Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]2[N:9]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[NH:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.C1COCC1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:21]=[CH:20][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2,6-dichlorophenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester (5.8 g) in 40 mL of MeOH/THF (1:1) was added 1N NaOH (20 mL). The mixture was stirred at RT for 18 h then 1N HCl was added until pH 3. The resulting precipitate was filtered, washed with water and dried under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl-].[Mg+2].[Cl-].[P:13]([Cl:17])(Cl)(Cl)=[O:14]>O>[C:3]1([O:9][P:13]([Cl:17])(=[O:14])[O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Product: Cc1cccc(C)c1OP(=O)(Cl)Oc1c(C)cccc1C
Temperature: 120 °C

Procedure:
A 1,000-ml four-necked flask provided with a stirring machine, a thermometer, a dropping funnel, and a nitrogen-introducing pipe was mounted with a condenser to which a water scrubber had been connected, and then 2.0 mol (244 g) of 2,6-dimethylphenol, and 0.016 mol (1.5 g) of magnesium chloride were loaded into the resultant reactor. The atmosphere in the reactor was replaced with nitrogen and then its temperature was increased to 120° C. 1.0 Mole (153 g) of phosphorus oxychloride was dropped into the reactor at that temperature over 2 hours. After the completion of the dropping, the temperature was increased to 180° C. over 2 hours. Thus, di(2,6-xylyl)phosphorochloridate was obtained. The temperature in the flask was cooled to 20° C., and then 0.5 mol (55 g) of 1,3-benzenediol and 0.016 mol (1.5 g) of magnesium chloride were loaded into the flask. The temperature was increased to 180° C. over 2 hours and then the mixture was aged for 2 hours. After that, the catalyst was removed by an ordinary method and then the remainder was dried at 140° C. under reduced pressure. Thus, X-1 represented by the following general formula (5) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:41]=[CH:40][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([N:25](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:41]=[CH:40][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.3 %

Procedure:
To a dichloromethane (120 mL) solution of di-tert-butyl (3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-yl)imidodicarbonate (11.8 g, purity about 70%) described in Manufacturing Example 3-1-2 was added trifluoracetic acid (40 mL) at 0° C., which was stirred at room temperature for 14 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate at 20° C. or less, which was then extracted with ethyl acetate and purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1). The solvent was concentrated under a reduced pressure, tert-butylmethyl ether was added to the resulting residue, and the solids were filtered out to obtain the title compound (7.29 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](O)=[N:7][N:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:15])=[N:7][N:6]=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nncc2cc(Br)ccc12
Product: Clc1nncc2cc(Br)ccc12
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromophthalazin-1-ol (10.0 g, 44.4 mmol) in phosphorus oxychloride (104 mL, 1111 mmol) was heated at 105° C. in an oil bath for 3 h. After cooling to RT, the volatiles were removed by vacuum distillation. The residue was diluted with CH2Cl2 and treated with 10% Na2CO3 solution. After stirring for 3 h, the mixture was diluted with 10% Na2CO3 and extracted with CH2Cl2 (3×). The combined organic solution was dried over Na2SO4, filtered through a short pad of silica gel, eluted with EtOAc, and concentrated in vacuo to yield the title compound as a tan solid. MS (ESI, pos. ion) m/z: 242.9, 244.9 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.CN(C)[C@@H]1CCCC[C@H]1N.[CH3:41][OH:42]>[Cu]I>[OH:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([O:42][CH3:41])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Reactant: CO
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Product: COc1ccc(Cc2cc3c(=O)n([C@@H]4CCCC[C@H]4O)cnc3c3ccccc23)cn1
Temperature: 25 °C

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.150 g, 0.357 mmol) in 3 mL of MeOH under an atmosphere of nitrogen was added trans-N,N-dimethylcyclohexane-1,2-diamine (1.7 mg, 0.012 mmol), and copper(I) iodide (2.3 mg, 0.012 mmol). The mixture was irradiated in a microwave reactor at 160° C. for 4 h, cooled to rt and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-100% ethyl acetate in hexanes, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 416.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.03-8.99 (m, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 8.02-7.99 (m, 2H), 7.70-7.65 (m, 2H), 7.37-7.34 (m, 1H), 6.62 (d, J=8.5 Hz, 1H), 4.82 (br s, 1H), 4.39 (s, 2H), 4.01 (br s, 1H), 3.90 (s, 3H), 2.30-2.23 (m, 1H), 2.18-2.12 (m, 1H), 1.99-1.84 (m, 3H), 1.53-1.42 (m, 3H).
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=S.CCN(C(C)C)C(C)C>C(#N)C>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:13]2[S:12][CH2:18][C:16](=[O:17])[N:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C1CSC(=S)N1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 40.8 %

