Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][SH:5].[H-].[Na+].S(O[CH2:15][C@H:16]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=O)(=O)C.C(OCC)(=O)C>C1COCC1>[CH3:1][Si:2]([CH2:3][CH2:4][S:5][CH2:15][C@@H:16]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([CH3:7])[CH3:6]
Reactant: C[Si](C)(C)CCS
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)CSCC[Si](C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 2-trimethylsilylethanethiol (0.86 g, 6.41 mmol), synthesis described by Anderson, Ranasinghe, Palmer, and Fuchs, above) in THF (10 mL) was added sodium hydride (0.256 g, 6.41 mmol as a 60% mineral oil dispersion). The mixture was stirred for 10 minutes. Boc-homophenylalaninol mesylate (2.00 g, 5.82 mmol, synthesis described in Example 13, above) was added. The solution was stirred for 2 hours. Ethyl acetate (50 mL) was added. The solution was washed with 30 mL each of 1M HCl, saturated aqueous sodium bicarbonate, and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure, giving the intermediate (S)-2-tert-butoxycarbonylamino-4-phenylbutyl trimethylsilylethyl sulfide. TLC: (5% ethyl acetate/hexane) Rf =0.22. This material was dissolved in CH2Cl2 (50 mL), cooled to -10° C., and treated with 4-chloroperbenzoic acid (3.24 g, 12.22 mmol, estimated 65% peracid content). The mixture was stirred overnight. The suspension was filtered, and saturated aqueous NaHSO3 (40 mL) and saturated aqueous sodium bicarbonate (50 mL) were carefully added to the filtrate. The organic phase was separated, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the product, Boc-Hph-β-SO2CH2CH2TMS in quantitative mass recovery from the mesylate. TLC: (30% ethyl acetate/hexane) Rf =0.49.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C>ClCCl>[F:10][C:8]([F:11])([F:9])[C:6]1[C:5]([Cl:12])=[CH:4][C:3]2[N:13]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[C:28](=[O:30])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(C(F)(F)F)cc2N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(C(F)(F)F)c(Cl)cc32)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(2-amino-5-chloro-4-trifluoromethylphenyl)amino]-1-piperidinecarboxylate (D62, 2.2 g) was dissolved in 25 ml of dichloromethane at 0° C. and triphosgene (0.6 g) and diisopropylethylamine (1.0 ml) were added and the mixture was stirred at 0° C. for 1 h, then washed with aqueous citric acid, dried over MgSO4, filtered and evaporated The product was chromatographed on silica gel eluting with methanol-dichloromethane mixtures, then crystallised from diethyl ether to yield the subtitle compound, 1.0 g.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 2-fluorobenzenesulfonyl chloride (380 μl). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(2-fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (891 mg).
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[S:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[S:31])[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=S)Cc3ccccc3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=S)Cc3ccccc3)[C@H]2S1
Yield: 98.7 %

Procedure:
Acetic acid (4.5 ml) and zinc powder (3.6 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylate (2.79 g) in anhydrous dimethylformamide (15 ml), and the mixture was stirred for 2 hours at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was poured into a mixture of 5% hydrochloric acid (75 ml) and ethyl acetate (50 ml), and extracted. The extract was washed with water and dried. After the solvent was distilled off, the residue was crystalized by adding ether to give colorless crystals of 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid (2.0 g), mp 168° to 171° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([Br:22])=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Br
Yield: 77 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)-pyrimidine-4-carboxylic acid methyl ester (778 mg, 2.5 mmol) and N-bromosuccinimide (489 mg, 2.75 mmol) were combined in chloroform and heated at reflux for 12 hours. The cooled reaction mixture was concentrated and the product was isolated by column chromatography to yield 6-amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester (752 mg, 77% yield): mp 173-175° C.: 1H NMR (CDCl3): δ 7.66 (dd, 1H), 7.24 (dd, 1H), 5.73 (br s, 2H), 4.03 (s, 3H), 4.01 (d, 3H).
Reaction SMILES: [K].[CH2:2]([O:4][C:5](=[O:11])[C:6]([C:9]#[N:10])=[CH:7]O)[CH3:3].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>ClCCl>[CH2:2]([O:4][C:5](=[O:11])[C:6](=[CH:7][Cl:13])[C:9]#[N:10])[CH3:3]
Reactant: CCOC(=O)C(C#N)=CO
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K]
Solvent: ClCCl
Product: CCOC(=O)C(C#N)=CCl
Reaction time: 2 h

