Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH:5]=[C:4]1[CH2:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[OH:32][N:31]=[N:13][CH2:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:3]2[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: CCn1c(CC[C@@H]2CCCN2C(=O)Cc2ccccc2)cc2ccc(C#N)cc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1c(CC[C@@H]2CCCN2C(=O)Cc2ccccc2)cc2ccc(CN=NO)cc21
Yield: 5.3 %

Procedure:
190 mg of 1-ethyl-2-[2-[(S)-1-(2-phenylacetyl)pyrrolidin-2-yl]ethyl]indole-6-carbonitrile obtained in Example 14-a) was dissolved in methanol. 103 mg of hydroxylamine hydrochloride and 210 mg of sodium carbonate were added and the reaction solution was refluxed overnight with stirring. After water was added, the reaction solution was extracted two times with dichloromethane. The extract was dried over MgSO4 and distilled under reduced pressure. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol (20:1)] to obtain 11 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]3[N:23]=[C:24]([OH:26])[CH:25]=[C:19]3[C:18]2=[O:27])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:26][C:24]1[CH:25]=[C:19]2[C:18](=[O:27])[N:17]([C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=3)[CH2:22][CH2:21][N:20]2[N:23]=1
Reactant: O=C1c2cc(O)nn2CCN1c1ccc(F)cc1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C1c2cc(OCc3ccccc3F)nn2CCN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
2-Fluorobenzyl bromide (0.049 mL, 0.39 mmol) was added to a stirred suspension of 5-(4-fluorophenyl)-2-hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.092 g, 0.36 mmol) and Cs2CO3 (0.234 g, 0.72 mmol) in ACN (1.85 mL). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo. The residue was diluted with water and extracted with AcOEt. The organic layer was separated, washed with a saturated solution of NaCl, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 2[(2-fluorobenzyl)oxy]-5-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.109 g, 85% yield) as a white solid. C19H15F2N3O2. 1H NMR (500 MHz, CDCl3) δ ppm 4.14 (dd, J=6.8, 5.1 Hz, 2H), 4.37 (dd, J=6.9, 5.2 Hz, 2H), 5.30 (s, 2H), 6.37 (s, 1H), 7.04-7.15 (m, 3H), 7.17 (td, J=7.5, 0.9 Hz, 1H), 7.28-7.36 (m, 3H), 7.53 (td, J=7.4, 1.4 Hz, 1H).
Reaction SMILES: CN(C1CCCCC1)C.[C:10]([OH:15])(=[O:14])[CH:11]([CH3:13])[OH:12].Cl[CH2:17][Si:18]([CH3:23])([CH3:22])[CH2:19][CH2:20][CH3:21]>C(OCC)C>[CH3:17][Si:18]([CH2:23][O:14][C:10](=[O:15])[CH:11]([OH:12])[CH3:13])([CH3:22])[CH2:19][CH2:20][CH3:21]
Reactant: CC(O)C(=O)O
Reactant: CCC[Si](C)(C)CCl
Solvent: CN(C)C1CCCCC1
Solvent: CCOCC
Product: CCC[Si](C)(C)COC(=O)C(C)O
Temperature: 100 °C

Procedure:
12.7 of N,N-dimethyl-cyclohexylamine were dropped into 9.8 g (0.1 mole) of the S-enantiomer of the lactic acid and 30 g of chloromethyl-dimethyl-n-propyl-silane at room temperature with stirring. The reaction mixture was heated to 100° C. for 16 hours. After cooling the reaction mixture to room temperature 50 ml of diethylether were added, the precipitate which deposited was filtered with suction, the filtrate was concentrated under reduced pressure and the remaining residue was distillated under reduced pressure. 11.7 g (54.2% of theory) of S-enantiomer of the 2-hydroxypropionic acid (dimethyl-n-propyl-silyl)-methylester of a purity of 90% were obtained in this manner. Boiling point: 105°-108° C./18.6 mbar.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].O.CCOC(C)=O>CC(N(C)C)=O>[C:30]([O:29][C:28]([NH:27][C@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]1[NH:20][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1)=[O:34])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1-c1cnn(C)c1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (155 mg, 0.560 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (144 mg, 0.672 mmol) in DMA (2 mL) was stirred at 150° C. for 1 h under microwave irradiation. To the resulting mixture were added H2O and EtOAc. The organic phase was washed with H2O (3×) and brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 to give the title compound as a yellow oil (100 mg, 39.3%). 1H NMR (500 MHz, CDCl3) δ ppm 1.34-1.95 (m, 17H), 3.92 (s, 3H), 3.93 (s, 3H), 4.87 (br s, 1H), 5.66 (br s, 1H), 6.52 (s, 1H), 7.78-7.83 (m, 2H). [M+H] calc'd for C23H30N6O4, 455. found, 455.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[N:16]1([C:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH2:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1ccc(N2CC=C(N3CCCC3)CC2)cc1

