Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].C([N:15](CC)CC)C>C(Cl)Cl>[NH2:15][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: CCN(CC)CC
Reactant: O=C(NCCO)c1ccccn1
Solvent: ClCCl
Product: NCCNC(=O)c1ccccn1
Reaction time: 2 h

Procedure:
3.0 g of N-(2-hydroxyethyl)pyridine-2-carboxamide were placed in a round flask with 20 ml of methylene chloride and 2.5 ml of triethylamine and the mixture was cooled to 0°-5°. A solution of 1.4 ml of methanesulfochloride in 30 ml of methylene chloride was added dropwise thereto while cooling well at 0°-5°. The reaction mixture was stirred at 0°-5° for a further 2 hours and thereafter added dropwise at 0°-5° to 30 ml of concentrated (25%) ammonia. The reaction mixture was stirred at room temperature overnight and thereafter concentrated under reduced pressure. The residue was dissolved in methylene chloride, extracted with 2N hydrochloric acid and washed with water. The aqueous extracts were combined, made basic with concentrated (28%) sodium hydroxide solution and extracted 3 times with methylene chloride. The organic extracts were dried over magnesium sulfate, filtered and evaporated. There was obtained a yellow oil which was chromatographed on silica gel for further purification. As the elution agent there was used firstly ethyl acetate, thereafter an ethyl acetate/alcohol mixture and finally alcohol. There was obtained N-(2-aminoethyl)pyridine-2-carboxamide which, in accordance with thin-layer chromatography, was identical with the compound described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(F)ccc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 28 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a stirred solution of 2,5-difluorotoluene (0.544 g, 4.25 mmol, Aldrich, used as received) in conc. H2SO4 (5.0 mL) at 0° C., KNO3 (0.430 g, 4.25 mmol) was added in one portion. The resulting pale yellow solution was warmed to 28° C. and stirred at that temperature overnight. It was then poured into ice (25 g) and extracted with ethyl acetate (40 mL). The extract was dried over Na2SO4 and evaporated to afford 0.555 g (91%) of the title compound as a light red oil; 1H NMR (CDCl3): 2.369 (d, 3H, J=1.8 Hz), 7.127 (dd, 1H, J1=8.1 Hz, J2=6.0 Hz), 7.734 (dd, 1H, J1=8.4 Hz, J2=6.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([O:28][CH3:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:31]1([NH2:37])([CH:34]2[CH2:36][CH2:35]2)[CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C)C=O>[C:31]1([NH:37][C:21]([C:20]2[C:15]([NH:14][C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([O:28][CH3:29])[CH:11]=3)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]3[C:19]=2[NH:24][N:25]=[CH:26]3)=[O:23])([CH:34]2[CH2:36][CH2:35]2)[CH2:33][CH2:32]1
Reactant: NC1(C2CC2)CC1
Reactant: COc1cc(-c2nc3c(C)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2c(C)cc3cn[nH]c3c2C(=O)NC2(C3CC3)CC2)n(-c2ncccc2Cl)n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 8 mL of N,N-dimethylformamide is added 244 mg (1.83 mmol) of bicyclopropyl-1-ylamine hydrochloride and 340 μL (2.44 mmol) of triethylamine. The reaction is stirred at 70° C. for 16 hours and then concentrated in vacuo. The residue is taken-up with water and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed several times with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 3:7) affords 90 mg (15% over two steps) of product as a pale yellowish solid; LC/MS:506/508 (M+H)+, m.p.: 150-154° C.
Reaction SMILES: C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1(O)[CH2:36][C@@H:35]2[C@@H:31]([CH2:32][C:33]3([O:40][CH2:39][CH2:38][O:37]3)[CH2:34]2)[CH2:30]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH2:36][C@@H:35]2[C@@H:31]([CH2:32][C:33]3([O:37][CH2:38][CH2:39][O:40]3)[CH2:34]2)[CH:30]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC1(CCCCCOCc2ccccc2)C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Solvent: c1ccccc1
Product: C1=C(CCCCCOCc2ccccc2)C[C@H]2CC3(C[C@@H]12)OCCO3
Reaction time: 3.5 h
Yield: 97.2 %

