Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6]([O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH2:20])[C:17]([OH:19])=[O:18])=[O:10])[CH3:7].Cl[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34].Cl>O1CCOCC1.O>[CH2:6]([O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH:20][C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[C:17]([O:19][CH:11]([CH2:12][CH3:13])[CH3:9])=[O:18])=[O:10])[CH3:7]
Reactant: C=CCOC(=O)Cl
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCOC(=O)N[C@@]1(C(=O)OC(C)CC)[C@H](OCc2ccc(Cl)c(Cl)c2)C[C@@H]2[C@H]1[C@@]2(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2 mL of saturated sodium hydrogen carbonate was added to 200 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-ethyl ester suspended in 1 mL of dioxane, and the mixture was stirred for 10 minutes at room temperature. 0.18 mL of allyl chloroformate was added thereto, and the solution was stirred for 8 hours at room temperature. After the reaction solution was acidified with 1 mL of 1N hydrochloric acid, 10 mL of water was added thereto, and the mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was dissolved in 20 mL of N,N-dimethylformamide. 141 mg of 1-iodobutane and 106 mg of potassium carbonate were added to the solution, and the mixture was stirred for 16 hours at room temperature. Water was added thereto, and the reaction solution was extracted twice with ethyl acetate. After the ethyl acetate layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled under reduced pressure and purified by column chromatography (silica gel: Kanto Chemical silica gel 60 (spherical), eluent: hexane-ethyl acetate=5:1), thereby yielding 159 mg of (1R,2R,3R,5R,6R)-2-allyloxycarbonylamino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-butyl ester 6-ethyl ester.
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH:17]1([CH2:20][NH:21][C:22]([C:24]2[C:25]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:26]=3[S:27][C:28]=2[CH3:29])=[O:23])[CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:17]1([CH2:20][NH:21][C:22]([C:24]2[C:25]3[CH:33]=[CH:32][C:31]([O:34][C:13]4[CH:12]=[CH:11][N:10]=[C:9]5[CH:8]=[C:7]([C:5]([N:1]6[CH2:4][CH2:3][CH2:2]6)=[O:6])[S:15][C:14]=45)=[CH:30][C:26]=3[S:27][C:28]=2[CH3:29])=[O:23])[CH2:19][CH2:18]1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)NCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CCC5)sc34)ccc2c1C(=O)NCC1CC1
Yield: 53.8 %

Procedure:
This material was prepared by reacting 2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a (88 mg, 0.35 mmole) with 6-hydroxy-2-methyl-1-benzo[b]thiophene-3-carboxylic acid (cyclopropylmethyl)amide 130a (110 mg, 0.42 mmole) and Cs2CO3 (228 mg, 0.70 mmole) in a manner similar to that previously described for example 1 to give a yellow solid (90 mg, 54%). 1H NMR (DMSO-d6, 300 MHz) δ 8.58 (1H, d, J=5.46 Hz), 8.49 (1H, t, J=5.46 Hz), 7.96 (1H, d, J=2.26 Hz), 7.89 (1H, s), 7.83 (1H, d, J=8.85 Hz), 7.33 (1H, dd, J=2.35, 8.76 Hz), 6.75 (1H, d, J=5.46 Hz), 4.62 (2H, t, J=7.72 Hz), 4.10 (2H, t, J=7.82 Hz), 3.20 (2H, t, J=6.31 Hz), 2.62 (3H, s), 2.35 (2H, m), 1.07 (1H, m), 0.46 (2H, m), 0.26 (2H, m).
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH:6]([SiH:11]([Cl:13])[Cl:12])[Si:7]([Cl:10])([Cl:9])[Cl:8])[Cl:5]>C1C=CC=CC=1>[Cl:5][Si:4]1([Cl:3])[CH:2]=[CH:1][Si:11]([Cl:12])([Cl:13])[CH:6]1[Si:7]([Cl:8])([Cl:10])[Cl:9]
Reactant: C#C
Reactant: Cl[SiH](Cl)C([SiH](Cl)Cl)[Si](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cl[Si](Cl)(Cl)C1[Si](Cl)(Cl)C=C[Si]1(Cl)Cl
Yield: 50.8 %