Procedure:
To a suspension of (1R,2S)-2-phenyl-cyclopropylamine hydrochloride (0.85 g, 5 mmol) and Rhodanine (0.68 g, 5 mmol) in acetonitrile (20 mL) was added DIPEA (2.61 mL, 15 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (1.35 g, 5 mmol) was added in two portions within a period of 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with ethyl acetate (500 mL). The solvent was removed under the vacuum and the crude residue was diluted with water (100 mL) and ethyl acetate (100 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to obtain 0.474 g (42% yield) of 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C12H12N2OS (M+) 232.0670. found 232.0665.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C[O:15][B:16](OC)[O:17]C>O1CCCC1.CCOCC>[CH2:7]([C:8]1[CH:13]=[CH:12][C:11]([B:16]([OH:17])[OH:15])=[CH:10][CH:9]=1)[CH2:6][CH3:5]
Reactant: BrCCCc1ccccc1
Reactant: COB(OC)OC
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium shavings (217 mg, 8.9 mmol) in 3 mL of dry tetrahydrofuran under argon, a crystal of iodine along with a solution of 4-bromopropylbenzene (1.69 g, 8.5 mmol) dissolved in 6 mL of tetrahydrofuran was added at such a rate that a gentle reflux was maintained. The solution was refluxed for an additional 0.5 h, cooled to room temperature and added in portions over 10 min to a solution of trimethylborate (924 mg, 8.9 mmol) previously dissolved in 4 mL of dry ether at −78° C. After 30 minutes, the solution was warmed to room temperature; and stirring was continued for 90 min. The reaction was then quenched by the addition of 2 mL of a 10% hydrochloric acid solution. The tetrahydrofuran was removed under reduced pressure and the remaining residue was extracted into diethyl ether (3×25 mL). The combined ether extracts was extracted with 1 M NaOH (3×25 mL) and the resulting aqueous layer was acidified to pH 2.0 using 6N HCl, then reextracted back into diethyl ether (3×25 mL). The combined organic layers was washed with water (1×25 mL), brine (1×25 mL) and dried over magnesium sulfate. Evaporation of solvent left a brown solid which was filtered through a small plug of silica gel using 10% MeOH/CHC3. Evaporation left 448 mg (32%) of a brown solid, m.p. 90-93° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[O:22]=[C:23]([CH2:29][C:30](=[O:32])[CH3:31])[C:24](OCC)=[O:25]>>[C:30]([C:29]1[CH:18]([C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)[N:12]([C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[CH:7]=2)[C:24](=[O:25])[C:23]=1[OH:22])(=[O:32])[CH3:31]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cc(N)cn2c(C)nnc12
Product: CC(=O)C1=C(O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 84.5 using 3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine (Step 67.4), 4-chlorobenzaldehyde and ethyl 2,4-dioxovalerate. tR: 0.70 min (LC-MS 2); ESI-MS: 397 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H) 2.44 (s, 3H) 2.63 (s, 3H) 6.14 (s, 1H) 7.27 (d, J=8.4 Hz, 2H) 7.33-7.40 (m, 3H) 8.53 (s, 1H).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([S:19][CH2:20][CH2:21][C:22](OCC)=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>O1CCCC1>[CH2:3]([S:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCSCCC(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCSCCCO
Yield: 99.1 %

Procedure:
To a slurry of 147.4 mg of lithium borohydride in 20 ml of tetrahydrofuran is added 2.4 g of 3-(hexadecylthio)propanoic acid, ethyl ester. This mixture is refluxed overnight, poured into water and extracted with ethyl acetate, to give 2.1 g of the desired compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH2:18][CH2:19]O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.C(N(CC)CC)C.[B-](F)(F)(F)[F:29].CCN([S+](F)F)CC.C([O-])(O)=O.[Na+]>ClCCl>[F:29][CH2:19][CH2:18][C:17]#[C:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[CH:9]2
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: F[B-](F)(F)F
Agent: CCN(CC)[S+](F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.9 %

Procedure:
To a solution of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (1.0 g, 3.7 mmol; Intermediate 17) in dry dichloromethane (25 mL), was added triethylamine.3HF (1.2 g, 7.4 mmol). XtalFluor-E (1.2 g, 5.5 mmol) was then added. The resulting solution was stirred at room temperature for 30 minutes. Upon completion, the reaction solution was neutralized by slow addition of saturated NaHCO3 (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-20% EtOAc in petroleum ether) affording the title compound (100 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.88 (s, 1H), 7.73 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 4.60 (dt, 2H), 3.88 (m, 1H), 3.78-3.71 (m, 1H), 2.89 (dt, 2H), 2.48-2.34 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.72 (m, 1H), 1.58 (m, 2H); LCMS: 273 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:20][CH2:19][CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:2]([N:12]1[CH2:20][CH2:19][CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 14 h
Yield: 85.8 %