Procedure:
Ethylene glycol (0.05 ml) and 10 mg of p-toluenesulfonic acid were added to a solution of 209 mg of 3-(5-benzyloxypentyl)-7,7-ethylenedioxy-3-hydroxy-cis-bicyclo[3,3,0]octane (prepared as described in Preparation 9) in 2 ml of benzene, and the mixture was heated, with stirring, for 3.5 hours, whilst removing water as an azeotropic mixture. Upon completion of the reaction, the reaction mixture was neutralized with a 5% w/v aqueous solution of sodium bicarbonate. The reaction mixture was then washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off from the reaction mixture under reduced pressure, giving 193 mg of a residue. This residue was purified by silica gel column chromatography and 142 mg of the title compound were obtained as an oil from the fractions eluted with hexane containing 2-5% by volume of ethyl acetate. The product had the same properties as that of Preparation 4.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.S(Cl)([Cl:15])=O>>[ClH:15].[Cl:15][CH2:2][C:3]1[N:4]=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: OCc1cc2ccccc2cn1
Reactant: O=S(Cl)Cl
Product: Cl
Product: ClCc1cc2ccccc2cn1
Temperature: 5 °C

Procedure:
3-Hydroxymethylisoquinoline (110 g) is added to thionyl chloride (130 cc), whilst cooling so as to keep the temperature between 25° C. and 30° C. The reaction mixture is then heated to the reflux temperature at a rate which is such that the evolution of gas is not excessive. The mixture is heated under reflux for 90 minutes (until the evolution of gas ceases) and then for a further 30 minutes. It is cooled to 5° C. with ice, the slurry formed is filtered and the solid is washed with diethyl ether. 3-Chloromethylisoquinoline hydrochloride (136 g), melting at 202° C., is obtained.
Reaction SMILES: Cl[C:2]1[C:3]([N+:21]([O-:23])=[O:22])=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH3:24][SeH-:25](C)=[Se].[BH4-].[Na+].N1C=CN=CC(=O)C=1.C(CN)O>C(O)(C)C.O1CCOCC1>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[C:3]([N+:21]([O-:23])=[O:22])[C:2]([Se:25][CH3:24])=[N:12][C:11]1=2)[CH3:14]
Reactant: CCN1c2ncccc2C(=O)Nc2c1nc(Cl)c([N+](=O)[O-])c2C
Reactant: C[SeH-](C)=[Se]
Agent: O=c1cnccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: NCCO
Product: CCN1c2ncccc2C(=O)Nc2c1nc([Se]C)c([N+](=O)[O-])c2C
Temperature: 110 °C
Reaction time: 72 h

Procedure:
To a mixture of 2-chloro-5,11-dihydro-11-ethyl-4-methyl-3-nitro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.063 g) and dimethyldiselenide (0.11 g) in isopropanol (0.5 mL) in a pressure tube was added sodium borohydride (0.006 g). The tube was sealed and heated at 110° C. for 5 minutes and then left at room temperature for 3 days. The mixture was eluted from a short silica gel column (chloroform) and then fractionated by preparative layer chromatography to give a mixture of 2-chloro-5,11-dihydro-11-ethyl-4-methyl-3-nitro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 5,11-dihydro-11-ethyl-4-methyl-2-methylseleno-3-nitro- 6H-dypyrido[3,2-b:2', 3'-e][1,4]diazepin-6-one. The mixture was dissolved in dioxan (1 mL) and ethanolamine (0.1 g) was added. The mixture was heated at 100° C. for 2 hours whereupon the remaining starting material had reacted. Evaporation of the solvent and chromatography over silica gel gave the title compound which crystallized on trituration with diisopropyl ether, m.p. 261°-267° C. dec.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Na+].[Na+].[C-]#N.[Na+].[Cu][C:11]#[N:12].Cl.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.CCOC(C)=O>[CH3:20][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[O:4][C:1]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)[C:11]#[N:12]
Reactant: N#C[Cu]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)ccc1Oc1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 17 %

