Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1)=[C:2]=[S:3].[NH2:18][CH2:19][CH2:20][CH2:21][NH2:22]>C(#N)C>[CH2:21]([NH:22][C:2]([NH:1][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:16])[CH3:17])[CH:9]=1)=[S:3])[CH2:20][CH2:19][NH:18][C:2]([NH:1][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:16])[CH3:17])[CH:9]=1)=[S:3]
Reactant: NCCCN
Reactant: CN(C)Cc1cccc(OCCCN=C=S)c1
Solvent: CC#N
Product: CN(C)Cc1cccc(OCCCNC(=S)NCCCNC(=S)NCCCOc2cccc(CN(C)C)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.9 %

Procedure:
A mixture of 3-(3-isothiocyanatopropoxy)-N,N-dimethylbenzenemethanamine (2.24 g) and 1,3-diaminopropane (0.42 g) in acetonitrile (50 ml) was stirred at room temperature for 24 hours. The solvent was evaporated in vacuo and the oily residue chromatographed (silica/methanol) to yield the title compound (0.46 g) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>C(O)(C)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(I)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OCc1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A solution of 2-fluoro-5-iodobenzaldehyde (1.173 g, 4.692 mmol) in isopropanol (25 mL) was treated with sodium borohydride (0.379 g, 10.02 mmol), stirred at room temperature for 18 h, poured into water (125 mL), and extracted with isopropyl ether (2×25 mL). The combined organic phase was dried (Na2SO4), and concentrated in vacuo to give the title compound (1.187 g, 99%) as a pale yellow solid; NMR δH (400 MHz, CDCl3) 7.77 (1H, m), 7.57 (1H, m), 6.82 (1H, t, J 8.8 Hz), 4.73 (2H, d, J 6.1 Hz), and 1.79 (1H, t, J 6.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][CH:36]([F:55])[C:37]1[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][N:38]=1.O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:39][N:38]=[C:37]([CH:36]([F:55])[F:35])[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)F)ns1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc(C(F)F)ns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (50 mg, 0.100 mmol), 3-(difluoromethyl)-5-(tributylstannyl)isothiazole (296 mg, 0.699 mmol) and tetrakis (triphenylphosphine)palladium(0) (57.7 mg, 0.050 mmol) in toluene (2.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to yield the title compound as a mixture with byproduct. The crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[CH2:7]Br.C(=O)([O-])[O-].[K+].[K+].[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>CN(C)C=O.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24][CH2:7][C:6]=2[CH:9]=1
Reactant: Oc1ccccc1S
Reactant: Clc1ccc(I)c(CBr)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)CSc1ccccc1O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
A solution of 125.6 g of 5-chloro-2-iodobenzyl bromide in 500 ml of dimethylformamide is added to a mixture of 640 ml of dimethylformamide, 52.4 g of potassium carbonate and 47.8 g of 2-hydroxythiophenol (R. Leuckart, J.Prakt.Chem. /2/ 41, 192, 1890). Then, the mixture is stirred for 1 hour at room temperature, treated with 57 g. of potassium carbonate and 4.5 g of copper and is refluxed for 6 hours. Dimethylformamide is distilled off under reduced pressure, the residue diluted with water and shaken with benzene. After filtration, the benzene layer is separated, washed with water, dried with potassium carbonate and evaporated. By distillation of the residue there are obtained 42.5 g (45%) of 2-chloro-11H-dibenz(b.f)-1,4-oxathiepin with a b.p. of 148°-168° C./85 Pa and m.p. of 66.76° C. The pure product is obtained by crystallization from methanol and melts at 78°-79° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[CH:4]=1.[N+:11]([O-])([OH:13])=[O:12]>C(OC(=O)C)(=O)C>[CH3:1][S:2][C:3]1[S:7][C:6]2[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[S:10][C:5]=2[CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: CSc1cc2sccc2s1
Solvent: CC(=O)OC(C)=O
Product: CSc1cc2sc([N+](=O)[O-])cc2s1
Temperature: -20 °C

