Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][C@@H:27]4[O:53][C@H:52]([CH2:54][O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[C@@H:44]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C@H:36]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C@H:28]4[O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:18]=23)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:69][C:70]([O:72][CH3:73])=[O:71].[I-].[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:69][C:70]([O:72][CH3:73])=[O:71])[N:24]=[C:25]([O:26][C@@H:27]4[O:53][C@H:52]([CH2:54][O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[C@@H:44]([O:45][C:46](=[O:51])[C:47]([CH3:48])([CH3:49])[CH3:50])[C@H:36]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C@H:28]4[O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:32])[CH3:33])[C:18]=23)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OCc5ccccc5)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: COC(=O)Cn1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c2c(CCc3ccc(OCc4ccccc4)cc3)ccnc21

Procedure:
To a solution of 4-[2-(4-benzyloxyphenyl)ethyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]pyridine (0.43 g) in acetone (7 mL) were added cesium carbonate (0.33 g), methyl 2-bromoacetate (0.072 mL) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-3/2) to give 4-[2-(4-benzyloxy-phenyl)ethyl]-1-methoxycarbonylmethyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]pyridine (0.42 g). This material was dissolved in a mixed solvent of methanol (10 mL) and tetrahydrofuran (5 mL). To the solution was added sodium methoxide (28% methanol solution, 0.3 mL), and the mixture was stirred at 55° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added 2 mol/L aqueous sodium hydroxide solution (15 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (17 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (0.16 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.CC1C=CC(S(O)(=O)=O)=CC=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][O:22]1
Reactant: C1=COCCC1
Reactant: Clc1ncnc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Clc1ncnc2c1ncn2C1CCCCO1
Temperature: 25 °C