Procedure:
Potassium salt of 2-cyano-3-hydroxy-acrylic acid ethyl ester described in Preparation Example C-1 (18 g, 0.1 mol) was dissolved in dichloromethane (80 mL), phosphorus pentachloride (20.9 g, 0.1 mol) was added, and the solution was stirred for 2 hours under reflux. After the reaction was completed, the residue obtained by evaporating dichloromethane was subjected to distillation in vacuo, and ethyl(chloromethylene)cyanoacetate (9.5 g, 56 mmol) was obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:2]=[CH2:3].[C:17](OC(=O)C)(=[O:19])[CH3:18]>[OH-].[Na+]>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:2]=[CH2:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCOc1cc(C=CC(=O)O)ccc1O
Agent: [Na+]
Agent: [OH-]
Product: C=CCOc1cc(C=CC(=O)O)ccc1OC(C)=O
Temperature: 0 °C

Procedure:
115.5 g (0.525 mol) of 3-allyloxy-4-hydroxy-cinnamic acid are dissolved in 530 ml of 2 N sodium hydroxide solution, 800 g of ice are added and 107 g (1.05 mols) of acetic anhydride are introduced dropwise over the course of quarter of an hour at 0°-5° C., whilst stirring. The crystals which have precipitated are then filtered off, suction-dried and recrystallised from chloroform. 3-Allyloxy-4-acetoxy-cinnamic acid of melting point 154°-155° C. is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=1>CO.O>[NH:26]1[CH:25]=[C:24]([NH:23][C:2]2[N:7]=[C:6]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]3)[C:5]([Cl:22])=[CH:4][N:3]=2)[CH:28]=[N:27]1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Solvent: CO
Solvent: O
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cn[nH]c3)ncc2Cl)CC1
Reaction time: 16 h
Yield: 19 %

Procedure:
A solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.070 g, 0.21 mmol) and tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.11 g, 0.63 mmol) was stirred in MeOH:water (10:1 ratio, 4 mL) at 70° C. for 2 hours and then at 90° C. for 16 hours. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Combiflash Rf, 0-15% MeOH in DCM) to give the title compound 19 as a light yellow solid (0.015 g, 19%). 1H NMR (300 MHz, d6-DMSO) δ 0.93-1.02 (m, 2H), 1.38-1.49 (m, 2H), 3.04-3.16 (m, 4H), 6.03 (brs, 1H), 6.98 (brs, 1H), 7.18-7.39 (m, 4H), 7.48-7.72 (m, 1H), 7.79-8.00 (m, 1H), 8.37 (s, 1H), 9.62 (s, 1H). LCMS-C: rt 4.92 min; m/z 383 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([NH2:18])[CH:12]=1)(=[O:4])=[O:3].Cl.C(O[C:23](=N)[CH2:24][Br:25])C>C(O)C>[Br:25][CH2:24][C:23]1[NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:2]([CH3:1])(=[O:3])=[O:4])=[CH:12][C:13]=2[N:18]=1
Reactant: CCOC(=N)CBr
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(N)c(N)c1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1-c1ccc2[nH]c(CBr)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
A mixture of 2′-methanesulfonyl-biphenyl-3,4-diamine (8.09 g, 0.0308 mol) and 2-bromoacetimidic acid ethyl ester hydrochloride salt (11.82 g, 0.0370 mol) in anhydrous ethanol (200 proof, 120 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to provide 2-bromomethyl-5-(2-methanesulfonyl-phenyl)-1H-benzoimidazole (10.36 g, 92%) as a yellow oil. To a solution of this material in CH2Cl2, was added Boc2O (7.39 g, 0.0339 mol), Et3N (12.9 mL, 0.0924 mol), and DMAP (0.19 g, 0.00154 mol). After stirring 1 h at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography (silica, EtOAc: hexanes, 1:2) to afford the title compound as a yellow oil (10.17 g, 77%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]([CH2:18][O:19][C:20]4[C:24]([CH:25]=O)=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OP([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[C:1]1([C:7]2[O:8][C:9]([CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]([CH2:18][O:19][C:20]4[C:24](/[CH:25]=[CH:44]/[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
To a mixture of 3-[{4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g), ethyl diethylphosphonoacetate (0.27 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.050 g) under ice-cooling. The mixture was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (2E)-3-[3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]-2-propenoate as colorless crystals (0.51 g, yield 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 154-155° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:20][C:21]2[CH:22]=[N:23][C:24](Cl)=[C:25]([CH3:27])[CH:26]=2)[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[F-].[K+].[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:20][C:21]2[CH:22]=[N:23][C:24]([C:39]3[CH:38]=[CH:37][C:36]([O:35][C:34]([F:33])([F:45])[F:46])=[CH:41][CH:40]=3)=[C:25]([CH3:27])[CH:26]=2)[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)(C)C)Oc2cnc(Cl)c(C)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)(C)C)Oc2cnc(-c3ccc(OC(F)(F)F)cc3)c(C)c2)cc1
Yield: 85.6 %