Procedure:
Hydrosilation of acetylene with bis(dichlorosilyl)trichlorosilylmethane in the presence of Pt(C2H4)(PPh3)2. Into the same apparatus as described in Example 1 were placed 0.103 g of Pt(C2H4)(PPh3)2, 2.99 g of bis(dichlorosilyl)trichlorosilylmethane, and 20 ml of dried benzene forming a mixture. The mixture was brought to reflux and acetylene gas was blown into the mixture at 90 ml per minute for 4 hours. The mixture was vacuum distilled at 67 Pa to yield a mixture comprising 2.02 g of 1,1,3,3-tetrachloro-2-trichlorosilyl-1,3-disilacyclopent-4-ene (TCD-GC area 50.8%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:37][O:38][C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][C@H:45]([CH2:48][NH2:49])[O:44][C:43]=2[CH:50]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][NH:49][CH2:48][CH:45]2[O:44][C:43]3[CH:50]=[C:39]([O:38][CH3:37])[CH:40]=[CH:41][C:42]=3[O:47][CH2:46]2)=[CH:2]1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Reactant: COc1ccc2c(c1)O[C@@H](CN)CO2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
3-Indolebutyric acid (1.3 g, 6.5 mmole), 1-hydroxybenzotriazole hydrate (1.1 g, 7.8 mmole) and 1,3-diisopropylcarbodiimide (2.4 ml, 15.6 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise (S)-7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.5 g, 6.5 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Evaporation of product fractions gave 1.5 g (61%) of the desired product, (S)-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-butanamide, as a foam.
Reaction SMILES: [C:1]1([P:7]2(=[O:16])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]=[C:19]=[O:20]>C(#N)C>[C:1]1([P:7]2(=[O:16])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]2[C:19]([NH:18][CH3:17])=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P1(c2ccccc2)NCc2ccccc21
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)N1Cc2ccccc2P1(=O)c1ccccc1
Temperature: 26 °C
Yield: 86 %

Procedure:
A mixture of 1-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.5 g, 0.0065 mol) and methylisocyanate (1.92 g, 0.0337 mol) in 15 ml. of acetonitrile was heated with constant stirring at reflux for 16 hours. The mixture was allowed to air cool to 26° C. and was then cooled to 0° C. in an ice bath. The mixture was filtered and the precipitate washed with anhydrous ether to yield 1-phenyl-2-methylaminocarbonyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.6 g, 86% yield) as a white solid having a melting point of 219°-221° C. and the following analysis:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.O>CN(C=O)C>[C:7]1(=[O:11])[C:8]2[C:4](=[CH:3][C:2]([O:1][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)[CH2:5][NH:6]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C1NCc2cc(O)ccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
To a slurry of Nail (0.39 g, 16.1 mmol) in DMF at 0° C. was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp. and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was heated at 70° C. for 3 h. The mixture was cooled to 0° C. and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf 0.35.
Reaction SMILES: [O:1]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])S(C(F)(F)F)(=O)=O.O[C@@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[Si:9]([O:1][C@@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 59 %

Procedure:
tert-Butyldimethylsilyl triflate (1.44 ml) was added to a stirred solution of 1-tert-butyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (1.03 g) and triethylamine (1.76 ml) in DCM (50 ml) at room temperature, under an atmosphere of nitrogen. The reaction mixture was stirred for 2 hours and then the mixture was washed with saturated aqueous potassium hydrogensulfate, dried (Na2SO4), and concentrated in vacuo to give a clear oil. Purification by column chromatography, using 0-30% ethyl acetate in hexane as eluent, gave 1-tert-butyl 2-methyl (2R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate as a clear oil (891 mg, 59%); NMR spectrum (CDCl3) 4.43-4.32 (m, 2H), 3.75-3.72 (m, 2H), 3.65-3.56 (m, 1H), 3.43-3.31 (m, 1H), 2.21-2.15 (m, 1H), 2.07-1.98 (m, 1H), 1.47 (s, 3H), 1.42 (s, 6H), 0.88 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH2:19][OH:20])[CH:12]=1)(=[O:3])[CH3:2].O[C:27]1[C:28]([OH:37])=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N#N.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH2:19][O:20][C:34]2[CH:35]=[CH:36][CH:27]=[C:28]([OH:37])[C:29]=2[C:30]([O:32][CH3:33])=[O:31])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1noc(-c2cccc(/C=C/CO)c2)c1COC(C)=O
Reactant: COC(=O)c1cccc(O)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1noc(-c2cccc(/C=C/COc3cccc(O)c3C(=O)OC)c2)c1COC(C)=O
Reaction time: 16 h
Yield: 42.8 %