Procedure:
To a solution of a given 6-chloro-9H-purine (A-1) (1.29 mol, 1 eq) and TsOH (0.02 mol, 0.015 eq) in ethyl acetate (1000 mL), 3,4-dihydro-2H-pyran (1.94 mol, 1.5 eq) is added and the resulting mixture is stirred at reflux for 2 h. The reaction mixture is allowed to cool to RT, aqueous Na2CO3 solution (3%, 500 mL) is added and the resulting mixture is stirred for 10 min. The organic layer is separated, washed with water (500 mL×2) and brine (500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate is concentrated in vacuo. The product is dissolved in ethyl acetate (50 mL), and then n-heptane (500 mL) is added. The resulting mixture is stirred at RT for 1 h. The precipitate is collected by filtration, rinsed with heptane (100 mL) and dried in vacuo to afford the product 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (A-2) as a yellowish solid.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:16]([O:17]CC2C=CC=CC=2)[C@H:15]([O:25]CC2C=CC=CC=2)[C:12]2([CH2:14][CH2:13]2)[O:11][C@H:10]1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=2)[CH:34]=1)C1C=CC=CC=1.Cl>CO.[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:10]2[C@H:9]([OH:8])[C@@H:16]([OH:17])[C@H:15]([OH:25])[C:12]3([CH2:14][CH2:13]3)[O:11]2)=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC4(CC4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3OC4(CC4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
To a solution of (5S,6S,7R,8S)-6,7,8-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-4-oxa-spiro[2.5]octane (70 mg, 0.10 mmole) in methanol (3 mL), 10% Pd/C (45 mg) and 2 drops of con. HCl added and stirred under hydrogen atmosphere at room temperature for 18 hours. The reaction mixture was filtered through celite bed, washed with methanol (20 mL). Crude product was purified by preparative HPLC to furnish 15 mg of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][CH2:22][C:21]=3[CH:27]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:28]O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][CH2:22][C:21]=3[CH:27]=2)=[O:28])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: OO
Reactant: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)COC(=O)N3)cc1
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2ccc3c(c2)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-acetamido-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:25][CH:26]1[C:46](=[O:47])[N:28]2[C:29]([C:43]([OH:45])=[O:44])=[C:30]([CH2:33][S:34][C:35]3[N:39]([CH2:40][CH:41]=[CH2:42])[N:38]=[N:37][N:36]=3)[CH2:31][S:32][C@H:27]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:10]([NH:25][CH:26]2[C:46](=[O:47])[N:28]3[C:29]([C:43]([OH:45])=[O:44])=[C:30]([CH2:33][S:34][C:35]4[N:39]([CH2:40][CH:41]=[CH2:42])[N:38]=[N:37][N:36]=4)[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)O)cs1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(F)(F)F)c3csc(NC=O)n3)[C@H]2SC1
Yield: 39.5 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetic acid (syn isomer, 1.5 g.), N,N-dimethylformamide (0.40 g.) and phosphoryl chloride (0.84 g.) in ethyl acetate (15 ml.) and a solution of 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.77 g.) and trimethylsilylacetamide (3.93 g.) in ethyl acetate (25 ml.) were treated in a similar manner to that of Example 17 (1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.25 g.).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:8]([C:9](=[O:25])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])=[CH:13][C:12]=2[F:24])[CH:7]1[C:26](=[O:35])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:26]([CH:7]2[CH:8]([C:9](=[O:25])[NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[O:23])=[CH:13][C:12]=3[F:24])[CH:6]2[C:4]([OH:5])=[O:3])=[O:35])=[CH:33][CH:32]=1
Reactant: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A solution of 80 mg (0.16 mmol) of (1RS,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic acid ethyl ester (example 68) in a mixture of 10 ml of THF and 10 ml of a 1M aqueous LiOH-solution was stirred during 2 hrs at room temperature. The mixture was poured into 50 ml of a aqueous HCl-solution (0.5 M), extracted with AcOEt and the combined organic phases were dried over Na2SO4. Evaporation of the solvent gave 65 mg (86%) of the title compound. Off-white solid. MS: 468 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([NH2:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([NH:12][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
A solution of 1-(diphenylmethyl)-3-azetidinamine (synthesized according to the methods of Arimoto et. al., J. of Antibiotics 39 (9), 1243-56, 1986) (197 mg, 0.83 mmol) in dichloromethane (10 mL) was treated with excess triethylamine at 0° C. followed by methanesulfonyl chloride (71 μL, 0.91 mmol). The reaction was stirred for 30 minutes and then concentrated and purified on silica gel (0-10% methanol/dichloromethane) to provide 185 mg of the desired product as a white solid. LC/MS: M+H 317.19 at 0.31 minutes, Method D.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][CH:10]=3.C([O-])=O.[NH4+]>C(O)C.[Pd]>[OH:1][CH:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CCOC(=O)C1=C(O)c2cc3ccccc3n2CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C1CCn2c(cc3ccccc32)C1O
Temperature: 25 °C
Yield: 96413.3 %

Procedure:
A mixture of 18 g (0.07 mmol) of ethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate and 13.3 g of 0.21 mmol) of ammonium formate in 300 ml of ethanol is treated under a nitrogen atmosphere with 2.2 g of 10% palladium/charcoal and heated to reflux temperature for 4 hours. The resulting suspension is cooled to room temperature, filtered and the solid is washed with 50 ml of ethanol and twice with 50 ml of methylene chloride, each time. Then, the filtrate and the washings are evaporated and the residue is taken up in a mixture of ethyl acetate and water (5:4, total 450 ml). The organic phase is washed with 100 ml of sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. In this manner, there are obtained 17.5 g (96%) of ethyl 6,7,8,9-tetrahydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate as a beige solid, m.p. 116°-120° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][NH:10][CH2:11][CH:12]1[CH2:14][CH2:13]1)C.[H][H].[ClH:32]>C(O)C.[Pd]>[ClH:32].[CH:12]1([CH2:11][N:10]2[CH2:9][CH2:8][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:6][CH2:5][CH2:4]2)[CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: CCOC(COC(CCNCC1CC1)(c1ccccc1)c1ccccc1)OCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(C2(c3ccccc3)CCN(CC3CC3)CCO2)cc1

