Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH2:5]Br.C(=O)([O-])[O-].[Na+].[Na+]>COC(C)(C)C.O>[CH3:1][O:2][N:3]=[C:4]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:5]1
Reactant: CON=C(CBr)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: CON=C1COc2ccccc21
Reaction time: 120 h
Yield: 92 %

Procedure:
74 g (0.303 mol) of 2-bromo-1-(2-hydroxy-phenyl)-ethanone O-methyl-oxime are dissolved in 350 ml of tert-butyl methyl ether and heated under reflux with a solution of 40 g (0.377 mol) of sodium carbonate in 400 ml of water with vigorous stirring for 5 days. The organic phase is separated off and dried over sodium sulphate and the solvent is distilled off under reduced pressure, affording 45.5 g (82.8% of theory, 90% of Z isomer according to HPLC analysis) of crude benzofuran-3-one O-methyl-oxime.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:22]=[CH:21][C:13]3[N:14]([C:18](Cl)=[O:19])[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29].C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]1([S:7]([C:10]2[CH:22]=[CH:21][C:13]3[N:14]([C:18]([NH:29][C:28]([NH2:30])=[NH:27])=[O:19])[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N=C(N)NC(=O)N1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 20.3 %

Procedure:
To a suspension of 7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl chloride (0.360 g., 1 mmol) in 20 mL acetonitrile, was added guanidine carbonate (0.180 g., 1 mmol), followed by the dropwise addition of N,N-diisopropyl ethylamine (0.523 mL, 3 mmol.) The reaction mixture was partitioned between 50 mL each of water and ethyl acetate. The organic fraction was washed with dilute aqueous hydrogen chloride followed by 50 mL water. The organic fraction was dried over sodium sulfate and concentrated in vacuo. The resulting white solid was dissolved in 20 mL refluxing dichloromethane. On cooling, white crystals formed, which were filtered and dried under vacuum to give 73 mg (21 %) of N-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-guanidine free base, which recrystallized from EtOH/HCl/Et2O to provide the hydrochloride salt. MS: 361 (M+H)+, mp (as hydrochloride): 148.5-151.6° C.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1)/[C:3](O)=[O:4].C(N(CC)CC)C.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH3:1][C:2](=[CH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1)[C:3]([N:39]=[N+:40]=[N-:41])=[O:4]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C/C(=C\c1cc(-c2ccccc2)cs1)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=Cc1cc(-c2ccccc2)cs1)C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (E)-2-methyl-3-(4-phenyl-thiophen-2-yl)-acrylic acid (924 mg, 3.78 mmol) and triethylamine (617 μl, 4.43 mmol) in THF (10 ml) was added diphenylphosphoryl azide (897 μl, 6.27 mmol) at 0° C. The reaction was next stirred for 4 h at room temperature. At which point the contents of the reaction flask were partitioned between ethyl acetate (25 ml) and sodium hydrogencarbonate (25 ml). The organic phase was separated and the solvent removed in vacuo. The crude residue was suspended between methanol (25 ml) and distilled water (25 ml), the precipitate collected and dried (MgSO4) to afford the title compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2([CH2:20][C:21]([OH:23])=[O:22])O>ClCCl>[F:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12]/[C:13]/2=[CH:20]\[C:21]([OH:23])=[O:22]
Reactant: O=C(O)CC1(O)CCc2c(F)cc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Yield: 60.9 %

Procedure:
Trifluoroacetic acid (39.9 g, 0.35 mol) was added dropwise to a stirred, chilled (ice-methanol bath) mixture of 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid (11.3 g, 0.05 mol) in dichloromethane (250 mL). After 35 min. the mixture was concentrated in vacuo. Dichloromethane was added to the residue and the mixture was concentrated in vacuo. This procedure was repeated once more to give 6.4 g of crude (E)-2-(4,6-difluoro-1-indanylidene)acetic acid. Recrystallization of 0.9 g from acetone: water mixtures gave 0.15 g of (E)-2-(4,6-difluoro-1-indanylidene) acetic acid as a solid white: mp 238-239° C.; NMR (DMSO-d6): d 12.25 (br, 1H), 7.23-7.65 (m, 2H), 6.46 (t, 1H), 3.20-3.28, 2.97-3.20 (2m's, 4H); steady-state nOe: irradiation at 6.46 d, observed 21.6% nOe at 7.63 d.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4](OC)[CH:3]=1.[C-:12]#[N:13].[Na+].[C:15]1(C)C=CC=CC=1>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:12]#[N:13])=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1ccccc1
Reactant: COc1cc(Cl)ccc1CBr
Reactant: [C-]#N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)ccc1CC#N

