Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]([C:8]1[O:9][C:10]([CH3:30])=[C:11]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH:12]=1)=[O:7].[F:31][CH:32]([F:41])[O:33][C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:4][O:5][C:6]([C:8]1[O:9][C:10]([CH3:30])=[C:11]([CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]([C:37]3[CH:38]=[CH:39][C:34]([O:33][CH:32]([F:41])[F:31])=[CH:35][CH:36]=3)=[CH:19][CH:20]=2)[CH:12]=1)=[O:7]
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: COC(=O)c1cc(CSc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cc(CSc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
[1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (12.8 mg) was added to a degassed mixture of 5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulphanylmethyl]-furan-2-carboxylic acid methyl ester (151) (200 mg, 0.516 mmoles), 1-difluoromethoxy-4-iodo-benzene (153 mg, 0.568 mmoles) and 2M aqueous cesium carbonate (4.12 ml) in 1,4-dioxan (15 ml). The mixture was placed under an argon atmosphere and was heated at 100° C. for 20 hours. After cooling, the mixture was concentrated and the residue was partitioned between ethyl acetate and water, and the mixture adjusted to pH=2 with 1M aqueous hydrochloric acid. The organic phase was washed with brine and dried. After evaporation of the solvent, the residue was purified by flash chromatography, using heptane/ethyl acetate 9:1v/v as eluent, to afford compound 152(126 mg) as a white solid. LC/MS System A; Rt=4.17 mins.
Reaction SMILES: O=[O+][O-].[CH3:4][C:5]([S@:8]([N:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][N:13]=1)=[O:9])([CH3:7])[CH3:6].ClCCl.[BH4-].[Na+].[CH3:29][OH:30]>>[OH:30][CH2:29][C@@H:11]([NH:10][S:8]([C:5]([CH3:4])([CH3:6])[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:14][N:13]=1
Reactant: CO
Reactant: CC(C)(C)[S@@](=O)N=Cc1ccc(OCC(F)(F)F)cn1
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)S(=O)N[C@H](CO)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
Ozone was bubbled through a mixture of (R)-2-methyl-N-[(5-(2,2,2-trifluoroethoxy)pyridine-2-yl)methylene]propane-2-sulfinamide (8.10 g, 24.1 mmol) in a 1:1 mixture of dichloromethane and methanol (96 ml) at −78° C. until no starting material was observed by LC/MS. Nitrogen was bubbled through the reaction for fifteen minutes. To the solution was added in portions sodium borohydride (3.64 g, 96.0 mmol) over ten minutes. The reaction was allowed to warm to room temperature, stirred for 16 hours and then concentrated in vacuum. The resulting residue was washed with brine (2×60 ml) and extracted with ethyl acetate (2×75 ml). The organic extracts were combined, dried over Na2SO4, filtered and concentrated to give an oil. Purification by flash chromatography (SiO2, 50-100% ethyl acetate in hexanes, followed by 0-10% methanol in ethyl acetate, gradient) gave N-{(1S)-2-hydroxy-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}-2-methylpropane-2-sulfinamide as a white solid (5.10 g, 61.6%); 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=2.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.28 (dd, J=2.8 Hz and 8.4 Hz, 1H), 4.62-4.60 (m, 1H), 4.53-4.48 (m, 1H), 4.39 (q, J=8.0 Hz, 2H), 3.91-3.88 (m, 2H), 3.22 (m, 1H), 1.27 (s, 9H); MS (Electrospray): m/z 341.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[N:16][OH:17])([O-:3])=[O:2]
Reactant: NO
Reactant: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(C=NO)c([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 71 %

Procedure:
9.7 parts of 2-nitro-4-dimethylaminobenzaldehyde is dissolved in 50 parts of ethyl alcohol and a solution of 4.1 parts of hydroxylamine hydrochloride and 5 parts of sodium acetate in water is added. After the mixture has been boiled for one hour it is suction filtered. 7.5 parts (71% of theory) of 2-nitro-4-dimethylaminobenzaldoxime is obtained having a melting point of 140° to 143°C: ##SPC18##
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([OH:17])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>CC(=O)CC>[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22][O:17][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:19]
Reactant: CCN(CC)C(=O)CCl
Reactant: Oc1cc2ccccc2c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN(CC)C(=O)COc1cc2ccccc2c(-c2ccccc2)n1
Yield: 39.1 %