Procedure:
The solution of 6.0 g of 2-(3-cyclopropylmethylamino-1,1-diphenylpropoxy)-acetaldehyde diethyl acetal in 60 ml of 95% ethanol and 10 ml of 6N hydrochloric acid is stirred at 20-45° for 3 hours, cooled and 0.5 g of 10% palladium on charcoal are added. The mixture is hydrogenated at 2.7 atm. and 40° until the hydrogen uptake ceases. It is filtered, the filtrate neutralized with aqueous sodium hydroxide and evaporated. The resudue is partitioned between water and methylene chloride, the organic phase separated, dried and evaporated. The residue is taken up in the minimum amount of acetone, the solution acidified with hydrogen chloride and diluted with diethyl ether, to yield the 4-cyclopropylmethyl-7,7-diphenyl-hexahydro-1,4-oxazepine hydrochloride melting at 268°-270°; it is identical with compound No. 11 of Example 2.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12](=[O:19])[CH2:13][C:14]([O:16]CC)=[O:15])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C(O)C>[C:1]([C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:12](=[O:19])[CH2:13][C:14]([OH:16])=[O:15])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)N1CC(Oc2ccccc2C(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccccc1OC1CN(C(=O)CC(=O)O)C1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
To an ice-cold stirred solution of ethyl 3-(3-(2-tert-butylphenoxy)azetidin-1-yl)-3-oxopropanoate (0.26 g, 0.81 mmol) in ethanol (10.0 mL) was added lithium hydroxide (2.44 ml of 1.0 M solution in water, 2.44 mmol) and the mixture was warmed at room temperature. After 2 h the reaction mixture was adjusted to about pH 1 with 1.0 M hydrochloric acid and concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The yellow residue was recrystallized from heptane/ethyl acetate to provide 3-(3-(2-tert-butylphenoxy)azetidin-1-yl)-3-oxopropanoic acid (0.12 g, 51%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCN12
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)n1
Yield: 64 %

Procedure:
A solution of 1.1 g (0.00281 mol) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 70 ml of tetrahydrofuran was treated with 7.7 ml (0.0562 mol) of dipropylamine. After stirring at reflux for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with ethyl acetate as the eluent and recrystallized from ethyl acetate/ether. There was obtained 0.82 g (64%) of (S)-8-chloro-1-(4-dipropylaminomethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepin-9-one as white crystals; m.p. 200°-201° and [α]D20 =-181.2° (CHCl3, c=1%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[CH2:30](N)[CH2:31][NH2:32]>>[NH:5]1[CH2:30][CH2:31][N:32]=[C:4]1[C:3]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:9][C:2]=1[NH2:1]
Reactant: NCCN
Reactant: N#Cc1ccc(N2CCOCC2)cc1N
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: Nc1cc(N2CCOCC2)ccc1C1=NCCN1
Temperature: 140 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a solution of 2-amino-4-(morpholin-4-yl)benzonitrile 3.65 g (18.0 mmol) in ethylenediamine 20mL was added phosphorus pentasulfide 4.00 mg (0.018 mmol) and stirred at 140° C. for 16 hours. After cooling to room temperature, the solvent was evaporated. The residue was washed with water and diethyl ether to give the title compound 3.70 g as off-white solid. Yield 83.5%.
Reaction SMILES: [CH3:1][NH:2][N+:3]([O-:5])=[O:4].[C:6]1(Cl)[C:7](=[CH:11][C:12](=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[N+:13]([O-:15])=[O:14])[N+:8]([O-:10])=[O:9]>>[CH3:1][N:2]([N+:3]([O-:5])=[O:4])[C:11]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CN[N+](=O)[O-]
Product: CN(c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-])[N+](=O)[O-]