Procedure:
269 g of 4-chloro-2-methoxybenzyl bromide in 214 ml of toluene are reacted with 68.2 g of sodium cyanide in 69 ml of water and 1.8 g of Aliquat 336. 141 g of colorless oil are obtained (b.p. 107° C./0.08 mbar).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33](O)=[O:34])[N:27]=1>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=2[C:28]2[N:27]=[C:26]([CH3:25])[O:30][N:29]=2)=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: Cc1nc(-c2ccccc2C(=O)O)no1
Product: Cc1nc(-c2ccccc2C(=O)NC[C@@H]2CNCCO[C@H]2c2ccc(Cl)c(F)c2)no1
Product: Cl

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 2-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:27]=[C:26]([OH:28])[C:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1.N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36]>CN(C)C=O>[C:35]([O:28][C:26]1[C:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=[C:17]([CH2:16][NH:15]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)[CH:27]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2cc(CN/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc(O)c2O1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc2c1OC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4Z)-6-bromo-4-({[(7-hydroxy-2,2-dimethyl-1,3-benzodioxol-5-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (30 mg, 67 μmol) in dimethylformamide (0.5 mL) is added pyridine (12 μL, 0.17 mmol) and acetyl chloride (10 μL). The reaction mixture is shaken overnight at room temperature and then purified by reverse-phase high performance liquid chromatography to give 6-({[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)-2,2-dimethyl-1,3-benzodioxol-4-yl acetate.
Reaction SMILES: [Br:1][C:2]1([C:5]([NH:7][CH2:8][C:9](=[O:11])[CH3:10])=O)[CH2:4][CH2:3]1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1([C:5]2[O:11][C:9]([CH3:10])=[CH:8][N:7]=2)[CH2:3][CH2:4]1
Reactant: CC(=O)CNC(=O)C1(Br)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cnc(C2(Br)CC2)o1
Temperature: 0 °C
Yield: 65.8 %

Procedure:
4.62 g of 1-bromo-N-(2-oxopropyl)-cyclopropane-1-carbamide is held at 60° C. in 35.47 ml of concentrated sulfuric acid for 30 minutes. The cooled reaction mixture is stirred into ice water and made basic in batches with sodium carbonate decahydrate. Then, it is extracted with ethyl acetate, dried on sodium sulfate, and concentrated by evaporation. Chromatography of the oily residue on silica gel with ethyl acetate/hexane yields 2.79 g of title compound 8 a as a yellowish oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[N:12]1[CH:17]=CC=CC=1.C(Cl)(Cl)=[O:19].C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[C@:5]([N:12]=[C:17]=[O:19])([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6]
Reactant: c1ccncc1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@@](N)(CC(C)C)N=C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
L-leucine methyl ester hydrochloride (25 g, 0.14 mmol) was dissolved in methylene chloride (450 mL), cooled to 0° C., and pyridine (43.5 g, 0.55 mmol, 44.5 mL) was added, then a 1.93 M solution of phosgene in toluene (0.18 mol, 92.7 mL) was added slowly. After stirring at 0° C. for 2 h, the mixture was poured into 1400 mL of 0.5 N Hcl and 900 mL of ice. The organic layer was washed with 1400 mL of 0.5 N Hcl and 900 mL of ice. The aqueous layers were extracted with methylene chloride (450 mL) and the combined organic layers were washed with 1400 mL of saturated brine and 900 mL of ice, then dried (MgSO4), filtered and concentrated. The residue was distilled (56-58° C.; 0.78 mmHg) to provide the title compound as a colorless liquid (20.4 g, 86%). 1H NMR (250 MHz, CDCl3) δ 4.04 (dd, 1H), 3.82 (s, 3H), 1.92-1.72 (m, 1H), 1.69-1.62 (m, 2H), 0.96 (d, 3H), 0.94 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:45]#[CH:46])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:45]#[CH:46])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1ccc(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc(Oc2ccc(C#N)cc2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in example 6a, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(4-cyano-phenoxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.65 g, 0.96 mmol) was reacted with trimethylsilyl acetylene (0.94 g, 9.6 mmol), CuI (10 mg), triethylamine (2.89 g, 28.7 mmol), and dichlorobis(triphenylphosphine) palladium (0) (53.6 mg, 0.077 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(4-cyano-phenoxy)-5-ethynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 0.285 g, 51%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N:9]=[CH:10]N(C)C)=[C:4]([Cl:14])[N:3]=1.P([O-])([O-])([O-])=[O:16].[K+].[K+].[K+].OP([O-])(O)=O.[K+].P(=O)(O)(O)O>P(=O)(O)(O)O.CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:16])=[C:4]([Cl:14])[N:3]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: CN(C)C=Nc1c(Cl)nc(N)nc1Cl
Agent: O=P(O)(O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc(Cl)c(NC=O)c(Cl)n1
Temperature: 125 °C
Yield: 68 %