Procedure:
1.0 g (5.4 mmol) of 2-methylthiothieno[3,2-b]thiophene is dissolved in 20 ml of acetic anhydride, and the solution is cooled to -20° C. At this temperature, a mixture of 0.6 ml of 70% nitric acid in 5 ml of acetic anhydride is added dropwise. The mixture is then allowed to warm to room temperature. For working up, the mixture is added to ice water end extracted several times with diethyl ether, and the organic phase is washed with saturated sodium hydrogen carbonate solution until neutral and dried with anhydrous magnesium sulfate. After removal of the solvent in a rotary evaporator under reduced pressure, the orange-yellow crude product obtained is purified by preparative column chromatography (SiO2 //2:1 cyclohexane/ethyl acetate, Rf : 0.62) and recrystallized from cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([NH:28][CH2:29][CH:30]1[CH2:31][CH2:32][N:33]([C:4]2[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=2)[CH2:34][CH2:35]1)=[O:36])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(N2CCC(CNC(=O)OC(C)(C)C)CC2)nc(Cl)n1
Temperature: 25 °C

Procedure:
A 30 mL round-bottomed vial methyl 2,6-dichloropyrimidine-4-carboxylate (300 mg, 1 equiv.) was partially dissolved in anhydrous THF (5 mL). DIEA (278 μL, 1.1 equiv.) was added at once at 0° C. tert-Butyl(piperidin-4-ylmethyl)carbamate (311 mg, 1 equiv.) dissolved in THF (5 mL) was added at 0° C. in 5 min. The reaction mixture was warmed to RT in 3 h15. LC-MS showed mostly the desired product (2.77 min, M+1=385) and a small amount of the other regioisomer (3.28 min, M+1-isobutene=329). The solvent was evaporated and the residue was purified by biotage (SiO2, 10 g, Hex/EtOAc 9:1 to 1:1) to give the desired isomer (386.8 mg, 69.4%) as a white solid. LC-MS m/z 385 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[C:19]=2[OH:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[CH3:28][O:29]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[C:19]([OH:27])=[C:20]([CH3:26])[C:21]([CH3:25])=[C:22]([CH:28]=[O:29])[C:23]=2[CH3:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(Cl)Cl
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)cc(C)c(C)c1O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C=O)c(C)c(C)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl (R)-7-(4-fluorophenyl)-7-(2-hydroxy-3,4,6-trimethylphenyl)heptanoate (0.8 g, 2.1 mmol) and dichloromethyl methyl ether (0.62 ml) in dichloromethane (10 ml) was added dropwise a solution of titanium tetrachloride (0.76 ml) in dichloromethane (3 ml) under argon atmosphere while maintaining the temperatures of the reaction mixture at a range from -10 ° C. to -12° C. The reaction mixture was then stirred for 30 minutes at the same temperature range. The reaction mixture was then added to ice-water, which was subjected to extraction with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous saline solution, successively, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform/hexane to afford 0.63 g of methyl (R)-7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoate. Physico-chemical properties and spectral data of the product were shown in [Table 4].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[N:10][N:11]([CH3:13])[N:12]=3)=[CH:4][CH:3]=2)[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: Cn1nnc(-c2ccc(Br)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cn1nnc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1

Procedure:
Prepared in analogy to example 4.4 (a) from 5-(4-Bromo-phenyl)-2-methyl-2H-tetrazole and N-BOC-piperazine. MS (m/e): 345.1 (MH+, 41%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([Cl:11])=[C:9]([C:12](OC)=[O:13])[S:8][C:7]=2[CH:16]=1.CO.[NH2:19][NH2:20].II>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([Cl:11])=[C:9]([C:12]([NH:19][NH2:20])=[O:13])[S:8][C:7]=2[CH:16]=1
Reactant: NN
Reactant: COC(=O)c1sc2cc(OC)ccc2c1Cl
Agent: II
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(Cl)c(C(=O)NN)sc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 57 %