Procedure:
The amine prepared above (2.75 g, 13.8 mmol) was added to 2N HCl (20 mL), then cooled to 5° C., giving a thick purple slurry. A solution of sodium nitrite (0.84 g, 14.2 mmol) in water (2 mL) was added dropwise, keeping the reaction temperature -5° C. Addition of another small portion of sodium nitrite to the reaction resulted in a positive HONO test with a Kl-starch strip, so the pH was adjusted to 7-8 using solid Na2CO3. This solution was added in portions to a vigorously stirred mixture of toluene (10 mL) and a solution of sodium cyanide (1.65 g, 33.6 mmol) and copper(I) cyanide (1.45 g, 16.2 mmol) in water (15 mL), keeping the reaction temperature -5° C. The very thick, brown reaction mixture was diluted with more toluene, stirred at 5° C. for 15 minutes, then at room temperature for 2 hours. The reaction mixture was added to EtOAc and 2N HCl; the organic layer was dried with Na2SO4 and concentrated in vacuo. The residue obtained was chromatographed eluting with 95:5 hexane-Et2O to give the title compound as an orange-red oil (500 mg, 17%). 1H NMR (CDCl3) δ 7.55 (d, 1H), 7.40 (m, 3H), 7.20 (m, 1H), 7.00 (m, 2H), 6.79 (d, 1H), 2.35 (s, 3H). MS (DCl/NH3) m/e 227 (M+H+NH3)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].Cl.[OH:13][CH:14]1[CH2:17][NH:16][CH2:15]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:16]1[CH2:17][CH:14]([OH:13])[CH2:15]1)=[S:11]
Reactant: OC1CNC1
Reactant: S=C=Nc1ccc(Br)cc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OC1CN(C(=S)Nc2ccc(Br)cc2Br)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,4-Dibromophenylisothiocyanate (CAS #13037-63-3, 3.02 g, 0.0103 mole), and 3-hydroxyazetidine hydrochloride (CAS #18621-18-6, 1.18 g, 10.8 mmol) were suspended in acetonitrile (35 mL). Triethylamine (1.53 mL, 0.011 mole) was added dropwise to the stirred suspension. After 20 minutes of stirring at room temperature, the reaction mixture had become a light yellow solution. After another 10 minutes of stirring at room temperature, the isothiocyanate was consumed and the intermediate, N-(2,4-dibromophenyl)-3-hydroxyazetidine-1-carbothioamide had formed. Although not necessary, this intermediate thiourea was isolated and purified by partitioning between 1:1 hexane/ethyl acetate (150 mL) and 1 M aqueous KH2PO4 (35 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and dried (Na2SO4). The filtrate was partially concentrated at which point the thiourea crystallized. The crystals were collected by filtration and dried under vacuum to provide N-(2,4-dibromophenyl)-3-hydroxyazetidine-1-carbothioamide.
Reaction SMILES: COC1C=CC(C[O:8][N:9]([CH2:20][CH2:21][CH2:22][P:23](=[O:30])([O:27]CC)[O:24]CC)[S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=CC=1.Cl.C(O)(=[O:36])C>>[C:16]1([CH3:17])[CH:15]=[CH:14][C:13]([S:10]([OH:11])(=[O:12])=[O:36])=[CH:19][CH:18]=1.[OH:8][NH:9][CH2:20][CH2:21][CH2:22][P:23](=[O:24])([OH:30])[OH:27]
Reactant: CCOP(=O)(CCCN(OCc1ccc(OC)cc1)S(=O)(=O)c1ccc(C)cc1)OCC
Reactant: CC(=O)O
Agent: Cl
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: O=P(O)(O)CCCNO
Reaction time: 12 h

Procedure:
A mixture of diethyl 3-[N-(p-methoxybenzyloxy)-N-tosylamino]propylphosphonate (3.0 g), 6 N hydrochloric acid (25 ml) and acetic acid (25 ml) was refluxed with stirring for 12 hours. The resultant mixture was concentrated under reduced pressure to give a brownish oily residue. The residue was washed with ethyl ether (100 ml), and then water (100 ml) was added thereto with stirring. Insoluble materials were filtered off from the mixture, whereafter the filtrate was washed with ethyl ether, and then treated with an activated charcoal. The aqueous solution was concentrated under reduced pressure to give a faint yellowish oily residue. The residue was allowed to stand overnight in desiccator under reduced pressure to give crystals. The crystals were washed with ethyl ether to give p-toluene sulfonic acid salt of 3-(N-hydroxyamino)propylphosphonic acid (1.50 g) in the form of fiant yellowish crystals. MP: 129°-135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1>[CH:30]1([C:33]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=2)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]3)=[O:34])[CH2:32][CH2:31]1
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Yield: 75.2 %