Procedure:
A slurry of 2-amino-4,6-dichloro-5-{[(dimethylamino)methylene]amino}pyrimidine (Example 2, 1.50 g, 6.41 mmol) and 1.5M aqueous potassium phosphate buffer (35 mL, prepared by adjusting the pH of a 1.5M solution of KH2PO4 to 3.2 by addition of 85% phosphoric acid) was gently refluxed (in an oil bath at 125° C.). After 4 hours of reflux, the pH of the mixture was adjusted from 4 to 3 by addition of 4 drops of 85% phosphoric acid. After a total of 6 hours of reflux, TLC(silica gel plates developed in 5% methanol-chloroform) showed that the starting material had been largely converted to a lower-Rf product. The solid was filtered and washed with water (5 mL), methanol (5 mL), and dried to give the title compound as a white solid (0.900 g, 68%), mp. >250° C. dec.; mass spectrum (CI/CH4): 209, 207 (M+1); 1H-NMR (DMSO-d6)δ: 9.81 and 9.46 (s and d, J=11 Hz, total 1, NH), 8.25 and 8.00 (s and d, J =11 Hz, total 1, CHO), 7.69 and 7.63 (both s, total 2, NH2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([N:28]([CH3:37])[CH3:27])=[CH:30][CH:31]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)cc1

Procedure:
To a mixture 2-[4-(2-amino-5-bromo-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.100 g, 0.22 mmol) and ethanol (3 ml) was added 4-dimethylamino benzaldehyde (0.044 g, 0.29 mmol) and 1M aq. Na2S2O4 (900 μL, 0.9 mmol). The reaction mixture was stirred at reflux for 16 h then concentrated in vacuo. The crude product was purified by chromatography on silica gel (dichloromethane/ethyl acetate v/v 7:3, and then 0.5% to 2% methanol in ethyl acetate) to give the title compound as an off white solid (0.034 g, 27%); 1H-NMR (250 MHz, DMSO-d6) 2.77 (broad m, 4H, piperazine N(CH2)2), 2.99 (s, 6H, N(CH3)2), 3.40 (s, 2H, NCH2CO), 3.67 (broad m, 4H, piperazine N(CH2)2), 6.82 (d, J=8.8 Hz, 2H) and 8.02 (d, J=8.8 Hz, 2H) 2,6-ArH and 3,5-ArH, 7.23 (d, J=3.5 Hz, 1H) and 7.49 (d, 1H, J=3.5 Hz) (thiazole 4-H, 5-H), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.80 (broad s, 1H, CONH), 13.12 (broad s, 1H, imidazo[4,5-b]pyridine NH); LC-MS (ESI, m/z) Rt=6.0 min—541/543 [(M+H+), Br isotopic pattern, 100%]; ESI-HRMS Found: 541.1203, calculated for C23H26N8OSBr (M+H+): 541.1134.
Reaction SMILES: [CH2:1]=O.[F:3][N:4]([F:19])[C:5]([N:16]([F:18])[F:17])([CH2:11][NH:12][N+:13]([O-:15])=[O:14])[CH2:6][NH:7][N+:8]([O-:10])=[O:9]>[N+]([O-])(O)=O>[F:3][N:4]([F:19])[C:5]1([N:16]([F:17])[F:18])[CH2:11][N:12]([N+:13]([O-:15])=[O:14])[CH2:1][N:7]([N+:8]([O-:10])=[O:9])[CH2:6]1
Reactant: O=[N+]([O-])NCC(CN[N+](=O)[O-])(N(F)F)N(F)F
Reactant: C=O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])N1CN([N+](=O)[O-])CC(N(F)F)(N(F)F)C1