Procedure:
Benzyl chloroformate (16.4 mL, 115 mmol) in toluene (50 mL) was added dropwise to a stirred solution of 12.9 g (100 mmol) of isonipecotic acid (Aldrich) and 21.0 g (250 mmol) of sodium bicarbonate in 200 mL of water. After 14 h, the mixture was extracted with ether (3×50 ml) and the ether layers were discarded. The aqueous layer was acidified with conc. HCl to pH 2, causing the product to precipitate. The product was partitioned into ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield 22.6 g (86%) of N-CBZ-isonipecotic acid as a viscous oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][C:2]=1O.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[C:9]([OH:11])[CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc2cccc(O)c2n1
Product: Oc1cccc2ccc(Cl)nc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a stirred mixture of quinoline-2,8-diol (1 g, 6.21 mmol) was added POCl3 (10 mL) and the mixture stirred at 100° C. for 1 hour before cooling. The mixture was then poured into ice-water (100 mL) slowly and filtered. The collected solid was dried and used in next step without further purification. (780 mg, Yield 70%). 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.17 (dd, J1=8.8 Hz, J1=1.6 Hz, 1H).
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)=O.C(O)(C)C.C1([Mg]Br)C=CC=CC=1.[CH:29](=[O:33])[CH:30]([CH3:32])[CH3:31]>O1CCCC1>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH:29]([OH:33])[CH:30]([CH3:32])[CH3:31])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1I
Reactant: CC(C)C=O
Agent: Br[Mg]c1ccccc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29.6 %

Procedure:
To a solution of 1-iodo-2,6-dinitrobenzene (1.55 g, 5.27 mmol) in anhydrous tetrahydrofuran (18 mL) cooled at minus 53° C. (dry ice-isopropanol bath) under nitrogen atmosphere, phenylmagnesium bromide (2 M in THF, 3.16 mL, 6.32 mmol) was added at a rate to keep the temperature at or below minus 45° C. Upon completion of the addition the mixture was stirred for five minutes, then isobutyraldehyde (0.957 mL, 10.54 mmol) was added. The mixture was allowed to gradually warm up to room temperature, then quenched with saturated NH4Cl (5 mL) and poured into water (50 mL)/dichloromethane (100 mL). The organic layer was separated; aqueous layer was extracted three times with dichloromethane (50 mL each). Combined organic extract was washed with water (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to yield racemic (RS)-1-(2,6-dinitrophenyl)-2-methyl-1-propanol (0.375 g, 30%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, 2H, J=8.0 Hz, Ph-H), 7.59 (t, 1H, J=8.0 Hz, Ph-H), 4.84 (dd, 1H, J=7.6 and 9.2 Hz, Ph-CH), 2.87 (d, 1 H, J=7.6 Hz, OH), 2.18 (m, 1H, CHCH(CH3)2), 1.12 (d, 3H, J=6.4 Hz, CH3), 0.77 (d, 3H, J=6.8 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 150.82 (C), 130.62 (C), 129.31 (CH), 127.30 (CH), 74.52 (CH), 34.19 (CH), 19.84 (CH3), 19.14 (CH3).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]([OH:16])=O)=[C:4]([O:17][CH3:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[N+:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33])([O-:28])=[O:27]>ClCCl.CN(C=O)C>[N+:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:14]([C:5]1[CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([F:1])=[CH:3][C:4]=1[O:17][CH3:18])=[O:16])([O-:28])=[O:27]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: COc1cc(F)c(-c2ccccc2)cc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(F)c(-c2ccccc2)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Yield: 64.8 %