Procedure:
3-{4-[1-(6-Chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-benzoylamino}-propionic acid methyl ester (200 mg, 0.46 mmol), potassium fluoride (80 mg, 1.38 mmol), 4-trifluoromethoxyphenyl boronic acid (190 mg, 0.92 mmol) and tetrakis(triphenylphosphine)palladium (53 mg, 0.046 mmol) are placed in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give the titled compound (220 mg).
Reaction SMILES: C(N(CC)CC)C.C([SiH](CC)CC)C.C([O:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([O:38][C@@H:39]([CH3:49])[CH2:40][O:41][Si](C(C)(C)C)(C)C)[CH:37]=1)[C:26]([NH:28][C:29]1[S:30][C:31]([CH3:34])=[CH:32][N:33]=1)=[O:27])C1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([O:38][C@@H:39]([CH3:49])[CH2:40][OH:41])[CH:37]=1)[C:26]([NH:28][C:29]1[S:30][C:31]([CH3:34])=[CH:32][N:33]=1)=[O:27]
Reactant: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)s1
Reaction time: 0.25 h
Yield: 21.4 %

Procedure:
Triethylamine (0.11 mL, 0.79 mmol) and triethylsilane (4.88 mL, 27.3 mmol) were added to palladium (11) acetate (56 mg, 9 mol %) in DCM (14 mL) under an atmosphere of argon. The reaction was stirred for 15 mins then 3-(benzyloxy)-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-(5-methyl-1,3-thiazol-2-yl)benzamide (1.4 g, 2.73 mmol) in DCM (14 mL) added dropwise and stirred for a further 48 hours. The reaction was filtered through celite and the filtrate concentrated in vacuo to give a residue which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (0.18 g).
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: C=O
Reactant: O=[N+]([O-])NCC(CN[N+](=O)[O-])(N(F)F)N(F)F
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: [H-].[Na+].[C:3](Cl)(=[O:5])[CH3:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16][C:17]2[C:18]([CH3:23])=[N:19][NH:20][C:21]=2[CH3:22])[CH:15]=1)[C:11]#[N:12]>CN(C)C=O>[C:3]([N:20]1[C:21]([CH3:22])=[C:17]([O:16][C:14]2[CH:13]=[C:10]([CH:9]=[C:8]([Cl:7])[CH:15]=2)[C:11]#[N:12])[C:18]([CH3:23])=[N:19]1)(=[O:5])[CH3:4]
Reactant: Cc1n[nH]c(C)c1Oc1cc(Cl)cc(C#N)c1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1nc(C)c(Oc2cc(Cl)cc(C#N)c2)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Sodium hydride (60% dispersion in oil, 840 mg, 21.0 mmol) was added to a stirred solution of acetyl chloride (1.50 ml, 21.0 mmol) and the pyrazole of Example 76 (4.80 g, 19.4 mmol) in N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 15 minutes and then quenched by the addition of water (200 ml). The reaction mixture was extracted with ethyl acetate (3×120 ml). The combined organic phases were washed with water (50 ml) and brine (50 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow solid. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane to provide the title compound (5.00 g) as a white solid, m.p. <60° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl.Cl.[CH2:7]([N:9]([CH2:31][CH3:32])[CH2:10][CH:11]([N:13]1[C:26]2[CH:25]=[C:24]([C:27](=[NH:30])OC)[CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH3:8].O>CO>[CH2:7]([N:9]([CH2:31][CH3:32])[CH2:10][CH:11]([N:13]1[C:26]2[CH:25]=[C:24]([C:27]([NH:4][CH2:1][CH2:2][CH3:3])=[NH:30])[CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH3:8]
Reactant: CCCN
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)OC)cc21
