Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=O.C(Cl)(=O)C.Cl.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C@@H:32]([N:36]1[CH2:39][C:38]3([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[CH2:37]1)[CH2:31][CH2:30]2.C(N(CC)CC)C>>[CH3:14][C:11]1[CH:12]=[CH:13][C:5]([CH2:4][C:1](=[O:3])[N:42]2[CH2:43][CH2:44][C:38]3([CH2:37][N:36]([CH:32]4[C:33]5[C:29](=[CH:28][C:27]([C:22]6[N:21]=[CH:26][CH:25]=[CH:24][N:23]=6)=[CH:35][CH:34]=5)[CH2:30][CH2:31]4)[CH2:39]3)[CH2:40][CH2:41]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(CC(=O)O)c(C(=O)O)c1
Reactant: c1cnc(-c2ccc3c(c2)CC[C@@H]3N2CC3(CCNCC3)C2)nc1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(CC(=O)N2CCC3(CC2)CN(C2CCc4cc(-c5ncccn5)ccc42)C3)c(C(=O)O)c1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
To 2-(carboxymethyl)-5-methylbenzoic acid (100 mg, 0.52 mmol, prepared according to the procedure described in Tetrahedron, 1975, 31(20), 2607-2619) in a microwave reaction vessel was added acetyl chloride (0.5 mL). The tube was sealed and irradiated (Biotage Inc., microwave) while stirring at 130° C. for 20 minutes. The reaction was cooled to room temperature and the excess acetyl chloride was removed in vacuo. Dichloromethane was added to azeotrope the excess acetyl chloride and the crude anhydride was dried under vacuum. The crude anhydride was dissolved in acetonitrile (2 mL) and 2-[(1S)-5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1e, 220 mg, 0.52 mmol) was added followed by triethylamine (0.16 mL, 2.06 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and the desired product was purified using reverse phase chromatography (Biotage SNAP (15 g), water/CH3CN=95/5% to 50/50%) to afford (176 mg, 69%) 5-methyl-2-{2-oxo-2-[2-(5-pyrimidin-2-yl-indan-1-yl)-2,7-diaza-spiro[3.5]non-7-yl]ethyl}benzoic acid. MS (ES+) 497.6 (M+H)+. 1H NMR (CDCl3) δ 1.54-1.58 (m, 2H), 1.60-1.64 (m, 2H), 2.15-2.38 (m, 5H), 2.78-3.02 (m, 2H), 3.04-3.24 (m, 1H), 3.26-3.52 (m, 6H), 3.62-3.66 (m, 2H), 4.41-4.45 (m, 1H), 7.06-7.27 (m, 3H), 7.34-7.57 (m, 1H), 7.68 (s, 1H), 8.31 (s, 2H), 8.73-8.79 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21](Cl)=[N:20][CH:19]=[C:18]([C:23]2[N:24]=[C:25]([N:32]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH2:44][CH2:43][N:42]([CH:45]5[CH2:48][O:47][CH2:46]5)[CH2:41][CH2:40]4)=[C:35]([O:49][CH2:50][CH2:51][O:52][CH:53]4[CH2:58][CH2:57][CH2:56][CH2:55][O:54]4)[CH:34]=3)[C:26]3[N:27]([CH:29]=[CH:30][N:31]=3)[CH:28]=2)[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:66]B(O)O>C(=O)([O-])[O-].[Na+].[Na+].COCCOC.C(Cl)Cl.O.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>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:66])=[N:20][CH:19]=[C:18]([C:23]2[N:24]=[C:25]([N:32]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH2:44][CH2:43][N:42]([CH:45]5[CH2:48][O:47][CH2:46]5)[CH2:41][CH2:40]4)=[C:35]([O:49][CH2:50][CH2:51][O:52][CH:53]4[CH2:58][CH2:57][CH2:56][CH2:55][O:54]4)[CH:34]=3)[C:26]3[N:27]([CH:29]=[CH:30][N:31]=3)[CH:28]=2)[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2cn3ccnc3c(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C5COC5)CC4)c(OCCOC4CCCCO4)c3)n2)cnc1Cl
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: Cc1ncc(-c2cn3ccnc3c(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C5COC5)CC4)c(OCCOC4CCCCO4)c3)n2)nc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
A microwave vial was charged with tert-butyl tert-butoxycarbonyl(6-(8-((tert-butoxycarbonyl)(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)amino)imidazo[1,2-a]pyrazin-6-yl)-3-chloropyrazin-2-yl)carbamate XXXIV (258 mg, 0.28 mmol), methylboronic acid (503 mg, 8.4 mmol), Pd(PPh3)4 (32 mg, 0.03 mmol) in sodium carbonate (0.8 mL, 1M in H2O) and DME (2.5 mL). The mixture was heated at 150° C. for 20 min. The reaction was cooled to room temperature, diluted with DCM and H2O. The aqueous layer was separated and extracted with DCM. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography ISCO Rf (4 g column) eluting with a gradient of 100% DCM—100% 75/18/7 DCM/Et2O/MeOH to provide the desired compound tert-butyl tert-butoxycarbonyl(6-(8-((tert-butoxycarbonyl)(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)amino)imidazo[1,2-a]pyrazin-6-yl)-3-methylpyrazin-2-yl)carbamate XXXV.
Reaction SMILES: [H][H].[NH3:3].[NH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]>[B].O.[Ni].[Re]>[C:10]1(=[O:11])[NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1.[NH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:3]
Reactant: [H][H]
Reactant: N
Reactant: NCCCCCCO
Agent: [Ni]
Agent: [Re]
Agent: [B]
Solvent: O
Product: NCCCCCCN
Product: O=C1CCCCCN1