Procedure:
A solution of 24 g (0.1199 mol) of the compound of (B), 15 ml (12.78 g/0.1796 mol) of pyrrolidine, 240 mg of p-toluenesulfonic acid, and 100 ml of benzene is stirred at reflux with the azeotropic removal of water for 6 hours. After cooling, the resulting precipitate is collected and triturated with ethyl ether to afford 20 (66%) of title compound: m.p. 126°-129° C.; IR (KBr) 2200, 1635, and 1600 cm-1 ; NMR (CDCl3) δ7.48 (d, 2H), 6.7 (d, 2H), 4.3-4.1 (m, 1H) 3.95-3.45 (m, 4H), 3.2-2.85 (m, 4H) 2.65-2.25 (m, 2H), and 1.95-1.75 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:8]/[OH:9].[Cl:10]NC(=O)CCC(N)=O>CN(C=O)C.C(OCC)C>[OH:9]/[N:8]=[C:7](\[Cl:10])/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O/N=C/c1ccccn1
Reactant: NC(=O)CCC(=O)NCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of (E)-picolinaldehyde oxime (10.0 g, 82.0 mmol) in DMF (30 mL) at room temperature was slowly added over 30 minutes N-chlorosuccinamide (10.9 g, 82.0 mmol). An exotherm was noted during the addition. The reaction mixture was stirred overnight at room temperature, diluted with diethyl ether (300 mL), washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with dichloromethane, and the resulting solid was collected by vacuum filtration and dried to give (Z)—N-hydroxypicolinimidoyl chloride (12.8 g, 51.1 mmol, 62% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (ddd, 1H), 7.83-7.95 (m, 2H), 8.66 (ddd, J=4.73, 1.43, 1.32 Hz, 1H), and 12.64 (s, 1H).
Reaction SMILES: [Cl-:1].[NH4+:2].C[Al](C)C.[CH3:7][C@@H:8]([CH2:12][CH3:13])[CH2:9][C:10]#[N:11].CO>C1(C)C=CC=CC=1>[ClH:1].[CH3:7][C@@H:8]([CH2:12][CH3:13])[CH2:9][C:10]([NH2:2])=[NH:11]
Reactant: CC[C@H](C)CC#N
Reactant: [Cl-]
Reactant: [NH4+]
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CC[C@H](C)CC(=N)N
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In an argon atmosphere, 1.1 g (20.5 mmol) of ammonium chloride are suspended in 20 ml of toluene and cooled to 0° C. 10.29 ml of a 2M solution of trimethylaluminum in toluene are added dropwise, and the mixture is then stirred at RT for 2 h. 1 g (10.29 mmol) of (3S)-3-methylpentanenitrile is then added. The mixture is then stirred at 80° C. overnight. After cooling to 0° C., 40 ml of methanol are added dropwise, and then the resulting solid is filtered off with suction. It is thoroughly washed with methanol several times, and the combined filtrates are concentrated in vacuo. The residue is suspended in dichloromethane/methanol 10:1 and the insoluble solid is again removed. The filtrate then obtained is concentrated and affords 1.01 g (64% of theory) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[C:10]1=[O:18].FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[CH2:50][NH:49][CH2:48]2.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:49]2[CH2:48][C:47]3[C:51](=[CH:52][CH:53]=[C:45]([F:44])[CH:46]=3)[CH2:50]2)=[O:17])[C:10]1=[O:18]
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2Cl)C1=O
