Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:22]=[CH:13][C:12]([CH3:17])=[CH:4][CH:23]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.10 g, 0.22 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (s, 3 H) 4.14 (s, 2 H) 6.92 (s, 1 H) 7.13 (d, J=8.09 Hz, 2 H) 7.28 (d, J=2.94 Hz, 1 H) 7.30 (d, J=5.88 Hz, 2 H) 7.56 (t, J=7.72 Hz, 1 H) 7.67 (d, J=8.46 Hz, 1 H) 7.79 (t, J=7.72 Hz, 1 H) 7.94 (d, J=7.72 Hz, 1 H) 8.22 (d, J=5.52 Hz, 1 H) 14.21 (s, 1 H) 14.82 (s, 1 H). MS (ESI−) m/z 465 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[C:38]([S:40][CH3:41])[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[CH:35]=[CH:34][CH:33]=[CH:32][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=[O:44].C(OO)(C)(C)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:39]=[C:38]([S:40]([CH3:41])=[O:44])[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[CH:35]=[CH:34][CH:33]=[CH:32][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CSc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: CC(C)(C)OO
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 8 h
Yield: 133.3 %

Procedure:
The 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (291 mg, 0.49 mmol) was dissolved in chloroform (2.5 mL). Camphorsulfonic acid (20 mg, 0.09 mmol) was added, followed by t-butyl hydroperoxide solution (0.1 mL, 1.00 mmol). The reaction was stirred overnight and then loaded directly onto a column for flash column chromatographic purification (about 30 g silica, 10% EtOAc/CH2Cl2 through 100% EtOAc). The pure material (75 mg, 0.12 mmol, 25%) was obtained as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:28][CH:29]=4)[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2ccc(CNC(=O)c3ccc(OC(F)(F)F)cc3)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.4 mmol) in acetonitrile (10 mL), was added 4-trifluoromethoxy-benzoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.63 mL, 3.6 mmol). The mixture was stirred at room temperature for one hour. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethoxy-benzamide as an off-white solid (500 mg, 71% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.40 min (99.5%); mp, 165-167° C.; 1HNMR (DMSO-d6) 2.15-2.20 (m, 1H, CHH), 2.56-2.88 (m, 6H, CHCH2, CH3), 4.60 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.458-8.04 (m, 7H, Ar), 9.28 (t, J=5 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.90, 23.40, 30.60, 42.35, 56.53, 119.93 (q, JC-F=257 Hz), 120.01, 120.67, 123.87, 126.62, 129.56, 133.19, 134.17, 134.07, 137.97, 145.83, 150.35, 154.61, 160.43, 165.06, 169.45, 172.59. LCMS MH=489; Anal Calcd For C23H19N4O5F3+1.1H2O: C, 54.36; H. 4.20; N, 11.02; F, 11.21. Found: C, 54.40; H, 3.89; N, 10.67; F, 11.06.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([C:3]([CH:2]2[CH2:6][CH2:7][CH2:8][NH:1]2)=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: C1CCNCC1
Product: O=C(C1CCCN1)N1CCCCC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-tert-butoxycarbonyl)-L-proline was reacted with piperidine to give (2S)-1-tert-butoxycarbonyl)-2-piperidinocarbonylpyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.5–1.9 (m, 10H), 1.9–2.0 (m, 1H), 2.1–2.2 (m, 1H), 2.4–2.5 (m, 1H), 2.55–2.65 (m, 1H), 2.8–2.9 (m, 1H), 3.3–3.7 (m, 6H), 4.3 (br s, 1H); Mass Spectrum: M+H+ 227.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][C:21]([C:23]([N:25]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:24])=[CH:22][C:15]=3[N:14]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(N(CC)CC)C.Cl[C:47]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:48].O>C(Cl)Cl>[CH3:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][O:49][C:47](/[N:4]=[C:2](\[NH2:3])/[C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][C:21]([C:23]([N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:24])=[CH:22][C:15]=3[N:14]=2)=[CH:9][CH:10]=1)=[O:48]
Reactant: CCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Reaction time: 0.5 h