Procedure:
A 100 ml, round bottomed flask, reflux condenser, gas inlet and Teflon stirrer were oven dried for 12 hours at 160° C. The apparatus was rapidly assembled, flushed with dry nitrogen gas, and cooled to room temperature. The reaction flask was charged with methyl 6-methoxy-3-chlorobenzo[b]thiophene-2-carboxylate (1.50 g, 5.85 mmole), anhydrous methanol (Aldrich, 50 ml), and anhydrous hydrazine (Aldrich, 2.5 equivalents, 0.47 g, 0.45 ml, 14.61 mmole). The stirred reaction mixture was brought to reflux and the progress of the reaction monitored by TLC (Silica, 1:1 hexane:ethyl acetate, iodine and UV visualization). After 72 hours, the completed reaction was cooled to room temperature, and further cooled to 5° C. for 1 hour. The resulting solid was filtered, washed with cold methanol (2×10 ml), and dried in vacuo. This resulted in 0.856 g of the desired material, as a white amorphous powder which was used directly.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[NH2:11].C([C:15]([NH:17][C:18]#[N:19])=O)C>C(O)C>[CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[NH:11][CH:15]=[N:17][C:18]#[N:19]
Reactant: CC1(C)Cc2ccccc2C1N
Reactant: CCC(=O)NC#N
Solvent: CCO
Product: CC1(C)Cc2ccccc2C1NC=NC#N
Yield: 96 %

Procedure:
250 Parts of 2,3-dihydro-2,2-dimethyl-1H-inden-1-amine were dissolved in 80 parts of ethanol. 150 Parts of ethyl-N-cyanoformamidate were added within 10 minutes and the mixture was heated to reflux. The cooled solution was concentrated, the precipitate was filtered off and dried, yielding 316 parts (96%) of N-(2,3-dihydro-2,2-dimethyl-1H-inden-1-yl)-N'-cyanoformamidine; mp. 164°-167° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[C:9]([OH:15])=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:14])[CH:7]=1.[CH3:17][C@@H:18](O)[CH2:19][CH:20]=[CH2:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[C:9]([O:15][C@H:20]([CH2:19][CH:18]=[CH2:17])[CH3:21])=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:14])[CH:7]=1
Reactant: Cc1ccc(Br)cc1-c1c(O)cccc1Cl
Reactant: C=CC[C@@H](C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cccc(Cl)c1-c1cc(Br)ccc1C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
5′-Bromo-6-chloro-2′-methyl-[1,1′-biphenyl]-2-ol (540 mg, 1.82 mmol, 1.0 equiv) were mixed with (R)-pent-4-en-2-ol (313 mg, 3.63 mmol, 2.0 equiv) and Ph3P (952 mg, 3.63 mmol, 2.0 equiv) in THF (6 ml). To this solution was added DEAD (1653 μl, 3.63 mmol, 2.0 equiv) dropwise and stirred overnight. The solution was mixed with silica gel and concentrated and purified by 40 g ISCO column with 0-10% EtOAc/hex to afford 5-bromo-2′-chloro-2-methyl-6′-((S)-pent-4-en-2-yloxy)-1,1′-biphenyl (350 mg, 52.7%). 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J=8.2, 2.1 Hz, 1H), 7.25-7.21 (m, 2H), 7.14 (d, J=7.5 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.86 (dd, J=8.0, 5.3 Hz, 1H), 5.66-5.50 (m, 1H), 5.05-4.90 (m, 2H), 4.35-4.24 (m, 1H), 2.30-2.12 (m, 2H), 2.01 (s, 3H), 1.16 (dd, J=11.0, 6.0 Hz, 3H). LCMS (M+1)=365.0.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH3:17])[C:10]([C:18]([O:20]CC)=[O:19])=[CH:9]2)([O-:5])=[O:4].O.Cl>CS(C)=O>[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH3:17])[C:10]([C:18]([OH:20])=[O:19])=[CH:9]2)([O-:5])=[O:4]
Reactant: CCCn1c(C(=O)OCC)cc2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCn1c(C(=O)O)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
236 mg (3.68 mmol, 85% pure) of potassium hydroxide (powder) are initially charged in 10 ml of dimethyl sulphoxide, 961 mg (3.48 mmol) of the compound from Example I are added and the mixture is stirred at RT for half an hour. The reaction mixture is poured into about 100 ml of water and with cooling, 10% strength hydrochloric acid is added a little at a time to the solution until no more precipitate is formed. The precipitated solid is filtered off with suction and dried in a desiccator under reduced pressure overnight.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:54])[C@@H:13]([NH:24][C:25]([C:27]2[CH:31]=[C:30]([O:32][CH2:33][C:34]([N:36]3[CH2:40][CH2:39][CH2:38][C@H:37]3[C:41](=[O:47])[NH:42][CH:43]3[CH2:46][CH2:45][CH2:44]3)=[O:35])[N:29]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:28]=2)=[O:26])[CH2:14][CH2:15][O:16]CC2C=CC=CC=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:54])[C@@H:13]([NH:24][C:25]([C:27]2[CH:31]=[C:30]([O:32][CH2:33][C:34]([N:36]3[CH2:40][CH2:39][CH2:38][C@H:37]3[C:41](=[O:47])[NH:42][CH:43]3[CH2:46][CH2:45][CH2:44]3)=[O:35])[N:29]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:28]=2)=[O:26])[CH2:14][CH2:15][OH:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCO)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 543 mg 4-[(S)-4-benzyloxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 15 ml ethyl acetate were added 200 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (1 bar) for 12 h. The reaction mixture was filtrated, washed with ethyl acetate and concentrated. The crude product was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 178 mg MS (ES+): m/e=654.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:11])[C:7]([CH3:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].[CH2:44]([NH2:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CC(C)=O.O.C(Cl)(Cl)(Cl)Cl>[CH2:44]([N:51]1[CH2:11][C:6]2[C:7](=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:10]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C
Reactant: NCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)CN(Cc1ccccc1)C2
Reaction time: 48 h
Yield: 32.9 %