Procedure:
A stirring slurry of 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid (1.0 g, 4.06 mmol) in dichloromethane (8.2 mL, 0.5 M) was treated with oxalyl chloride (1.1 mL, 12.2 mmol) and DMF (1 drop). The mixture was heated to 40° C. until the solution was clear (1-2 h). Next, the mixture was allowed to cool to room temperature, concentrated under reduced pressure, and then diluted with dichloromethane (8.2 mL, 0.5 M). To the stirring mixture at 0° C. was added diisdpropylethyl amine (1.8 mL, 10.2 mmol) followed by 3-nitrobenzylamine hydrochloride salt (1.2 g, 6.1 mmol). Stirring under nitrogen, the solution was gradually warmed to room temperature and stirred overnight. The mixture was then diluted with dichloromethane and washed with 2N HCl (2×50 mL) and saturated aq NaCl (1×100 mL) The organic layer was dried over Na2SO4, filtered, and concentrated to afford a yellow oil. Purification by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid 3-nitro-benzylamide (1.0 g, 65%) as a yellow solid: Rf 0.33 (50% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 8.90 (bd t, J=6.2 Hz, 1H), 8.10 (dd, J1=7.2 Hz, J2=2.4 Hz, 1H), 7.84 (d, J=9.3 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.52-7.43 (m, 5H), 7.40-7.34 (m, 1H), 7.20 (d, J=12.9 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 3.96 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20].N1C=CN=CC1=O>>[N+:19]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)=[CH:6][CH:5]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: O=c1cnc(-c2ccccc2)c[nH]1
Agent: O=S(=O)(O)O
Agent: O=c1cncc[nH]1
Product: O=c1cnc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
5-Phenyl-2-(1H)-pyrazinone (56 g) was added in portions over 30 minutes to a stirred mixture of concentrated sulphuric acid (35 ml) and fuming nitric acid (200 ml). The temperature of the nitrating mixture was initially at -20° C. and care was taken to ensure that the temperature did not rise above -15° C. When the pyrazinone had completely dissolved the reaction mixture was allowed to warm to -10° C., stirred for a further 30 minutes, and poured slowly on to ice/water (1500 ml). A pale yellow solid precipitated which was collected by filtration, washed with a small amount of cold water and dried to afford 5-(4-nitrophenyl)-2-(1H)-pyrazinone (58.1 g).
Reaction SMILES: [N:1]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:5]([C:6]([O:8]CC2C=CC=CC=2)=[O:7])[CH2:4][C@@H:3]2[CH2:16][CH2:17][CH2:18][C@H:2]12>[Pd].C(O)C>[C:22]([O:21][C:19]([N:1]1[C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][C@@H:3]2[CH2:16][CH2:17][CH2:18][C@H:2]12)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)O)C[C@@H]2CCC[C@@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 104.5 %

Procedure:
To a 250 mL round bottom flask charged with a stir bar and (2S,3aS,6aS)-2-benzyl 1-tert-butyl hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (5.76 g, 16.68 mmol) was added 10% Palladium on carbon (1.77 g). Ethanol was poured over the mixture and the reaction mixture was evacuated and flushed with hydrogen gas three times. The suspension was stirred at room temperature under an atmosphere of hydrogen for 24 hours. Upon completion, the reaction mixture was filtered through celite and concentrated to give (2S,3aS,6aS)-1-(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (4.45 g, >99%). MS (ESI) m/z 256.21 [M+H]|.
Reaction SMILES: [I-].[Na+].[C:3](OC(=O)C)(=[O:5])[CH3:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[C:26]3[C:25](=[N:27]O)[CH2:24][CH2:23][CH2:22][C:21]=3[N:20]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:19]=2[CH3:35])=[CH:13][CH:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C(C)=CC=CC=1.C(O)(=O)C.O>[C:3]([NH:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:18]([S:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)=[C:19]([CH3:35])[N:20]2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:5])[CH3:4]
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=NO
Reactant: CC(=O)OC(C)=O
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(C)=O)cccc21
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
A mixture of sodium iodide (0.05 mol equiv) in xylene (1.0 rel vol), acetic acid (1.0 rel vol) and acetic anhydride (1.2 mole equiv) was heated to 97-103° C. in vessel 1 with stirring. In vessel 2, acetic anhydride (1.3 mole equiv) was added to a stirred slurry of ethyl [3-(4-chlorophenylsulfanyl)-4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (1 mole equiv, limiting reagent) in xylene (1.0 rel vol) and acetic acid (1.0 rel vol) at 19-25° C. After stirring at this temperature for 2 h, this mixture was added to the solution in reaction vessel 1 over 2.5 h, maintaining the temperature at between 98 and 102° C. Vessel 2 was rinsed with a mixture of xylene (0.25 rel vol) and acetic acid (0.25 rel vol) which was added to vessel 1. The reaction was held at 98 to 102° C. for a further 1.5 h then cooled to 60° C. Xylene (0.9 rel vol) was added followed by a warm (60° C.) solution of sodium chloride (0.19 rel wt) in water (1.5 rel vol) and the temperature adjusted to 60° C. The aqueous layer was separated and discarded. A warm (60° C.) solution of sodium thiosulfate (0.1 mole equiv) in water (0.5 rel vol) was added and after mixing, the aqueous layer was separated and discarded. The product was precipitated by the is addition of heptanes (3 rel vol) to the organic layer, whilst maintaining the temperature at between 57 and 63° C. The resulting slurry was cooled to 20° C. over 1 h then the solid product was collected by centrifugation, washed with ethanol (3.0 rel vol) and dried to afford crude ethyl [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetate as a solid in 77% yield; purity by UHPLC 97.4 area %.