Procedure:
73 gm ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate hydrochloride of Formula (E) in 1460 mL methylene dichloride were stirred 25° C. to 35° C. and cooled to 0° C. to 5° C. To the reaction mixture was treated with 61.1 mL triethylamine at 0° C. to 5° C. and stirred for 30 minutes followed by addition of n-hexyl chloroformate solution (31.35 mL in 365 mL methylene dichloride for 2 hrs. The residue was treated with 730 mL water and extracted with 370 mL methylene dichloride. The methylene dichloride was distilled and the residue was purified using mixture of methylene dichloride and ethanol to afforded amorphous form of dabigatran Etexilate of Formula (F). The amorphous form of dabigatran etexilate of Formula (F) is characterized by x-ray powder diffraction pattern as depicted in FIG. 4.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH2:12](N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1)(=[O:22])=[O:21]
Reactant: CCN(CC)CC
Reactant: O=C([O-])c1cccc(CO)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(COS(C)(=O)=O)n1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
6-(Hydroxymethyl)picolinate (200 mg, 1.196 mmol) and triethylamine (363 mg, 3.588 mmol, 0.5 mL) were combined and stirred at 0° C. in dichloromethane (2 mL). Methanesulfonyl chloride (206 mg, 1.794 mmol) was added and the reaction allowed to warm to room temperature over 1 hour. The reaction was washed with water, dried over sodium sulfate and concentrated under vacuum to afford the title compound (293 mg). MS (ESI) m/z 246.3 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccnc(N2CCNCC2)c1
Yield: 42.9 %

Procedure:
A solution of 2-chloro-4-(trifluoromethyl)pyridine (2.0 g, 11 mmol), piperazine (3 g, 30 mmol) and triethylamine (3.1 mL, 22 mmol) in DMF (10 mL) was heated at 100° C. overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc to EtOAc/MeOH/Et3N=9/1/0.5) to give 1.09 g (43%) of pure product MS calculated for C10H12F3N3: (M+H) 232; found 232.1.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].I[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CCOCC>[CH2:10]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CCCCCI
Solvent: CCOCC
Product: CCCCCOC(C)C(=O)OCC
Yield: 43.5 %

Procedure:
98 g of ethyl L-lactate, 313 g of 1-iodopentane and 245 g of freshly prepared Ag2O were stirred at 60°-65° C. for 16 hours, and diluted with ether, followed by removal of insoluble matter by filtration. After distilling off the ether, the reaction liquid was distilled in vacuo to obtain 68 g of ethyl 2-pentyloxypropionate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(CC)CC)C.O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][O:5][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.2 %

Procedure:
To a solution of 3,3,3-trifluoro-propan-1-ol (1.1 g, 10.0 mmol) in DCM (10 mL) are added p-toluenesulfonyl chloride (2.3 g, 12.0 mmol), N,N-dimethylaminopyridine (0.1 g, 1.0 mmol) and triethyl amine (2.8 mL, 20.0 mmol). The reaction is stirred at room temperature for 3 d, then poured into water and extracted with DCM. The combined organic extracts are washed with 1N aqueous HCl solution, saturated aqueous NaHCO3 solution, brine and dried over Na2SO4, filtered and concentrated to afford 2.34 g of title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.47 (3H, s), 2.47-2.6 (2H, m), 4.22 (2H, t, J=6.4 Hz), 7.36 (2H, d, J=8.08 Hz), 7.8 (2H, d, J=7.8 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].O.[C:12](O)(=O)[CH:13]=[O:14]>Cl>[O:14]=[C:13]1[CH:12]=[N:1][C:2]2[C:9](=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[NH:10]1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=CC(=O)O
Agent: Cl
Solvent: O
Product: N#Cc1ccc2[nH]c(=O)cnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3,4-diaminobenzonitrile (5.00 g, 37.6 mmol) in 5% aq HCl (20 mL) was added glyoxilic acid monohydrate (4.32 g, 46.9 mmol). The mixture was stirred overnight at rt and filtered. The filter cake was washed with water and MeOH to afford 2-oxo-1,2-dihydroquinoxaline-6-carbonitrile as a grey solid which was used directly in the next step.
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].Cl>ClCCl.C1C=CC=CC=1>[OH:25][C:19]1[CH:18]=[C:17]([O:16][CH3:15])[C:22]([O:23][CH3:24])=[CH:21][C:20]=1[C:10]([C:9]1[CH:13]=[CH:14][C:6]([F:5])=[CH:7][CH:8]=1)=[O:11]
Reactant: COc1ccc(O)cc1OC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: c1ccccc1
Product: COc1cc(O)c(C(=O)c2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1.0M solution of boron trichloride(142 ml) in dichioromethane was added to 4-fluorobenzoyl chloride(16.8 ml) in benzene (200 ml). Next, 3,4-dimethoxyphenol(20.0 g) in benzene (100 ml) was added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then poured onto ice water and allowed to stir for 15 minutes, then 1N HCl (500 ml) was added and stirred at room temperature for 17 hours. The reaction mixture was extracted with EtOAc, the EtOAc was separated, concentrated and dried to give the title product(41.7 g) as an orange solid. 1H NMR consistent with desired structures.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[H-].[Na+].I[CH3:29]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:17][N:18]([CH3:29])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(ncn2C2CCCCO2)c1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc2c(ncn2C2CCCCO2)c1Cl)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 56.2 %