Procedure:
To a catalyst basket in a 300 milliliter Parr reactor was charged 5.044 grams of a nickel, rhenium, boron catalyst prepared as described in Example 6 of U.S. Pat. No. 4,123,462. The catalyst was activated in 50 milliliters of water for 1 hour at 200° C. under 533 psig hydrogen. The reactor was cooled, vented, and the water discharged. 50 Milliliters of 17% NH3 in water was charged to the reactor and the reactor was heated to 235° C. under 220 psig of 3% hydrogen in nitrogen. A flow of 40 milliliters per minute of 3% hydrogen in nitrogen was maintained through the reactor using a Brooks Mass Flow Meter at a reactor pressure of 725 psig. A solution of 5.00 grams of 6-aminohexanol, 20 grams water and 2.04 grams of tetreglyme as internal standard was prepared and charged to a stainless steel pressure cylinder connected to a metering pump. The 6-aminohexanol in water solution was fed to the reactor at a rate of 1.0 milliliter per minute. The yields of products, i.e., epsilon caprolactam, hexamethyleneimine, and hexamethylenediamine, were determined using gas chromatographic analysis of samples taken over time and were based on the amount of 6-aminohexanol charged. From the time when the 6-aminohexanol feed was completed, the yields of epsilon caprolactam, hexamethyleneimine, and hexamethylenediamine with are shown in the table below.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[CH3:16][C:17]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])[C:18]#N.C[OH:29].Cl>CN(C=O)C.O>[C:22]1([N:21]2[C:17]([CH3:16])([CH3:20])[C:18](=[O:29])[N:1]([C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=3)[C:2]2=[S:3])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CC(C)(C#N)Nc1ccccc1
Reactant: CO
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
A mixture of 1a (0.274 g, 1.2 mmol) and 6a (0.160 g, 1 mmol) in dry DMF (0.2 ml) was stirred for 48 h. To this mixture were added methanol (10 ml) and 2N HCl (3 ml). The second mixture was refluxed for 6 h. After being cooled to room temperature, the reaction mixture was poured into cold water (20 ml) and extracted with ethyl acetate (20 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 4-[3-phenyl-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 6b, [RD10] (0.276 g, 0.71 mmol, 71%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[C@@H:7]2[CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C(#N)C.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:16][CH2:17]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([OH:41])=[O:40]
Reactant: COc1cccc(N2CCN(C3=Nc4c(F)cccc4[C@@H](CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: COc1cccc(N2CCN(C3=Nc4c(F)cccc4C(CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Temperature: 25 °C
Yield: 108.4 %