Procedure:
Under the conditions of nitrolysis of 2,2-bis(difluoramino)-N-(nitratomethyl)-N-nitro-N,N′-bis(4-nitrobenzenesulfonyl)-1,3-propanediamine in ca. 98% nitric acid, the liberated formaldehyde equivalent becomes available for cyclization of the N-desulfonated bis(primary nitramine), 2,2-bis(difluoramino)-N,N′-dinitro-1,3-propanediamine. The cyclization occurred spontaneously at room temperature, consuming the 2,2-bis(difluoramino)-N,N′-dinitro-1,3-propanediamine intermediate and forming 5,5-bis(difluoramino)hexahydro-1,3-dinitropyrimidine (RNFX) [1H NMR (CD3CN): δ4.85 (s, 4H), 6.06 (s, 2H); 1H NMR (acetone-d6): δ5.07 (s, 4H), 6.31 (s, 2H); 13C NMR (CD3CN): δ45.3 (m, J 6 Hz), 60.6 (s) (not all carbons detected due to low S/N); 19F NMR (CD3CN): δ29.67; 19F NMR (acetone-d6): δ29.31)].
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([C:16]#[N:17])[C:5](=O)[N:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[CH:7]=1.[OH2:19].[NH2:20][NH2:21].C(=O)([O-])O.[Na+]>C(O)C>[NH2:17][C:16]1[C:4]2[C:5](=[O:19])[N:6]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]3[CH3:14])[CH:7]=[C:2]([Br:1])[C:3]=2[NH:21][N:20]=1
Reactant: NN
Reactant: O
Reactant: CC1CCCCC1n1cc(Br)c(Cl)c(C#N)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1CCCCC1n1cc(Br)c2[nH]nc(N)c2c1=O
Temperature: 90 °C

Procedure:
To a solution of 5-bromo-4-chloro-1-(2-methylcyclohexyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step F (1.29 g) in ethanol (20 mL) was added hydrazine monohydrate (0.288 mL) at room temperature. The reaction mixture was heated at 90° C. for 2 hr, and cooled to room temperature. The reaction mixture was poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.21 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[C:15]([OH:16])=[C:14]([C:17](=O)[CH3:18])[C:13]([CH3:20])=[N:12]1.[CH3:21][O:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[C:15](=[O:16])[C:14](=[C:17]([NH:32][NH:31][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:34][CH:33]=2)[CH3:18])[C:13]([CH3:20])=[N:12]1
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: CC(=O)c1c(C)nn(-c2ccc3ccccc3n2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc4ccccc4n3)N=C2C)cc1
Yield: 30.5 %