Procedure:
The procedure is as in Example 47, starting with 1-phenyl-3-isoquinolinol (4.4 g), N,N-diethyl-2-chloroacetamide (3.3 g), sodium carbonate (4.25 g) and cuprous iodide (1 g) in 2-butanone (90 cc). After chromatography on silica gel with a chloroform/methanol (98:2 by volume) mixture as eluant and crystallization of the product in isopropyl ether, N,N-diethyl-(1-phenyl-3-isoquinolyl)oxyacetamide (2.6 g), m.p. 105° C., is obtained.
Reaction SMILES: C1C=CC(P(C2C=CC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=CC=2)C2C=CC=CC=2)=CC=1.[OH:47][CH2:48][C@@H:49]1[NH:53][C:52](=[O:54])[CH2:51][CH2:50]1.[Br:55][C:56]1[CH:57]=[N:58][CH:59]=[C:60](O)[CH:61]=1>C1COCC1>[Br:55][C:56]1[CH:61]=[C:60]([O:47][CH2:48][C@@H:49]2[NH:53][C:52](=[O:54])[CH2:51][CH2:50]2)[CH:59]=[N:58][CH:57]=1
Reactant: Oc1cncc(Br)c1
Reactant: O=C1CC[C@H](CO)N1
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCc1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CC[C@H](COc2cncc(Br)c2)N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
A 5 mL, one neck round bottom flask was charged with diphenyl-[4-(1 h,1 h,2h,2h-perfluorodecyl)phenyl]phosphine (Fluorous Technologies, Pittsburgh, Pa., 0.35 g, 0.49 mmol), a stirbar, and 1 mL dry THF. The flask was fitted with an inert atmosphere inlet, and swept with Ar for several minutes. The solution was cooled using a ice-water bath, and treated with fDEAD (Fluorous Technologies, 0.41 g, 0.49 mmol) dissolved in 1 mL dry THF. After 5 minutes, (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (0.056 g, 0.49 mmol) and 3-bromo-5-hydroxypyridine (0.0565 g, 0.32 mmol) were added in succession. The reaction warmed to room temperature over 1 h, and was stirred a total of 96 h. The THF was removed using a stream of nitrogen, and the residue was dissolved in 0.5 mL dry DMF. The solution was loaded onto a FluoroFlash® Fluorous SPE cartridge (5 g, 15 mL tube, PN 801-0058S) that had been pre-conditioned with 50 mL MeOH, followed by 50 mL 20% MeOH in water. Two additional 0.5 mL aliquots of DMF were used to quantitate the transfer. The cartridge was eluted with 50 mL of 70% aqueous methanol, 50 mL of 80% aqueous methanol. The combined eluents were concentrated in vacuo. The residue was taken up in 2 mL dry THF, and passed through 250 mg of SiO2 wet-packed with THF. The silica was washed with 5 mL dry THF, and concentrated in vacuo. The residue was dissolved in 3 mL dry THF, and treated with 0.68 mmol g−1 Si carbonate (0.48 g, 0.32 mmol). The slurry was stirred at room temperature for 30 minutes, and filtered. The silica was eluted with 5 mL dry THF, and the combined eluents were concentrated in vacuo to afford (R)-5-((5-bromopyridin-3-yloxy)methyl)pyrrolidin-2-one (0.0813 g, 92% yield). HPLC-MS: retention time=1.09 min (94.1%@215 nm; 93.2% @254 nm; m/z=271.0, calculated for C10H1179BrN2O2+H+=271.0; m/z=272.9, calculated for C10H1181BrN2O2+H+=273.0).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:71]1[CH2:76][CH2:75][CH:74]([N:77]2[CH2:82][CH2:81][O:80][CH2:79][CH2:78]2)[CH2:73][CH2:72]1>CN1C(=O)CCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([N:71]5[CH2:76][CH2:75][CH:74]([N:77]6[CH2:82][CH2:81][O:80][CH2:79][CH2:78]6)[CH2:73][CH2:72]5)=[O:34])=[CH:35][CH:36]=4)=[O:37])=[CH:23][CH:24]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: C1CC(N2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(C(=O)N2CCC(N3CCOCC3)CC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 61.6 %