Procedure:
(R)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethyl-phenyl)-3,4-dihydroquinazolin-4-yl}acetic acid (50 g) is dissolved in acetonitrile (500 ml) and treated with sodium methoxide (30% strength in methanol, 32.4 ml) and then stirred under reflux for 60 h. After cooling to room temperature, the mixture is concentrated to one half in vacuo, then it is adjusted to pH 7.5 using hydrochloric acid (20% strength, ca. 20 ml), MIBK (200 ml) is added and it is readjusted to pH 7 using hydrochloric acid (20% strength). The phases are separated, and the organic phase is dried over sodium sulphate and concentrated in a rotary evaporator to give a hard foam. The residue is dissolved in ethanol (150 ml) and concentrated, then again dissolved in ethanol (150 ml) and concentrated. A total of 54.2 g of (±)-{8 fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid are thus obtained in quantitative yield as an amorphous solid.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[CH2:24]([NH:26][CH2:27][CH2:28][OH:29])[CH3:25]>C(Cl)Cl>[Si:10]([O:29][CH2:28][CH2:27][NH:26][CH2:24][CH3:25])([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCNCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Imidazole (1.53 g, 22.44 mmol) and a solution of tert-butylchlorodiphenylsilane (4.63 g, 16.83 mmol) in DCM (10 ml) were added sequentially to a solution of 2-(ethylamino)ethanol (1.099 ml, 11.22 mmol) in DCM (30 ml) and the resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with 1N aq. NaHSO4 and saturated aq. NaHCO3. The organic layer was dried (Na2SO4), concentrated under reduced pressure to give a residue which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes) to provide the title compound (2.95 g, yield: 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[N:5]=[CH:4][N:3]=1.[CH2:19]([N:21]([CH2:24][CH3:25])[CH2:22]C)[CH3:20].ClC(OC1C=CC=CC=1)=[O:28].N1CCCC1>O1CCCC1>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][C:22]([N:21]2[CH2:24][CH2:25][CH2:20][CH2:19]2)=[O:28])[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCCC1
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (100 mg) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere, and then triethylamine (0.112 ml) and phenyl chloroformate (0.100 ml) were added dropwise thereto, followed by stirring for 1.5 hrs. To the reaction mixture was added pyrrolidine (0.313 ml), followed by stirring for 30 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=2:1). The solvent was evaporated under a reduced pressure to give a residue, which was partitioned between ethyl acetate and a 1 N aqueous solution of sodium hydroxide. The organic layer was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then dried in vacuum to provide the titled compound (96.6 mg, 69.5%) as a yellow solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:31])[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:16]2[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:15]=2[O:14]1>ClCCl>[C:29]([C:26]1[CH:27]=[CH:28][C:15]2[O:14][C:13]([CH3:31])([CH3:12])[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N+:20]=3[O-:9])[C:16]=2[CH:25]=1)#[N:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 64.3 %

Procedure:
406 mg of m-chloroperbenzoic acid were added to a solution of 528 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile in 15 ml of dichloromethane at room temperature. After 2 hours at room temperature the mixture was washed with sodium bicarbonate solution and the organic phase was dried over sodium sulphate and evaporated. The residue crystallized from t-butyl methyl ether and was recrystallized from toluene to give 360 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 158-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
2-chloro-4-nitrophenol (9.02 g, 52 mmol)), 3-fluorobenzyl bromide (9.85 g, 52 mmol) and acetonitrile (90 mL) was combined at room temperature under nitrogen. Potassium carbonate (7.9 g, 57 mmol)) was added and the reaction mixture stirred at 60° C. for 2 hours and then cooled to room temperature. After cooling the reaction mixture was poured into water. The solids were collected by filtration and washed with diethyl ether to afford the desired product (13.98 g, 95% yield). [TLC system=1:1 EtOAc:Hexanes, Rf=0.76]
Reaction SMILES: [C:1]([N:4]1[CH2:20][CH2:19][CH2:18][C:7]2=[N+:8]([O-])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>C1C=CC=CC=1>[C:1]([N:4]1[CH2:20][CH2:19][CH:18]([O:24][C:21](=[O:23])[CH3:22])[C:7]2=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CCCc2c(c(C)c3ccccc3[n+]2[O-])C1
Solvent: c1ccccc1
Product: CC(=O)OC1CCN(C(C)=O)Cc2c1nc1ccccc1c2C