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2Cl)C1=O)N1Cc2ccc(F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(2-chloro-4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 268A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 5-fluoroisoindoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.36 (dd, J=6.0, 8.7, 1H), 7.28-7.17 (m, 1H), 7.17-7.12 (m, 1H), 7.09-6.91 (m, 3H), 4.84 (dd, J=8.5, 17.8, 4H), 4.34 (d, J=8.0, 1H), 4.24-4.07 (m, 2H), 3.77-3.56 (m, 2H), 2.76-2.55 (m, 1H), 2.03 (ddd, J=8.6, 12.8, 16.4, 1H); MS (DCI) m/z 391.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][O:10]COCC[Si](C)(C)C)=[CH:4][N:3]=1.[F:19][C:20]1[CH:21]=[C:22]([C:27]2[N:28]=[C:29]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]3[CH3:48])[NH:30][C:31]=2[C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH:23]=[CH:24][C:25]=1[F:26].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:8][C:7]1[CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=[N:3][C:2]=1[N:45]1[CH2:46][CH2:47][N:42]([C:29]2[NH:30][C:31]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:34][CH:33]=3)=[C:27]([C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=3)[N:28]=2)[C@H:43]([CH3:48])[CH2:44]1
Reactant: C[C@@H]1CNCCN1c1nc(-c2ccc(F)c(F)c2)c(-c2ccc(C(F)(F)F)cc2)[nH]1
Reactant: C[Si](C)(C)CCOCOCc1cnc(Cl)c(Cl)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc(-c2ccc(F)c(F)c2)c(-c2ccc(C(F)(F)F)cc2)[nH]1

Procedure:
A mixture of 2,3-dichloro-5-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)pyridine from step (a) above (80 mg, 0.26 mmol), (2R)-1-(4-(3,4-difluorophenyl)-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)-2-methylpiperazine (100. mg, 0.236 mmol, Example 1(d)), and DIEA (0.082 mL, 0.47 mmol, Aldrich) in NMP (0.7 mL) was subjected to microwave irradiation at 170° C. for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on silica gel using ISCO Combiflash® system with EtOAc/Hexanes (1:9) as the eluant to give the title compound as a light brown solid. MS (ESI, positive ion) m/z: 694 (M+1).
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[BrH:28].CC(O)=O>C(Cl)(Cl)Cl>[CH3:26][C:25]([O:24][CH2:23][C@H:21]1[O:22][C@H:5]([Br:28])[C@H:6]([O:7][C:8]([CH3:9])=[O:10])[C@@H:11]([O:12][C:13]([CH3:14])=[O:15])[C@@H:16]1[O:17][C:18]([CH3:19])=[O:20])=[O:27]
Reactant: Br
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Yield: 85 %

Procedure:
β-D-Glucose pentaacetate (2.5 g, 6.41 mmol) was added to HBr-AcOH (30%) with shaking. The reaction mixture was stirred at room temperature for 2 hours. The resultant reaction mixture was diluted with CHCl3 (50 mL), and the mixture was poured into ice water (15 mL). The chloroform layer was separated into an aqueous layer and a chloroform extraction layer (2×20 mL of CHCl3). The chloroform extraction layer was combined with the chloroform layer, and the mixture was then washed with water and dried over MgSO4, to thereby obtain acetobromo-α-D-glucose (4). The solvent was removed under reduced pressure, and the residue was recrystallized from a mixed solution of AcOEt and n-hexane, to thereby obtain a colorless needles 4 (2.23 g, 85%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]2[CH:15]=[CH:16][S:17][C:3]=12.[NH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[NH:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:18][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[N:5]=[C:4]3[CH:15]=[CH:16][S:17][C:3]=23)[CH2:21][CH2:22]1
Reactant: NCC1CCNCC1
Reactant: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Product: Fc1ccc(-c2cc(NCC3CCNCC3)c3sccc3n2)cc1
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (60 mg, 0.23 mmole) in 4-aminomethylpiperidine (1 mL) is heated at 160°C. oil bath under N2 for 4 hours. The reaction mixture is cooled to room temperature and purified on preperative tlc plate to give N-(4-piperidinylmethyl)-5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-amine (15 mg, 19% yield) as a colorless oil. This material is dissolved in 1 mL ethyl acetate. Ethyl acetate saturated with HCl (2 mL) is added and then concentrated to afford N-(4-piperidinylmethyl)-5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-amine dihydrochloride (compound 1) as a greasy oil. The salt is triturated with ether, collected by filtration, washed with ether and dried in vacuo, m.p. >260° C. (dec).