Procedure:
A mixture of (3R)-3-(7-amino-1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide (450 mg, 1 mmol) and cyclopropane carbonyl chloride (0.13 mL, 1.4 mmol) in tetrahydrofuran (5 mL) was heated to reflux for 15 min. To the mixture was added 50% sodium hydrogen carbonate (40 mL) and ethyl acetate (50 mL). The organic layer was washed with sodium hydrogen carbonate (sat, 20 mL) and brine (20 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (Silica Gel, 1:1 ethyl acetate:methylene chloride) to give (3R)-3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide as a white solid (0.35 g, 67% yield); mp, 92-94° C.; 1H NMR (CDCl3) ˜0.82-0.89 (m, 2H, CH2), 1.05-1.11 (m, 2H, CH2), 1.43 (t, J=6.9 Hz, 3H, CH3), 1.64-1.70 (m, 1H, CH), 2.90 (s, 3H, CH3), 3.05 (dd, J=5.5, 16 Hz, 1H, CHH), 3.10 (s, 3H, CH3), 3.52 (dd, J=9.5, 15 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.07 (q, J=7 Hz, 2H, CH2), 4.26 (d, J=17 Hz, 1H, CHH), 4.44 (d, J=17 Hz, 1H, CHH), 5.60 (dd, J=5.7, 9.4 Hz, 1H, NCH), 6.82 (d, J=8.7 Hz, 1H, Ar), 6.93-6.99 (m, 2H, Ar), 7.39 (t, J=7.9 Hz, 1H, Ar), 8.39 (d, J=8.2 Hz, 1H, Ar), 10.59 (s, 1H, NH); 13C NMR (CDCl3) δ 8.04, 14.64, 16.03, 35.46, 36.19, 37.31, 48.72, 53.56, 55.85, 64.46, 111.41, 112.52, 116.56, 117.41, 117.82, 119.13, 131.79, 132.84, 137.84, 141.54, 148.48, 149.04, 169.50,169.58, 172.51; Anal Calcd for C26H31N3O5+0.5 H2O: C, 65.81; H, 6.80; N, 8.85; H2O, 1.90. Found: C, 65.83; H, 6.72; N, 8.72; H2O, 1.94.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.CCN(C(C)C)C(C)C.[NH2:24][CH2:25][CH2:26][OH:27]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:24][CH2:25][CH2:26][OH:27])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Fluoro-3-nitro-benzoic acid methyl ester (3 g, 15.64 mmol) was dissolved in DMF (20 ml) and DIPEA (5.8 g, 18.07 mmol) was added. 2-Aminoethanol (1.1 g, 18.07 mmol) was then added slowly by maintaining the temperature <20° C. Stirring continued at ambient temperature for 1 h. After checking the completion of reaction by TLC, the reaction mixture was added onto the ice cold water. The yellow solid which separated out was filtered, washed with cold water and finally washed with hexane affording 3.3 g (92%) of 4-(2-hydroxyethylamino)-3-nitro-benzoic acid methyl ester. 1H NMR (300 MHz, CDCl3) δ 3.5 (q, 2H), 3.7 (q, 2H), 3.9 (s, 3H), 5.1 (t, 1H), 7.2 (d, 1H), 8.0 (d, 1H), 8.6 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH3:28])[C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:29]O>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH3:28])[C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1C
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1C