Procedure:
Part A. A solution of 4-nitro-o-xylene (38.64 g, 255.9 mmol), NBS (91.1 g, 511.8 mmol), benzoyl peroxide (1.239 g, 5.118 mmol), and CCl4 (400 mL) was heated at reflux for 1 day, then at rt for 2 days. The solid was filtered off and washed with CCl4. The filtrate was evaporated to give the crude dibromo product (80 g). A portion of which (20 g) was dissolved in acetone (170 mL) and water (45 mL), then Na2CO3 (43.1 g, 407 mmol) was slowly added, followed by BnNH2 (7.05 mL, 64.6 mmol) in acetone (22 mL). After 10 h, the solution was concentrated to one-fourth its volume, the salt solid was filtered off, and the filtrate was evaporated. The residue was dissolved in EtOAc, washed with water and brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to provide the corresponding 2-benzyl-5-nitro-2,3-dihydro-1H-isoindole (5.41 g, 33% yield, over 2 steps): 1H NMR (300 MHz, CDCl3) δ 8.11 (d, 1H), 8.04 (s, 1H), 7.48–7.20 (m, 6H), 4.02 (s, 4H), 3.92 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[C:14]([N+:21]([O-])=O)[CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CCOC(C)=O>[NH2:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:24])[N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=1)[N:20]=[CH:19]2
Reactant: CC(C)(C)c1ccc(-n2ncc3cccc([N+](=O)[O-])c3c2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-n2ncc3cccc(N)c3c2=O)cc1
Reaction time: 4 h