Procedure:
To a solution of 216 (620 mg, 1.7 mmol) in DMF (8 mL) at 0° C. was added NaH (102 mg, 2.54 mmol, 60% in oil). The reaction was warmed to RT and stirred for 25 min then re-cooled to 0° C. and iodomethane (0.19 mL, 3.05 mmol) was added. The reaction was warmed to RT and stirred for 3 h. The conversion was low so the reaction mixture was cooled back to 0° C. and additional NaH (67 mg, 1.69 mmol, 60% in oil) was added. The reaction was warmed to RT and stirred for 20 min, re-cooled to 0° C. and iodomethane (0.11 mL, 1.69 mmol) was added. The reaction was warmed to RT and stirred for 3 h then partitioned between EtOAc and H2O. The combined organic extracts were thrice washed with H2O, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography to afford 363 mg (56%) of tert-butyl (4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl(methyl)carbamate (218): MS (ESI) m/z=380.2 [M+1]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:13])[CH2:10][C:11]#N.[CH2:14](O)C>N1CCCCC1>[CH:1](=[C:10]([C:11]#[CH:14])[C:9]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC#N
Reactant: O=Cc1ccccc1
Reactant: CCO
Solvent: C1CCNCC1
Product: C#CC(C#N)=Cc1ccccc1

Procedure:
To a solution of benzaldehyde (2 g; 18.9 mmol) and malononitrile (1.37 g; 20.7 mmol) in ethanol (40 ml) was added 5 drops of piperidine and the mixture was heated at reflux overnight. The reaction was cooled, evaporated then purified by flash column chromatography eluting with 1:9 ethyl acetate/hexane and the product containing fractions combined and evaporated to give 930 mg of 2-benzylidene-but-3-yne nitrile.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)([O-:3])=[O:2].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([O-:3])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:15])=[O:11])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCO[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
5-(Nitrooxy)pentanoic acid (489 mg, 3.00 mmol; US Patent 2006/189603) was dissolved in anhydrous DCM (30 mL) under N2, cooled to 0° C., and added in succession anhydrous DMF (1 drop) and oxalyl chloride (262 uL, 3.00 mmol). Allowed to stir at ambient temperature for 12 h. 13CNMR displayed acid chloride (δ171 ppm) with small amount of carboxylic acid (˜δ173 ppm). Evaporated and dried in vacuo to yield 450 mg (80%) of 5-chloro-5-oxopentyl nitrate as light yellow oil, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2([C:12](=[N+]=[N-])[CH3:13])[O:11]CCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][CH2:17][C:18](=[O:43])[C@:19]1([OH:42])[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@:33]([F:39])([C@@H:34]([OH:38])[CH2:35]2)[C@:31]2([CH3:32])[C:26](=[CH:27][C:28](=[O:40])[CH:29]=[CH:30]2)[CH2:25][CH2:24]3)[CH2:21][C@H:20]1[OH:41]>CO>[Cl:16][CH2:17][C:18](=[O:43])[C@:19]1([OH:42])[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@:33]([F:39])([C@@H:34]([OH:38])[CH2:35]2)[C@:31]2([CH3:32])[C:26](=[CH:27][C:28](=[O:40])[CH:29]=[CH:30]2)[CH2:25][CH2:24]3)[CH2:21][C@H:20]1[O:41][CH:12]([C:7](=[O:11])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:13]
Reactant: CC(=[N+]=[N-])C1(c2ccccc2)OCCO1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Solvent: CO
Product: CC(O[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl)C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of 2-phenyl-2-(1-diazoethyl)dioxolane in 3:2 ether-pentane is diluted with methanol and cooled to 0°C. 21-Chloro-9-fluoro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].[CH3:6][Al:7](C)C>C(Cl)Cl>[CH3:3][CH:2]([CH2:1][O-:5])[CH3:4].[CH3:3][CH:2]([CH2:1][O-:5])[CH3:4].[CH3:6][Al+2:7]
Reactant: CC(C)CO
Reactant: C[Al](C)C
Solvent: ClCCl
Product: CC(C)C[O-]
Product: C[Al+2]