Procedure:
To a solution of ethyl 4-((acetyloxy)methyl)-5-{3-((1E)-3-hydroxyprop-1-enyl)phenyl}isoxazole-3-carboxylate (960 mg, 2.78 mmol) in THF (14 mL) was added methyl dihydroxybenzoate (934 mg, 5.57 mmol) and PPh3 (1.46 g, 5.57 mmol). After purging the vessel with N2, diethyazodicarboxylate (968 mg, 5.57 mmol) was added. The mixture was stirred for 16 hours, concentrated under vacuo and the residue purified by column chromatography (0–40% ethyl acetate in hexanes) to provide the titled compound (590 mg, 43%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:30][C:31](=[O:49])[C:32]1[C:33](=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=1)[NH:34][C:35](OC1C=CC=CC=1)=[O:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31](=[O:49])[C:32]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:33]=1[NH:34][C:35]([NH:22][S:19]([C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:13]=1)(=[O:21])=[O:20])=[O:36])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: NS(=O)(=O)c1ccc(Cl)c(NC(=O)OCc2ccccc2)c1
Product: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Cl)c(NC(=O)OCc2ccccc2)c1
Yield: 77.7 %

Procedure:
From 1.0 g (2.93 mmol) of 3-benzyloxycarbonylamino-4-chlorobenzenesulfonamide and 1.18 g (2.93 mmol) of 4-chloro-2-N-phenoxycarbonylanthranilic acid benzylester in a similar manner to Preparation Example 1, 1.43 g (yield 78%) of 2-{[(3-benzyloxycarbonylamino-4-chlorobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoic acid benzylester (property: colorless amorphous, PMR (δppm, DMSO-d6): 5.19 (2H, s), 5.36 (2H, s), 7.21 (1H, dd), 7.34-7.48 (10H, m), 7.72-7.76 (2H, m), 7.97 (1H, d), 8.25 (1H, d), 8.30 (1H, d), 9.53 (1H, s), 10.30 (1H, s)) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+:24]>CO.O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O-:18])=[O:17])=[CH:19][CH:20]=2)=[O:7])=[CH:4][CH:3]=1.[Na+:24]
Reactant: O=C(O)c1ccc(OCCNC(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])c1ccc(OCCNC(=O)c2ccc(Cl)cc2)cc1
Yield: 67.5 %

Procedure:
4-[2-(4-Chlorobenzamido)ethoxy]benzoic acid (3.19 g) was dissolved in 50 ml of methanol. A solution of 0.40 g of sodium hydroxide in 5 ml of water was added to the above methanolic solution, the mixture was concentrated in vacuo, the crystallised residue was recrystallised from methanol, and 2.30 g of crystalline product was obtained. M.p. not lower than 300° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:9])=[C:4](C)[CH:5]=[CH:6][CH:7]=1.[C:10](OCC)(=O)C>>[N:9]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:10]=1
Reactant: Cc1cccc(N)c1N
Reactant: CCOC(C)=O
Product: c1ccc2[nH]cnc2c1