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethyl-phenylmercapto)-butoxy]-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH:15]=O)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH3-]C#N.[Na+]>CC(O)=O.CO>[CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH2:15][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=CC12CC1CCN(Cc1ccccc1)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CN2CCC3CC3(CNc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-Benzyl-3-aza-bicyclo[4.1.0]heptane-1-carbaldehyde (174) (300 mg, 1.39 mmol) in 5% HOAc in MeOH (2 ml) was added aniline (0.38 ml, 4.18 mmol) and NaCNBH3 (250 mg, 3.97 mmol). The mixture was stirred at room temperature 2 hrs. MeOH was removed by evaporation. Water (5 mL) was added to the residue. The mixture was neutralized with 2N KOH to pH=10. Extraction with CH2Cl2 (2×10 ml) followed by standard work-up provided crude 175 which was purified by silica gel chromatography (1% MeOH in CH2Cl2). LRMS (calculated for C20H25N2, M+1) 293. found 293.
Reaction SMILES: O=C1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([C:21]#[N:22])=[CH:19][CH:20]=[C:3]12.Cl.[NH2:24][OH:25].C(N(CC)C(C)C)(C)C.[CH3:35][OH:36]>C(Cl)Cl.CN(C)C=O>[OH:25][NH:24][C:21]([C:18]1[N:4]2[CH:5]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=3)[NH:7][C:35](=[O:36])[C:3]2=[CH:20][CH:19]=1)=[NH:22]
Reactant: N#Cc1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NO
Reactant: CO
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)c1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Yield: 70 %

Procedure:
A mixture of 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carbonitrile (Example 2), (0.05 g, 0.16 mmol), hydroxylamine hydrochloride (15 mg, 0.22 mmol) and N,N-diisopropylethylamine (86.4 μL, 0.49 mmol,) was stirred in methylene chloride (0.5 mL), methanol (0.5 mL) and N,N-dimethylformamide (0.2 mL) at 45° C. for 2 d. At this time, the resulting solids were collected by filtration to afford N-hydroxy-1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carboxamidine (40 mg, 70%) as an off-white solid. 1H NMR (methanol-d4) δ ppm 7.83 (q, J=8.4 Hz, 4H), 7.73 (s, 2H), 7.37 (s, 1H). LC-MS calcd. for C15H12F3N4O2 [(M+H)+] 337, obsd. 337.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=1.[CH2:18]([Mg]Br)[CH3:19]>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:15])[CH2:12][CH2:13][CH2:8][CH2:9][CH2:10][CH2:11][CH2:18][CH3:19])=[CH:10][CH:9]=1
Reactant: CC[Mg]Br
Reactant: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CCCCCCCCC(O)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-formyl-benzoylamino)-propionic acid methyl ester (1.2 g, 5 mmol) in THF (10 mL) at 0° C. is added ethylmagnesium bromide (2M, 1.1 mL). After stirring at room temperature for 2 hours, it is quenched with saturated ammonium chloride, extracted with EtOAc. The organic is concentrated to give the titled compound as colorless oil: 270 mg (15%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:19]2=[CH:20][CH:21]=[N:22][CH:23]=[C:18]2[C:5]2[C:6]([OH:17])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:25].[N:26]1([CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:25].[CH3:24][C:2]1([CH3:1])[C:19]2=[CH:20][CH:21]=[N:22][CH:23]=[C:18]2[C:5]2[C:6]([O:17][C:35](=[O:36])[CH2:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(2-heptyl)-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-8-(2-heptyl)-10-hydroxy-5H[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH2:22][CH2:23][S:24][CH3:25])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].[P:26](Cl)(Cl)(=[O:38])[O:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(Cl)[Cl:42]>>[Cl:42][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]=1[O:27][P:26](=[N:12][C@@H:13]([CH2:22][CH2:23][S:24][CH3:25])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:15])=[O:38]
Reactant: ClCCl
Reactant: CSCC[C@H](N)C(=O)OCC(C)(C)C
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CSCC[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)OCC(C)(C)C
Yield: 41 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates the tosylate salt of (S)-neopentyl 2-amino-4-(methylthio)butanoate (2.00 g, 5.11 mmol), naphthalene-1-yl phosphorodichloridate (1.30 g, 5.11 mmol) and TEA (1.42 mL, 10.22 mmol) in 30 mL of dry DCM, were combined to give (2S)-neopentyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)-4-(methylthio)butanoate in 41% yield (0.92 g), as a clear, yellow, thick oil.