Procedure:
Methylnitramine decomposes explosively in contact with concentrated sulfuric acid. It is evolved when aniline reacts with tetryl; a diphenylamine derivative is produced simultaneously. Methylnitramine reacts with picryl chloride to form tetryl.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].[N+:28]([C:31]1[CH:32]=[C:33]([S:37]([CH2:40][CH2:41][O:42][C:43](=[O:65])[CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:64])[CH2:49][O:50][C:51]2[CH:56]=[CH:55][C:54]([S:57](Cl)(=[O:59])=[O:58])=[C:53]([CH:61]([CH3:63])[CH3:62])[CH:52]=2)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29].O>C(Cl)Cl>[N+:28]([C:31]1[CH:32]=[C:33]([S:37]([CH2:40][CH2:41][O:42][C:43](=[O:65])[CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:64])[CH2:49][O:50][C:51]2[CH:56]=[CH:55][C:54]([S:57]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:59])=[O:58])=[C:53]([CH:61]([CH3:62])[CH3:63])[CH:52]=2)(=[O:38])=[O:39])[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: CC(C)c1cc(OCC(=O)NCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)ccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)NCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1C(C)C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (500 mg, 1.36 mmol) in CH2Cl2 (10 mL) was added NaH (40 mg, 1.65 mmol) at room temperature resulting in a clear solution. To this clear mixture was added 4-(4-chlorosulfonyl-3-Isopropylphenoxyactamido)-butyric acid 2-(3-nitrobenzenesulfonyl)ethyl ester (Intermediate 26, 1.0 g, 1.70 mmol, 1.25 eq) in CH2Cl2 (5 mL) at room temperature, and then the mixture was stirred for 2 h. Thereafter water was added, the mixture was extracted with CH2Cl2, the organic layers were dried and concentrated under reduced pressure. The residual oil was purified by column chromatography (CH2Cl2 to 3% MeOH in CH2Cl2) to yield Intermediate 27 (1.0 g, 80%) as an off-white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][N:12](C(=O)C)[CH2:13][CH2:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2].[ClH:18]>CCO.O>[ClH:18].[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][NH:12][CH2:13][CH2:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc2c1CN(C(C)=O)CC2
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1noc2c1CNCC2

Procedure:
31.1 g (130 mmol) of 5-acetyl-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester (C) were dissolved in 30 mL of EtOH and combined at RT with 30 mL (260 mmol) of 32% (weight percent) hydrochloric acid solution in water. After two hours' heating with refluxing, the solution was evaporated and introduced into 500 mL of cooled EtOAc (ice bath). The resultant precipitate was separated and dried under a vacuum. 8.13 g (27% of theoretical) of the desired product 4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester hydrochloride (D) were obtained.
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:9][C:10]([CH2:23][C:24]2[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:31])=[N:11][C:12](=[O:22])[C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[Li+].[OH-].O>O1CCCC1>[CH2:15]([O:14][C:13]1[C:12](=[O:22])[N:11]=[C:10]([CH2:23][C:24]2[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=2[Cl:30])[NH:9][C:8]=1[C:6]([OH:7])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Yield: 95.8 %

Procedure:
5-(Benzyloxy)-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid tert-butyl ester (61) (0.24 g, 520 μmol, Eq: 1.00) and LiOH (62.3 mg, 2.6 mmol, Eq: 5) were stirred in tetrahydrofuran (2 ml)/water (1.00 ml) at reflux overnight. The solvent was mostly removed. The residue was taken up in water and was extracted once with ethyl acetate. The aqueous layer was acidified with HCl conc. The precipitate was collected by filtration, washed with water and dried to afford 5-benzyloxy-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (62) (0.202 g, 498 μmol, 95.8% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:17][C:16]3[NH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>CN(C)C=O>[CH3:19][S:20]([N:15]1[C:16]2[CH2:17][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10][C:11](=[O:18])[C:12]=2[CH:13]=[CH:14]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1ccc2c1CC(c1ccccc1)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a suspension of 60% sodium hydride (0.18 g, washed with hexane thrice) in dimethylformamide (10 ml was added 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methanesulfonylchloride (0.48 g) in dimethylformamide (3 ml), and the mixture was stirred at the same temperature for 3 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) and recrystallized from ethyl acetate-hexane to give colorless crystals of 1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.51 g).