Procedure:
Whne diaminotoluene was treated with 4-chlorophenoxynitrile there was no precipitate observed immediately. The reaction mixture was condensed under vacuum. The crude brownish solid was dissolved in ethyl acetate. The resulting solution was washed with water, then brine, and then dried over sodium sulfate. The solvents were then removed in vacuo to produce brown crystals with a good yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]2[C:11]([CH2:14][CH2:15][C:16]3[N:17]=[C:18]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[Cl:31])[O:19][C:20]=3[CH:21]([CH3:23])[CH3:22])=[N:12][O:13][C:9]=2[C:8]=1[CH2:34][CH:35]=[CH2:36])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]2[C:11]([CH2:14][CH2:15][C:16]3[N:17]=[C:18]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[Cl:31])[O:19][C:20]=3[CH:21]([CH3:22])[CH3:23])=[N:12][O:13][C:9]=2[C:8]=1[CH2:34][CH2:35][CH3:36])[CH3:2]
Reactant: C=CCc1c(OCC(=O)OCC)ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(OCC(=O)OCC)ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc12
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Ethyl[[7-allyl-3-[2-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-1,2-benzisoxazol-6-yl]oxy]acetate (65 mg, 0.12 mmol) was dissolved in ethanol (7. 0 mL). To the solution, 10% Pd-C (6 mg) was added. The mixture was stirred for 3 hours under hydrogen atmosphere (and ordinary pressure). After insoluble was filtered off, the filtrate was condensed to give the desired compound (63 mg) as colorless oil in the residue (yield 97%).
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[N:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1.[C:14](OC)(=[O:17])[NH:15][NH2:16].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[CH3:9][N:6]1[C:5]2[N:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]2[C:14](=[O:17])[NH:15][N:16]=[C:2]2[C:7]1=[O:8]
Reactant: Cn1c(=O)c(Cl)nc2cccnc21
Reactant: COC(=O)NN
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1c(=O)c2n[nH]c(=O)n2c2cccnc21
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of 7.5 g. of 2-chloro-4-methyl-pyrido(2,3-b)pyrazine-3-one, and 4 g. of methyl carbazate in 200 ml. of Dowtherm A was stirred and heated at 80° C. for 1 hour and then at 230° C. for 20 minutes.
Reaction SMILES: [C:1]([NH:5][CH3:6])([CH3:4])([CH3:3])[CH3:2].[N+:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C1C=CC=CC=1>[C:1]([N:5]([CH3:6])[C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CNC(C)(C)C
Solvent: c1ccccc1
Product: CN(C(=O)c1ccc([N+](=O)[O-])cc1)C(C)(C)C
Yield: 72.6 %

Procedure:
The preparation of Example 1 was repeated with the changes that the starting reactants were N-tert-butyl-N-methyl amine (3.36 g, 0.0386 mole) and 4-nitrobenzoyl chloride (3.58 g, 0.0193 mole), the reaction was carried out in benzene, the product was crystallized from cold ethanol, and the desired product was 3.31 g of crystals (28% yield), mp 119°-121° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 8.252 ppm (d, 8.8 Hz, 2H; 3,5-aryl H); 7.569 ppm (d, 8.8 Hz, 2H; 2,6-aryl H); 2.838 ppm (s, 3H; N-CH3); 1.526 ppm (s, 9H; tert-butyl H) .
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2CN(CCC)[CH2:12][N:11](C)[C:10]2=[N:19][N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:11][CH3:12])=[N:19][N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1
Reactant: CCCN1CN(C)C(=N[N+](=O)[O-])N(Cc2ccc(Cl)nc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A mixture of 1.5 g of 1-(2-chloropyrid-5-ylmethyl)-2-nitroimino-3-methyl-5-n-propyl-1,3,5-triazacyclohexane, 0.5 g of solid sodium hydrogen carbonate, 20 ml of methanol and 10 ml of water is stirred for 24 hours at 50° C. The reaction mixture is concentrated by evaporation and the residue purified on silica gel with dichloromethane/methanol 95:5 as the eluant. This yields the title compound with a melting point of 149-151° C. (compound 2.2).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([NH:15][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN
Reactant: Clc1ccn2nccc2n1
Product: CCCCNc1ccn2nccc2n1