Procedure:
To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 1 mL of NMP was reacted according to example 68 with 4-(piperidin-4-yl)morpholine (67 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (40.1 mg, 62% yield); MS (ESI) m/z=658.7
Reaction SMILES: C1([C@H](CC(O)=O)C(O)=O)C=CC=CC=1.[NH2:15][C@H:16]1[C@H:20]([F:21])[CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C.[C:38](Cl)([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)Cl>[CH2:41]([O:40][C:38]([NH:15][C@H:16]1[C@H:20]([F:21])[CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](F)C1
Agent: O=C(O)C[C@H](C(=O)O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 95.6 %

Procedure:
A solution of (2S)-2-phenylbutanedioic acid-tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (1:1) (500 mg, 1.2 mmol) in DCM (20 mL) was cooled in an ice/water bath. DIPEA (0.69 mL, 4 mmol, 3.3 mol eq) was added, followed by CBZ-Cl (185 μL, 1.26 mmol, 1.05 mol eq). The resulting reaction solution was capped, stirred in the cold bath and allowed to warm to rt and stirred for 2 hr. The reaction was diluted with DCM (30 mL) and washed with sat. aq. NaHCO3 (10 mL). The organic layer was separated, dried over Na2SO4, and evaporated to give a colorless residue that was purified via flash chromatography (eluting with a gradient of 100% heptane to 50 ethyl acetate-50% heptane) to give the title compound as a colorless oil (388 mg, 96 yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.30-7.42 (m, 5 H) 5.12 (br. s., 2 H) 4.74-5.04 (m, 1 H) 4.28 (br. s., 1 H) 3.28-3.80 (m, 4 H) 1.47 (s, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −180.76-−178.52 (m, 1 F). m/z (APCI+) for C17H23FN2O4 239.2 (M+H)+. Chiral purity was determined as below (using the racemic material to compare):
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[Br:13])(=[O:3])[CH3:2].[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:14][NH:15][C:16]([NH2:18])=[S:17])=[CH:7][C:6]=1[Br:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1Br
Reactant: NNC(N)=S
Product: CC(=O)Nc1ccc(C=NNC(N)=S)cc1Br

Procedure:
Compound 26, 4-acetamido-3-bromobenzaldehyde, contains a formyl group, and reacts with thiosemicarbazide to produce 4-acetamido-3-bromobenzaldehyde thiosemicarbazone 29 as shown below.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=[O:8])[CH2:5][C@@H:4]([CH3:9])[C:3]1=[O:10].[CH3:12][C:13]([CH3:18])([CH2:16]O)[CH2:14][OH:15].C1C=CC=CC=1>O>[CH3:12][C:13]1([CH3:18])[CH2:14][O:15][C:6]2([CH2:5][C@@H:4]([CH3:9])[C:3](=[O:10])[C:2]([CH3:1])([CH3:11])[CH2:7]2)[O:8][CH2:16]1
Reactant: C[C@@H]1CC(=O)CC(C)(C)C1=O
Reactant: CC(C)(CO)CO
Solvent: O
Solvent: c1ccccc1
Product: C[C@@H]1CC2(CC(C)(C)C1=O)OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A mixture of (-)-(6R)-2,2,6-trimethyl-1,4-cyclohexandione (924 mg, 6.0 mmol), 2,2-dimethyl-1,3-propandiol (791 mg, 7.6 mmol), pyridinium p-tosylate (34 mg, 0.13 mmol), and benzene (15 mL) was heated to reflux under a Dean-Stark water separator for 4 h. The reaction mixture was allowed to cool to room temperature before it was washed with H2O, and dried over anhydrous Na2SO4. Evaporation of solvent gave a pale yellow oil (1.43 g) as the crude product, which was distilled using the Kugel-rohr apparatus (80°-100° C., 0.03 mm Hg) to give pure ketal as a colorless oil (1.31 g, 91%), [a]D -87.7° C. (c 1.10, CH3OH); ir: 1710 cm-1; 1H nmr d: 0.85 (s, 3H, CH3), 0.91 (d, J=6.6 Hz, 3H, CHCH3), 0.97 (s, 6H, 2 CH3), 1.16 (s, 3H, CH3), 1.56 (dd, J=13.5, 13.5 Hz, H-11ax), 1.58 (d, J=14.2 Hz, H-7ax), 2.38 (ddd, J=13.5, 5.3, 3.8 Hz, 1H, H-11eq), 2.47 (dd, J=14.2, 3.8 Hz, 1H, H-7eq), 2.85 (m, 1H, CHCH3), 3.41 and 3.48 (2dd, J=11.4, 1.6 Hz, 2H, 2 equatorial H at C2 and C4), 3.53 and 3.61 (2d, J=11.4 Hz, 2H, 2 axial H at C2 and C4); ms m/e: 240 (M+, 0.58), 141 (27), 155 (98), 83 (27), 69 (100).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:10][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1.[CH:21](O)=O.C=O.[OH-].[Na+]>O>[Br:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][N:16]([CH3:21])[CH2:15][CH2:14]3)[O:10][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: COc1ccc(Br)c2cc(COC3CCNCC3)oc12
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Br)c2cc(COC3CCN(C)CC3)oc12
Temperature: 95 °C