Procedure:
2.0 mL of an isopropyl alcohol solution of 28.7 mg (0.11 mmol) of 1-(1-(quinolin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone, 20.8 mg (0.11 mmol) of 4-methoxycarbonylbenzhydrazide and 6.1 mg (0.03 mmol) of p-toluenesulfonic acid monohydrate was refluxed with heating for 48 hours. After cooling, the precipitate was collected by filtration and washed with methanol and acetonitrile to obtain 14.9 mg of the desired product as a purple solid (yield 31%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([CH:7]=[N:8][OH:9])[CH2:4][O:3]1.[Cl:11]N1C(=O)CCC1=O.CCOCC.O>CN(C=O)C>[OH:9][N:8]=[C:7]([Cl:11])[C@@H:5]1[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)OC[C@@H](C=NO)O1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC1(C)OC[C@@H](C(Cl)=NO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde oxime (10.3 g, 71.0 mmol) in 40 mL DMF was added 1-chloropyrrolidine-2,5-dione (10.4 g, 78.1 mmol) and the reaction was stirred overnight at ambient temperature. The reaction mixture was poured into ether (1400 mL) and water (500 mL). The ether layer was extracted with water (5×500 mL), dried over MgSO4, filtered and concentrated to (S)-N-hydroxy-2,2-dimethyl-1,3-dioxolane-4-carbimidoyl chloride (10.0 g, 55.7 mmol, 78.5% yield) as white solid. Step C: A solution of (S)-N-hydroxy-2,2-dimethyl-1,3-dioxolane-4-carbimidoyl chloride (9.88 g, 55.01 mmol) in THF (200 mL) at 0° C. was added methanesulfonyl chloride (4.703 ml, 60.51 mmol), followed by N,N-diisopropylethylamine (10.54 ml, 60.51 mmol) and the reaction was stirred for 1 hour at ambient temperature, filtered and concentrated in vacuo. The residue was purified over silica gel (25 to 100% ethyl acetate in hexanes) to afford (S)-2,2-dimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbaldehyde chloride (12.28 g, 47.65 mmol, 86.63% yield) as colorless oil.
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH:35]2[CH2:37][CH2:36]2)=[C:32]([Pb+3])[CH:33]=1.Cl>C(Cl)(Cl)Cl.ClCCl>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([CH:35]2[CH2:37][CH2:36]2)=[C:30]([CH:2]2[C:3](=[O:6])[CH2:4][CH2:5][C:1]2=[O:7])[CH:29]=1
Reactant: O=C1CCC(=O)C1
Reactant: Brc1ccc(C2CC2)c([Pb+3])c1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1CCC(=O)C1c1cc(Br)ccc1C1CC1
Temperature: 80 °C

Procedure:
To a solution of cyclopentane-1,3-dione (0.57 g, 0.0058 mol) and N,N-dimethylaminopyridine (3.64 g, 0.030 mol) in chloroform (33 ml) is added toluene (9 ml) then 5-bromo-2-cyclopropylphenyl lead triacetate (3.77 g, 0.0065 mol). This solution is heated at 80° C. for 20 hours then cooled to room temperature and dilluted with dichloromethane and 2M aqueous hydrochloric acid. The resulting biphasic suspension is filtered through diatomaceous earth and the two phases are separated. The organic layer is further washed with 2M aqueous hydrochloric acid and the aqueous phase is extracted again with dichloromethane. All organic fractions are combined, washed with brine, dried over magnesium sulfate then concentrated in vacuo. The crude product is finally purified by flash column chromatography on silica gel (isohexane/ethyl acetate eluant) to afford 2-(5-bromo-2-cyclopropylphenyl)cyclopentane-1,3-dione as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.99 g, 15 mmole), morpholine (1.4 mL, 15.8 mmole), acetic acid (11.0 mL, 18 mmole) were dissolved in 30 mL dichloroethane and sodium triacetoxyborohydride (6.36 g, 30 mmole) was added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and then washed with 2N NaOH, water, and dried (MgSO4). Filtration and evaporation gave 3.84 g (95%) 4-morpholin-4-yl-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil that solidified on standing.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:24]([C:20]2[C:16]3=[N:17][CH:18]=[CH:19][C:14]([C:8]4[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:15]3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f4) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>>[F:10][C:4]1[CH:3]=[C:2]([C:18]2([OH:21])[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]2)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COc1ccc(Br)cc1F
Product: COc1ccc(C2(O)CCC3(CC2)OCCO3)cc1F

Procedure:
The title compound was prepared as a white solid from 4-bromo-2-fluoro-anisole (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.