Reaction SMILES: [O-2].[Mg+2].[CH:3](O)=[O:4].C(OC(=O)C)(=O)C.[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][C:16]([OH:18])=O.C(O)(C)C>>[CH:3]([NH:13][C@@H:14]1[C:19](=[O:20])[O:21][C:16](=[O:18])[CH2:15]1)=[O:4]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=CO
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)O
Product: O=CN[C@H]1CC(=O)OC1=O
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
0.12 grams (0.003 mole) of magnesium oxide, a catalyst, was dissolved in 16 milliliters (ml) (0.405 mole) of 95% formic acid. 60.2 ml of acetic anhydride was then added to the aforementioned solution which was heated to 35°-40° C. for 10-15 minutes. Subsequently, 39.93 grams (0.3 mole) of L-aspartic acid was added and this mixture was stirred for 2.5 hours at 50±2° C. At this point, an additional 8.6 ml of acetic anhydride was added and the reaction continued for an additional 2.5 hours at 50±2° C. 9.2 ml (0.120 mole) of isopropyl alcohol was then added to the reaction mixture and heating was continued for an additional two hours. N-formyl aspartic anhydride was formed at this point as shown by high performance liquid chromatography (HPLC).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][N:26]=[C:27]=[O:28].[NH:29]1[CH2:33][CH:32]=[CH:31][CH2:30]1.O>O1CCCC1>[O:16]=[C:9]1[N:10]2[CH2:15][CH2:14][N:13]([C:27]([NH:26][CH2:25][CH2:24][N:29]3[CH:33]=[CH:32][CH:31]=[CH:30]3)=[O:28])[CH2:12][CH:11]2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:8]1
Reactant: O=C=NCCBr
Reactant: C1=CCNC1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCn1cccc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.20 g, 0.68 mmol) was dissolved in tetrahydrofuran (7 mL). 2-Bromoethyl isocyanate (0.07 mL, 0.77 mmol) was added thereto at 0° C., and the mixture was stirred for 1 hour without modification. The reaction solution was concentrated under reduced pressure and dissolved in N-methyl-2-pyrrolidinone (7 mL). 3-Pyrroline (0.21 mL, 2.7 mmol) was added thereto, and the mixture was stirred at 60° C. for 25 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. Then, the organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with amino silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate) and silica gel column chromatography (hexane:ethyl acetate=8:2 to ethyl acetate) to obtain the title compound (0.21 g, yield 72%) as amorphous.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH2:20][OH:21])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:22]([O-:24])=[O:23])[C:7](=[O:25])[C:6]=1[CH2:26]Cl)([CH3:4])([CH3:3])[CH3:2].[OH:28][CH2:29][CH2:30][SH:31].C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[O:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH2:20][OH:21])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:22]([O-:24])=[O:23])[C:7](=[O:25])[C:6]=1[CH2:26][S:31][CH2:30][CH2:29][OH:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCS
Reactant: CC(C)(C)c1on(-c2ccc(S(=O)(=O)CCO)cc2[N+](=O)[O-])c(=O)c1CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1on(-c2ccc(S(=O)(=O)CCO)cc2[N+](=O)[O-])c(=O)c1CSCCO

Procedure:
15 g of 5-t-butyl-4-chloromethyl-2-(4-(2-hydroxyethylsulfonyl)-2-nitrophenyl)-4-iso-oxazolin-3-one was dissolved in 150 ml of tetrahydrofuran, 2.8 g of 2-hydroxyethanethiol and 4 g of triethylamine were added and the mixture was reacted at room temperature for a period of 5 hours. After reaction, the solvent was removed by distillation, ethyl acetate and water (150 ml:100 ml) were added and the mixture was partitioned. The organic layer was recovered, the solvent was removed by distillation and the residue obtained was used without further refinement in step 6.