Procedure:
4-(4-Bromo-7-methoxybenzofuran-2-ylmethoxy)-piperidine (0.98 g), formic acid (0.65 ml) and formaldehyde (0.56 g of a 37% w/w solution in water) were combined and heated to 95° C. overnight. After cooling to room temperature the mixture was diluted with water (70 ml) and a concentrated aqueous solution of sodium hydroxide added until the solution was basic (pH=14). It was extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a pale yellow oil (1.03 g).
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][C:3]([NH2:5])=[O:4].C(=O)=O.[NH2:13][C:14]([NH:16][C:17]([NH2:19])=[NH:18])=[NH:15]>CO>[NH2:18][C:17]1[N:16]=[C:14]([NH2:13])[N:15]=[C:1]([CH2:2][C:3](=[O:4])[NH2:5])[N:19]=1
Reactant: CCOC(=O)CC(N)=O
Reactant: N=C(N)NC(=N)N
Agent: O=C=O
Solvent: CO
Product: NC(=O)Cc1nc(N)nc(N)n1
Temperature: 15 °C

Procedure:
Ethyl malonamate (34.7 g, 0.26 mole) and methanol (100 ml) were placed in a flash equipped with a dropping funnel, a stirrer, and a soda lime trap (to exclude CO2). The flask was cooled to about 15° C. in an ice-water bath. Freshly prepared biguanide (26.3 g, 0.26 mole, in 250 ml methanol) was added, with stirring, over 35 ml at 15°-20° C. A white precipitate began to form within 8-9 min. The mixture was allowed to stir overnight at room temperature. It was then cooled to 15° C., and the white precipitate was filtered, washed with cold water to remove sodium sulfate, and finally washed with cold methanol. A crude yield of 32.7 g (76%) was obtained. A pure sample recrystallized from water had a mp of 295°-96° C. (dec.) when placed in a preheated bath at 295° C. Anal. calcd. for C5H8N6O: C, 36.59; H, 4.91; N, 48.76. Found: C, 36.73; H, 5.08; N, 48.51.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][C:21]1[CH:26]=[C:25]([N:27]=[O:28])[CH:24]=[C:23]([CH3:29])[C:22]=1[OH:30]>ClCCl>[OH:28][N:27]([C:25]1[CH:24]=[C:23]([CH3:29])[C:22]([OH:30])=[C:21]([CH3:20])[CH:26]=1)[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(N=O)cc(C)c1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1cc(N(O)C(=O)c2ccccc2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), 2,6-dimethyl-4-nitrosophenol (151 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 60 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [CH2:1]([O:3]CC)C.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](Cl)=[O:11]>CO>[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O:3][CH3:1])=[O:11]
Reactant: CCOCC
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: CO
Product: COC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a 1-liter flask fitted with a stirrer, addition funnel, condenser, and drying tube containing diethyl ether (200 ml) and methanol (anhd.; 64 g,; 2.0 moles) is added dropwise m-fluorobenzoyl chloride (317 g,; 2.0 moles) at room temperature over a 3 hour period. Additional methanol (10 ml) is added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is then filtered through a bed of silicic acid and the solvent removed under vacuum to afford 285 grams of methyl 3-fluorobenzoate (92.5% yield). This was identical to the product prepared in Example 2A.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:21]#[N:22])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[NH2:29][CH:1]([C:4]1[N:5]=[C:6]([C:21]#[N:22])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 3-acetyl-4-(3-fluorophenyl)isoquinoline-1-carbonitrile (4 mg, 0.01 mmol) and ammonium acetate (10.6 mg, 0.138 mmol) in methanol (0.078 mL) and acetonitrile (0.078 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (1.7 mg, 0.028 mmol) was added. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C18H15FN3 (M+H)+: m/z=292.1; Found: 292.1.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.C[Al]C.[C:9](Cl)([CH3:12])([CH3:11])[CH3:10]>ClC1C=CC=CC=1>[C:9]([C:2]1[CH2:1][CH:5]=[CH:4][CH:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)Cl
Reactant: C1=CCC=C1
Agent: C[Al]C
Solvent: Clc1ccccc1
Product: CC(C)(C)C1=CC=CC1