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCNC(=N)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of propylamine (1.95 cc) in methanol (5 cc) is added dropwise in the course of 5 minutes to a solution, cooled to 0°-5° C., of methyl 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboximidate dihydrochloride (3.49 g) in methanol (21 cc). The mixture is stirred for 2 hours at 5° C. and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give a residue which is taken up with distilled water (50 cc). The solution is washed with distilled water (50 cc) alkalinized to pH 9 with N sodium hydroxide. The two phases are allowed to settle and the organic phase is separated and washed with half-saturated (sodium chloride) solution (50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is purified by chromatography on neutral alumina (height: 20 cm; diameter: 2.1 cm), eluting with pure ethyl acetate (375 cc) and finally with mixtures of ethyl acetate and methanol in proportions (by volume) of 99:1 (375 cc), 98:2 (500 cc), 95:5 (500 cc), 90:10 (500 cc) and 80:20 (500 cc) and collecting 25-cc fractions. Fractions 40 to 70 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-propyl-2-phenothiazinecarboxamidine (1.49 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: O=C(Cl)[O:3][C:4]([Cl:7])(Cl)Cl.[CH3:9][O:10][C:11]1[C:21]([O:22][CH3:23])=[CH:20][C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:13]=2[CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11]1[C:21]([O:22][CH3:23])=[CH:20][C:14]2[CH2:15][CH2:16][N:17]([C:4]([Cl:7])=[O:3])[CH2:18][CH2:19][C:13]=2[CH:12]=1
Reactant: COc1cc2c(cc1OC)CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CCN(C(=O)Cl)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.2 mL (10 mmol/1 eq.) of diphosgene in 20 mL of dichloromethane, at about 0° C., there are added, dropwise, a solution of 3.55 g (20 mmol) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in 22 mL of dichloromethane, and then 4.2 mL (30 mmol/1.5 eq.) of triethylamine. Stirring overnight at ambient temperature and then concentration are carried out. The residue is taken up in dichloromethane, washed with water and dried over magnesium sulphate to yield, after concentration, the desired product.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.C1(N)C2C(=CC=CC=2)C=CC=1.[CH3:24][C:25](=[CH:27][CH2:28][CH2:29][CH:30]([CH2:32][CH:33]=O)[CH3:31])[CH3:26].C([BH3-])#N.[Na+]>CO>[CH2:33]([NH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:32][CH:30]([CH2:29][CH2:28][CH:27]=[C:25]([CH3:26])[CH3:24])[CH3:31]
Reactant: Nc1cccc2ccccc12
Reactant: CC(C)=CCCC(C)CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCCC(C)CCNc1cccc2ccccc12
Reaction time: 0.08 h
Yield: 21 %

Procedure:
2.0 g α-naphthylamine (14 mmol) and 0.01 gm α-naphthylamine-HCl were added to 25 ml absolute methanol along with 2.15 gm citronellal (14 mmol) and stirred for five minutes, after which the solution turned hazy. Then 0.53 gm (8.4 mmol) sodium cyanoborohydride was added and a brief exotherm occurred. The mixture was stirred overnight at room temperature. The bottom organic layer was separated from the top aqueous layer. An IR spectra of the organic layer (a brown oil) showed no carbonyl group and very little absorption in the OH/NH region (330-360 nm). Upon vacuum distillation of the organic layer the component having a bp of 175°-180° C. was collected. The desired product was recovered as a pale yellow oil in 21% yield. The structure of the amine product was confirmed by NMR.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:1]1([C:7](=[O:17])[CH:8]([Br:18])[C:9]2[CH:10]=[CH:11][C:12]([S:15][CH3:16])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: CSc1ccc(CC(=O)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(C(Br)C(=O)c2ccccc2)cc1
Reaction time: 20 h
Yield: 74.7 %

Procedure:
To a solution of the product of step 1 (60 g, 246 mmol) in CCl4 (900 mL) and CHCl3 (900 mL) was added dropwise a solution of Br2 (43.2 g, 270 mmol) in CCl4 (50 mL). After addition was completed, the mixture was concentrated to about 1/3 of its original volume. The mixture was washed with saturated NaHCO3 (500 mL) and Na2S2O8 (2×250 mL). The pale yellow solution was dried over Na2SO4 and concentrated to dryness. The residue was stirred in 10 % EtO2 /hexane for 20 h and filtered to give 59 g of the title compound.