Procedure:
A solution of the nitro compound (Step D) and EtOAc (10 mL) was hydrogenated over 10% Pd/C (20 mg) at RT and at atmospheric pressure. After 4 h, the mixture was filtered through Celite® and concentrated in vacuo to afford the desired compound as an orange oil. MS m/e 294 (M+H)+. Calc'd for C18H19N3O: 293.15.
Reaction SMILES: CN(C=O)C.[Si:6]([O:13][CH2:14][CH2:15][CH2:16][C@H:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C@H:26]([CH2:27][C@@H:28]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)[CH2:29][CH2:30]2)[CH2:25][C@H:24]3[OH:45])[CH2:21][CH2:20]1)[CH3:18])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1COCC1>[CH2:46]([O:45][C@@H:24]1[CH2:25][C@@H:26]2[C@:31]([CH3:32])([CH2:30][CH2:29][C@H:28]([O:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][O:40]3)[CH2:27]2)[C@@H:33]2[C@@H:23]1[C@H:22]1[C@:36]([CH3:37])([CH2:35][CH2:34]2)[C@@H:19]([C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][O:13][Si:6]([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:8])[CH3:7])[CH2:20][CH2:21]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 400 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A flame-dried round-bottom flask with stirring bar was charged with sodium hydride (60% in mineral oil, 28 mg, 0.69 mmol), equipped with a septum and a gas-needle inlet and flushed with argon. The mineral oil was removed by washing (3×) with dry pentane, and the pentane was removed to provide the sodium hydride as a powder. Dry DMF (2.0 ml) was added. A solution of alcohol 2006 (40 mg, 0.069 mmol) in dry THF (2 ml) was added dropwise via syringe. The reaction mixture was stirred overnight and then heated to 400° C. in an oil bath over a 20-minute period. Freshly distilled benzyl bromide (0.165 ml, 1.38 mmol) was added dropwise, and the reaction mixture was stirred at 400° C. for 10 hours. The reaction was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The flask was placed under vacuum overnight to remove any residual DMF. The crude material was purified by flash chromatography (SiO2, hexanes:EtOAc 50:1) giving compound 2007 as a white solid (40 mg, 0.060 mmol, 87%). A gradient of increasing EtOAc concentration provided other components, including the 7α-formate (1 mg, 1%) as well as recovered starting material (3 mg, 8%). Compound 2007:=1H NMR (500 MHz, CDCl3) δ 7.35-7.20 (m, 5 H, benzyl Ar-CH2), 4.73-4.66 (m, 1 H, methine H), 4.535 (d, J=12.0 Hz, 1/2 H, benzyl-CH2) , 4.53 (d, J=12.0 Hz, 1/2 H, benzyl-CH2), 4.26 (d, J=12.2 Hz, 1/2 H, benzyl-CH2), 4.245 (d, J=11.8 Hz, 1/2 H, benzyl-CH2), 3.95-3.85 (m, 1 H, THP CH2O), 3.66-3.52 (m, 3 H, THP CH2O & C-24 H), 3.50-3.45 (m, 1 H, C-3 H), 1.08 (s, 3 H, C-19 H), 0.91 (d, J=6.6 Hz, C-21 H), 0.89 (s, 9H, t-Bu), 0.64 (s, 3 H, C-18 H), 0.04 (s, 6 H, TBDMS CH3); MS (CI/isobutane) m/z 668 (M+1, 6%), 584 (M+1-THP, 18%), 475 (M+1-THPOH, 30%), 457 (M+1-THPOH-HOBn, 58%), 343 (M+1-THP-HOBn-TBDMSOH, 100%), 325 (M+1-THPOH-TBDMSOH-HOBn, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].CI.[CH3:14]N(C)C=O.[OH-].[Na+]>[Ag]=O.C(O)C>[CH3:14][O:11][C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: CN(C)C=O
Agent: O=[Ag]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CI
Product: COc1c(C)cccc1C(=O)O

Procedure:
A mixture of 7.1 g. (0.05 mole) of 3-methylsalicylic acid, 23.1 g. (0.1 mole) of silver oxide and 25 ml. of methyl iodide in 150 ml. of N,N-dimethylformamide was stirred at 25° C. for 16 hours, then filtered. The filtrate was evaporated to provide a residue which was hydrolyzed by heating at 50° C. in an equivolume mixture of ethanol and 6N sodium hydroxide solution. The resulting mixture was acidified and filtered. The filtrate was evaporated, and the residue dissolved in base and treated with decolorizing charcoal. Acidification provided white solid 2-methoxy-3-methylbenzoic acid, m.p. 70°-75° C.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O>[C:10]([CH:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])#[N:11]
Reactant: N#CCc1cccnc1
Reactant: COC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCC(C#N)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 8.6 g of sodium hydride (50% dispersion in mineral oil) in 200 mL of dimethylformamide is added in a solution of 17.7 g of 3-pyridylacetonitrile in 15 mL of dimethylformamide over a period of 0.5 hour. The reaction is stirred for a further 0.5 hour at room temperature, then cooled to -20° before adding 30 g of methyl 5-bromovalerate. The reaction is then allowed to warm up to room temperature over a period of several hours and left to stand for 18 hours. The reaction is then poured into 300 mL of ice water and extracted with 300 mL of ethyl acetate. The extract is washed with 3 portions of 75 mL of 1N hydrochloric acid and the aqueous solution neutralized with ammonium hydroxide and extracted with ethyl acetate. The extract is dried over magnesium sulfate, filtered and evaporated to yield methyl 6-cyano-6-(3-pyridyl)-hexanoate.