Procedure:
In runs 1 through 10, five ml. of 0.025 M dimethylaluminum cyclopentadiene (Me2AlCPD) in chlorobenzene was dispensed by pipette into 20×150 mm test tubes. The tubes were then capped with screw caps fitted with self-sealing gaskets and Teflon® liners. The reaction tubes were placed in a constant temperature bath. After allowing sufficient time for the tubes and contents to attain bath temperature, 0.12 M tert.-butyl chloride solution in chlorobenzene (tBuCl) already at bath temperature was added by syringe fitted with hypodermic needle. After the desired time, the reactions were quenched by the addition of normal-butyl alcohol.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:17][C:18]([O:20][CH2:21][CH:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[C:14](O)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[C:50]1([C:56]2[N:57]=[C:58]([CH:61]3[CH2:70][C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[CH2:63][NH:62]3)[NH:59][CH:60]=2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>ClCCl>[CH:24]1[C:23]2[CH:22]([CH2:21][O:20][C:18](=[O:19])[NH:17][CH:13]([CH2:12][C:9]3[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:11][CH:10]=3)[C:14](=[O:15])[N:62]3[CH:61]([C:58]4[NH:59][CH:60]=[C:56]([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)[N:57]=4)[CH2:70][C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[CH2:63]3)[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(-c2c[nH]c(C3Cc4ccccc4CN3)n2)cc1
Reactant: CC(C)(C)Oc1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)Oc1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2Cc3ccccc3CC2c2nc(-c3ccccc3)c[nH]2)cc1
Temperature: 0 °C
Yield: 88.2 %

Procedure:
3-(4-tert-Butoxy-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid (1.93 g, 4.2 mmol) was dissolved in dichloromethane (100 mL), cooled to 0° C., then N-methyl-morpholine (0.42 g, 4.2 mmol) was added neat followed by isobutyl chloroformate (0.52 mL, 4 mmol). After 1.25 hour 3-(4-phenyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydro-isoquinoline (1.10 g, 4 mmol) was added neat and the reaction was allowed to warm to room temperature. After 16 hours the reaction was extracted with water, then saturated NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2.53 g (88%) of brown foam desired product {1-(4-tert-butoxy-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester, which was used without further purification. (LC/MS; Measured MW (MH+): 717)
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[Br:18][CH2:19]C#N>ClCCl>[Br:18][CH2:19][C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: N#CCBr
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: BrCc1nsc2nc3ccccc3n12
Yield: 76.9 %

Procedure:
A solution of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzi-midazole-3(2H)-one (15 g, 60.65 mmol) and bromoacetonitrile (18.19 g, 151.6 mmol) in dichloromethane (150 mL) was stirred for 48 h. A white precipitate was formed and the insoluble solid was filtered to give 12.50 g (77%) of the title compound: 1H NMR (CDCl3)δ 4.79 (s, 2H, CH2), 7.42 (t, 1H, ArH), 7.51 (t, 1H, ArH), 7.84 (d, 1H, ArH), 7.94 (d, 1H, ArH); mp 242-244° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[OH:8].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[OH:8][C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[NH:1][C:10]1[CH2:14][S:13][C:12](=[O:15])[N:11]=1
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(N[C@H]2CCCC[C@@H]2O)CS1
Yield: 42.2 %

Procedure:
To a solution of (1S,2S)-2-aminocyclohexanol (1.00 g) in ethanol (30 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.17 g), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (786 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([N:22]3[CH2:26][CH2:25][S:24][CH2:23]3)=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([N:22]3[CH2:26][CH2:25][S:24](=[O:35])[CH2:23]3)=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCSC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCS(=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.26 mmol) of the compound of Example 5 is dissolved in 5 ml of dichloromethane, mixed with 63 mg (0.26 mmol, 70% purity) of meta-chloroperbenzoic acid, and stirred for 4 hours at room temperature. The reaction mixture is separated by means of preparative HPLC (mobile solvent: acetonitrile/water gradient). 97 mg (93% of theory) of the title compound is obtained.