Procedure:
In a sufficiently dried egg-plant type flask provided with a stirrer was charged 0.148 g (2 mmol) of sufficiently purified isobutanol, which was sufficiently dried. After completion of the drying, 3.3 ml of methylene chloride was added thereto. Then, under nitrogen atmosphere, 0.9 ml (1 mmol) of trimethylaluminum was slowly added dropwise with ice-cooling and stirring, and the mixture was mixed in the dark at room temperature for 1 hour to obtain a methylene chloride solution of methylaluminum bis(isobutoxide) (1 mmol/3.3 ml).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:33]B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH3:33])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2)c2cc(C)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Temperature: 100 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
A mixture of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), methylboronic acid (180 mg), tetrakis(triphenylphosphine)palladium(0) (70 mg), potassium carbonate (250 mg), toluene (6 ml) and THF (4 ml) was stirred at 100° C. for 12 hrs. under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (200 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:15])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1.Cl[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)=[O:19].CN(C)C=[O:33]>>[CH3:3][O:4][C:5](=[O:15])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:33][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)=[O:19]
Reactant: CC(C)(C)c1ccc(C(=O)CCl)cc1
Reactant: CN(C)C=O
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(=O)c1ccccc1OCC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium hydride (55%; 0.224 g) and 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.918 g) in dimethylformamide (12 mL) were stirred at room temperature for 30 minutes and then 2-chloro-1-[4-(1,1-dimethylethyl)phenyl]ethanone (1 g) in dimethylformamide (6 mL) was added. The reaction mixture was stirred at 60° C. overnight and worked up as in Example 20. The crude product (1.97 g) was purified initially by HPLC (ethyl acetate-hexane; 1:3) to give 0.79 g of material that was further purified by flash chromatography over silica gel (ethyl acetate-hexane-dichloromethane; 3:37:60) to afford of 0.535 g of 4-[2-[4-(1,1-dimethylethyl)phenyl-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([N:9]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11](=[O:23])[CH2:10]1)[CH3:8].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:7]([N:9]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH:11]([OH:23])[CH2:10]1)[CH3:8].[CH2:7]([N:9]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH:11]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:10]1)[CH3:8]
Reactant: CCN1CC(=O)COc2ccc([N+](=O)[O-])cc21
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CC(N2CCOCC2)COc2ccc([N+](=O)[O-])cc21
Product: CCN1CC(O)COc2ccc([N+](=O)[O-])cc21
Reaction time: 8 h
Yield: 31 %
Yield: 60 %

Procedure:
Morpholine (0.10 mL, 1.1 mmol) and 9-Ethyl-2-nitro-8,9-dihydro-5-oxa-9-aza-benzocyclohepten-7-one (74 mg, 0.31 mmol) in Methylene chloride (5 mL) was stirred for 4 h, then Sodium triacetoxyborohydride (0.13 g, 0.63 mmol) was added. After stirring overnight, a mixture of products was observed. The reaction mixture was partitioned between DCM and satd. sodium bicarbonate; the organic was washed with brine and dried over sodium sulfate. Chromatography (0-100% EtOAc:Hex) afforded 9-Ethyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ol (23 mg, 31%) and 9-Ethyl-7-morpholin-4-yl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (60 mg, 60%). 1H-NMR (CDCl3): 7.55 (m, 2H), 6.88 (m, 1H), 4.45 (m, 1H), 4.34 (m, 1H), 3.72 (m, 5H), 3.37 (m, 3H), 3.01 (m, 1H), 2.66 (m, 4H), 1.25 (t, 3H, J=7.0 Hz).