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:11]1[CH:20]=[N:19][C:18]2[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[CH:17]=2)[N:12]=1>CN(C=O)C>[CH:3]1([O:9][C:11]2[CH:20]=[N:19][C:18]3[C:13](=[CH:14][C:15]([O:23][CH:24]4[CH2:7][CH2:8][CH2:3][CH2:4][CH2:5]4)=[C:16]([O:21][CH3:22])[CH:17]=3)[N:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCCC1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(OC3CCCCC3)nc2cc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a DMF solution (5 mL) of NaH (0.32 g, 8 mmol) under argon, cyclohexanol (0.7 mL. 6.7 mmol) is added dropwise. The mixture is stirred at room temperature for 25 minutes, then 2-chloro-6,7-dimethoxyquinoxaline is added portionwise. The reaction is stirred for 15 minutes at room temperature, at 90° C. for 2 hours, and at 110° C. for 1 hour. The mixture is cooled, quenched with H2O, and partition between EtOAc/H2O. The organic layer is washed with H2O and brine, dried (MgSO4), and chromatographed (10% EtOAc/hexanes) to provide a waxy white solid (m.p. 75-78° C.). Anal. Calcd. for C21H28N2O3: C, 70.76; H, 7.92; N, 7.86; Found: C, 70.81; 1H, 7.79; N, 7.70.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCCC(=O)OC)ccc(C(C)=O)c1O
Yield: 59.7 %

Procedure:
A mixture of 4.30 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 5.10 g of methyl 8-bromooctanoate and 4.55 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 30 ml of anhydrous dimethyl formamide was stirred at reflux for 20 hours. The usual workup followed by purification by high pressure liquid chromatography using a solvent of 15% ethyl acetate-hexane gave 4.5 g (58% yield) of 8-(4-acetyl-3-hydroxy-2-propylphenoxy) octanoic acid methyl ester, the titled compound, mp 39-41°, after crystallization from hexane.
Reaction SMILES: [CH:1]([N+:8]([O-:10])=[O:9])([N+:5]([O-:7])=[O:6])[N+:2]([O-:4])=[O:3].[CH2:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CO>[N+:2]([C:1]([N+:8]([O-:10])=[O:9])([N+:5]([O-:7])=[O:6])[CH2:11][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([O-:4])=[O:3]
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=C(C(=O)OCC)C(=O)OCC
Solvent: CO
Product: CCOC(=O)C(CC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])C(=O)OCC

Procedure:
Carefully controlled reaction conditions are required because the addition of a nucleophile (nitro- or halonitroalkyl ion) to a methylenemalonate ester gives the salt of an alkylmalonate which is itself capable of undergoing further nucleophilic reactions. Nitroform, a strong acid, reacts with diethyl methylenemalonate in aqueous methanol at ambient temperature, without a base as catalyst, to produce diethyl 2,2,2-trinitroethylmalonate. The same conditions may also be used to produce dimethyl 2,2,2-trinitroethylmalonate. The reaction of 1,1-dinitroethane with methylenemalonates does not take place under these conditions, presumably because the nitro compound is not sufficiently ionized. However, the addition of triethylamine to an ether solution of 1,1-dinitroethane and dimethyl methlenemalonate at 0° C. resulted in a 72% yield of dimethyl 2,2-dinitropropylmalonate. In the same manner, diethyl 2,2-dinitropropylmalonate may be prepared. Finally, the addition fluorodinitromethane to methylenemalonates in ether solution in the presence of catalytic amounts of pyridine produces good yields of dimethyl and diethyl 2-fluoro-2,2-dinitroethylmalonates.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)(=[O:27])=[O:26]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)N2CCOCC2)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (149 mg, 0.322 mmol) in 5 mL of dichloromethane at 0° C. was added triethylamine (0.050 mL, 0.39 mmol), followed by morpholine (0.040 mL, 0.48 mmol). After four hours, the mixture was concentrated in vacuo to give the crude titled product. ESI+MS: 513.1 [M+H]+.