Procedure:
A solution of 5-chloro-pyrazolo[1,5-a]pyrimidine [29274-24-] (955.4 mg, 6.2 mmol) in butylamine [109-73-9] (6.2 mL, 62.7 mmol), under N2 blanket, was magnetically stirred at 65° C. for 17 h then partitioned between brine (pH adjusted to 10 with saturated aqueous sodium bicarbonate) and ethyl acetate. The phase separated extract was dried (MgSO4) and diluted with heptane to precipitate butyl-pyrazolo[1,5-a]pyrimidin-5-yl-amine as 1.2 g of yellow powder, mp. 75-76° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.33 Hz, 3 H) 1.37 (dq, J=15.00, 7.29 Hz, 2 H) 1.47-1.59 (m, 2 H) 3.24-3.34 (m, 2 H) 5.94 (d, J=1.52 Hz, 1 H) 6.22 (d, J=7.58 Hz, 1 H) 7.35 (br. s., 1 H) 7.74 (d, J=2.27 Hz, 1 H) 8.40 (d, J=7.58 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 13.69, 19.71, 30.65, 91.00, 99.95, 134.70, 143.45, 148.37, 155.43. LRMS (ESI) m/z 191.1 [(M+H)]+, calc'd for C10H14N4: 190.25
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[C:12]([CH3:15])=[N:13][CH:14]=1)(C)(C)C.[ClH:27]>CCOC(C)=O>[ClH:27].[ClH:27].[NH2:7][CH2:8][CH2:9][C:10]1[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[C:12]([CH3:15])=[N:13][CH:14]=1
Reactant: Cc1ncc(CCNC(=O)OC(C)(C)C)n1Cc1ccc(C#N)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ncc(CCN)n1Cc1ccc(C#N)c(F)c1
Reaction time: 2 h

Procedure:
A solution of {2-[3-(4-cyano-3-fluoro-benzyl)-2-methyl-3H-imidazol-4-yl]-ethyl}-carbamic acid tert-butyl ester (as described in Example 11, Step A) (1.0 g, 2.9 mmol) in EtOAc (30 mL) was cooled to −20° C. and saturated with HCl gas. The cooling bath was removed and the reaction was stirred for 2 hr. The solvent was removed in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([Pb+3])=[C:31]([CH2:36][CH3:37])[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH:4]2[C:5](=[O:10])[C@H:6]3[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:11])=[C:31]([CH2:36][CH3:37])[CH:30]=1
Reactant: CCc1cc(Br)ccc1[Pb+3]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 45.7 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (6 g, 38.96 mmol) and 4-dimethylaminopyridine (23.76 g, 194.75 mmol) are added to a mixture of chloroform (120 ml) and toluene (30 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethylphenyllead triacetate (24.3 g, 42.85 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases separated. The aqueous phase is extracted with dichloromethane (2×50 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4-bromo-2-ethylphenyl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (6 g).
Reaction SMILES: [N:1]([C:4]1[CH:8]=[C:7]([CH3:9])[O:6][N:5]=1)=[N+:2]=[N-:3].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:3]=[N:2][N:1]([C:4]3[CH:8]=[C:7]([CH3:9])[O:6][N:5]=3)[C:19]=2[NH2:20])=[CH:14][CH:13]=1
Reactant: Cc1cc(N=[N+]=[N-])no1
Reactant: COc1ccc(CC#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nnn(-c3cc(C)on3)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To an ice-cooled and stirred mixture of 3-azido-5-methyl-isoxazole (0.5 g, 1 eq) and commercial (4-methoxy-phenyl)-acetonitrile (0.712 g, 1.2 eq) in ethanol (10 ml) kept under nitrogen, a solution of sodium methoxide (0.327 g, 1.5 eq) in ethanol (10 ml) is added drop-wise (15 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (40 ml), washed with water (2×50 ml), dried over MgSO4 and evaporated to dryness. The yellow semisolid residue (˜0.900 g) is purified by flash chromatography using 60-120 mesh silica gel and eluting with 20% ethylacetate in hexane, to afford the title compound as a white solid (0.120 g, 11% yield). M.p. 136.3-141.2° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[CH2:15]=[O:16]>O>[OH:16][CH2:15][N:9]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Reactant: C=O
Solvent: O
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1CO

Procedure:
A stirred mixture composed of 6-nitro-2H-1,4-benzoxazin-3(4H)-one (5.82 g), 37% formaldehyde aqueous solution (28.5 ml) and water (5.4 ml) is refluxed for 2 hours, and cooled. The resultant solid is collected by filtration, washed with water, ethanol, ether and n-hexane successively, and dried to obtain 4-hydroxymethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (5.19 g).