with ethyl acetate (300 mL). The filtrate was cooled with ice-water and water (150 mL) was added to the mixture to be separated. The aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with water and brine successively, and dried over anhydrous sodium sulfate, followed by removal of the solvent under reduced pressure. The obtained residue was crystallized from ether and collected by filtration to obtain the titled compound (12.7 g) as crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]#[C:16][C:17]2[N:25]=[C:24]3[C:20]([N:21]=[CH:22][N:23]3[C@@H:26]3[CH2:30][C@H:29]([NH:31][C:32](=[O:35])[CH2:33][OH:34])[C@@H:28]([OH:36])[C@H:27]3[OH:37])=[C:19]([NH:38][C@H:39]([CH2:47][OH:48])[CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CO>[OH:36][C@H:28]1[C@@H:27]([OH:37])[C@H:26]([N:23]2[CH:22]=[N:21][C:20]3[C:24]2=[N:25][C:17]([C:16]#[C:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][C:19]=3[NH:38][C@H:39]([CH2:47][OH:48])[CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:30][C@@H:29]1[NH:31][C:32](=[O:35])[CH2:33][OH:34]
Reactant: CC(C)(C)OC(=O)N1CCC(CC#Cc2nc(N[C@H](CO)Cc3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)CC1
Agent: Cl
Solvent: CO
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(C#CCC4CCNCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-{3-[9-[(1R,2S,3R,4S)-2,3-Dihydroxy-4-(2-hydroxy-acetylamino)-cyclopentyl]-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid tert-butyl ester (Intermediate XB) is dissolved in 1.25 M HCl in MeOH. After stirring at RT for 3 days, the solvent is removed in vacuo to yield the title compound. This is used in the next step without further purification.