Procedure:
A mixture of 3 gm (11 millimols) of 2-acetyl-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline 6-oxide, 80 ml of benzene and 23 ml of acetic acid anhydride was heated at its boiling point for 3 hours. Thereafter, the benzene was distilled off and the residue ws recrystallized from ether.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:9](=[O:28])[N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[NH2:7][C@@H:8]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:9]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1)=[O:28].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1cccc(Oc2ccccc2)c1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](C(=O)N1CCC[C@H]1c1cccc(Oc2ccccc2)c1)C1CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of {(S)-1-cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolidine-1-yl]-ethyl}-carbamic acid tert-butyl ester in CH2Cl2 (20 mL) is added TFA (10 mL) and the mixture is stirred for 30 minutes. The mixture is concentrated under reduced pressures to give (S)-2-amino-2-cyclohexyl-1-[(S)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethanone as a TFA salt quantitatively (1.65 g). LCMS m/z 379 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:33][C:34]1([CH3:41])[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.O>CN(C=O)C>[CH3:33][C:34]1([CH3:41])[CH2:39][CH2:38][CH:37]([NH:40][C:8]([C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[CH:4][N:5]=2)=[O:10])[CH2:36][CH2:35]1
Reactant: CC1(C)CCC(N)CC1
Reactant: Nc1ccnc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCC(NC(=O)c2cc(N)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-amino-pyridine-6-carboxylic acid (250 mg, 1.81 mmol) with TBTU (600 mg, 1.87 mmol) and TEA (1 mL, 7.2 mmol) in 4 mL DMF was added 4,4-dimethyl-cyclohexylamine (300 mg, 1.83 mmol) and the mixture stirred at ambient temperature for 1 h. Then the mixture was poured into water at 0° C. and stirred for 5 min. The precipitate was filtered off, washed with water and dried at 55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCCC)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][O:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH:39]([CH2:42][NH:43][CH3:44])[CH2:38]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:43]([CH2:42][CH:39]5[CH2:40][CH2:41][N:37]([CH2:36][CH2:35][O:34][CH3:33])[CH2:38]5)[CH3:44])=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:31])([F:32])[F:30])[CH:3]=1
Reactant: CCCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCC1CCN(CCOC)C1
Product: COCCN1CCC(CN(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-{[1-(2-methoxy-ethyl)-pyrrolidin-3-ylmethyl]-methyl-amino}-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazolidin-4-one and [1-(2-Methoxy-ethyl)-pyrrolidin-3-ylmethyl]-methyl-amine following General Procedure B.
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: NNC(=O)N(CC(F)([N+](=O)[O-])[N+](=O)[O-])CC(F)([N+](=O)[O-])[N+](=O)[O-]
Reactant: N#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: C([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:18]([O:17][C:15]([NH:14][C@H:10]1[C@H:11]([CH3:13])[CH2:12][NH:8][CH2:9]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: [H][H]
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Yield: 93.3 %

Procedure:
A suspension of 1-benzyl-trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (4.8 g) and 10% palladium-on-charcoal (1.8 g) in ethanol (40 ml) was shaken with hydrogen were absorbed under elevated pressure (100 kg/cm2) at 50°-70° C. for 6.5 hours. The catalyst was removed by filtration and the filtrate was evaporated to give the title compound (3.09 g) as brown oil. This oil was gradually solidified at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](N)=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[OH-:20].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:20])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: [OH-]
Reactant: NC(=O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1

Procedure:
A mixture of 2,2',4'-trifluoro-4-biphenylylacetamide (100 mg.), aqueous caustic soda (18N; 1 ml.) and water (5 ml.) was stirred under reflux overnight. The mixture was acidified and extracted with ether. The ether was evaporated and the product recrystallised from 80-100 petroleum ether to give 2,2',4'-trifluoro-4-biphenylylacetic acid, m.p. 144°-147° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[CH:20][C:21](N)=[N:22][CH:23]=2)O1.[C:26]([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1.O>[NH2:22][C:23]1[CH:18]=[CH:19][C:20]([C:2]2[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=2)=[CH:21][CH:26]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Nc1ncc(Br)nc1Br
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2nc(Br)cnc2N)cc1
Temperature: 90 °C

Procedure:
A suspension of 3,5-dibromopyrazin-2-amine (CAS No. 957230-70-5) (15 g), Pd(PPh3)4 (3.2 g), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (12 g), and Na2CO3 (12 g) in a 3 to 1 mixture of dioxane/water (600 mL) was degassed with a stream of nitrogen for 10 minutes. The reaction was heated at 90° C. overnight, at which time LC/MS indicated the reaction was complete. The mixture was concentrated, diluted with water (200 mL) and extracted with EtOAc (3×300 mL). The organic layers were combined, dried over Na2SO4, and evaporated under reduced pressure. The crude solid was triturated with a 1 to 1 mixture of DCM/MTBE (100 mL) to give the title compound (11 g) having the following physical data as a yellow solid.