Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4]Cl.O.Cl.[C:10]([O:16]CC)(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>N1C=CC=CC=1>[CH3:14][C:12]1[O:13][CH:3]=[CH:4][C:11]=1[C:10]([OH:16])=[O:15]
Reactant: COC(CCl)OC
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1occc1C(=O)O
Temperature: 0 °C

Procedure:
A first reaction mixture of chloroacetaldehyde dimethylacetal (300 g), water (400 mL) and 36% hydrochloric acid (40 mL) was stirred and brought to reflux. When the first reaction mixture became homogenous, it was cooled and added to a stirred solution of ethyl acetoacetate (260 g) and pyridine (500 mL) and left stirring at ambient temperature for 72 hours, to produce a second reaction mixture. The organic layer was then separated from the second reaction mixture and the aqueous layer was diluted with water and then extracted with methylene chloride. The combined organics were washed with 2N hydrochloric acid, followed by removal of the solvent. The residue was treated with a solution of sodium hydroxide (80 g) in water (700 mL) and ethanol (100 mL), to produce a third reaction mixture. After refluxing for 1 hour the third reaction mixture was poured into ice/water and acidified with hydrochloric acid. A cream colored precipitate formed. This precipitate was collected on a filter, washed with water and dried to give 2-methyl-3-furancarboxylic acid, 180 g. 100 g of the 2-methyl-3-furancarboxylic acid was added in portions to thionyl chloride (500 mL) and refluxed for 3 hours. Excess thionyl chloride was then distilled off to produce a residue. The residue was distilled using a water pump, to give 2-methyl-3-furanylcarboxylic chloride, bp. 62° C., 100 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NC(C)C)(C)C.[Si:29]([O:36][C:37]1[CH:42]=[C:41]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH:40]=[CH:39][C:38]=1[C@H:51]1[CH2:56][CH2:55][C@H:54](O)[CH2:53][CH2:52]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]([O:19][C@H:54]1[CH2:53][CH2:52][C@H:51]([C:38]2[CH:39]=[CH:40][C:41]([O:43][Si:44]([C:47]([CH3:49])([CH3:50])[CH3:48])([CH3:46])[CH3:45])=[CH:42][C:37]=2[O:36][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[CH2:56][CH2:55]1)=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O[C@H]1CC[C@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a round bottomed flask was added N-(tert-butoxycarbonyl)-L-phenylalanine (109 mg) and dichloromethane (10 ml). To the solution was added diisopropylcarbodiimide (64 μl), trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (150 mg) and 4-dimethyl aminopyridine (catalytic). The solution was stirred at room temperature for 15 hr. The reaction mixture was partitioned between water (20 ml) and dichloromethane (30 ml), the layers were separated and the aqueous phase was extracted with dichloromethane (2×30 ml). The combined organic phases were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether, 1:19 v/v) furnished the title compound (236 mg, 100%) as a yellow oil. δH (CDCl3): 0.18 (6H, s), 0.23 (6H, s), 0.97 (9H, s), 1.03 (9H, s), 1.35-1.47 (13H, m), 1.80-1.90 (2H, m), 1.95-2.07 (2H, m), 2.77-2.86 (1H, m), 3.05-3.12 (2H, m), 4.49-4.58 (1H, m), 4.73-4.82 (1H, m), 4.93-5.00 (1H, m), 6.28 (1H, d), 6.40 (1H, dd), 6.93 (1H, d), 7.15 (2H, d), 7.19-7.31 (3H, m).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].[CH3:24]CCCCC.[H-].[Na+].[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][C:42](=O)[CH2:41][CH:40]1[C:46]([OH:48])=[O:47])=[O:38])([CH3:35])([CH3:34])[CH3:33]>C1COCC1.O>[CH3:24][O:48][C:46]([CH:40]1[CH2:41][C:42](=[CH:2][CH2:3][CH3:4])[CH2:43][CH2:44][N:39]1[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[O:47]
Reactant: CCCCCC
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1C(=O)O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC=C1CCN(C(=O)OC(C)(C)C)C(C(=O)OC)C1
Reaction time: 2 h

Procedure:
Propyltriphenylphosphonium bromide (1.24 g, 3.22 mmol) in THF (10 mL) was added to hexane washed sodium hydride (123 mg, 3.22 mmol), in THF (10 mL) and stirred at room temperature for 3 h. Methyl ester 12a (P=Boc, m=2, P2=Me) (0.55 g, 2.15 mmol) in THF (5 mL) was added to the above reaction mixture slowly and then allowed to stir for additional 2 h. It was then poured into water and extracted with ethyl acetate (30 mL). The organic phase was dried with magnesium sulfate, filtered and evaporated to dryness, the resulting residue was chromatographed using 20% EtOAc in hexanes to provide the product 4-propylidene-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. (0.100 g, 16%): MS (ESPOS): 284 [M+H]+; 1H NMR (300 MHz, CD3OD) δ 5.18 (m, m), 4.60-4.93 (m, 1), 3.91 (m, 1), 3.67 (s, 3), 2.94-3.04 (m, 2), 2.40-2.48 (m, 2), 1.99-2.06 (m, 1), 1.85-1.97 (m, 2), 1.38 (bs, 9), 0.85 (t, J=5 Hz, 3).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.O.[NH2:15][NH2:16]>>[NH:15]([C:2]1[CH:7]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1)[NH2:16]
Reactant: Clc1cc(C2COCCO2)ccn1
Reactant: NN
Solvent: O
Product: NNc1cc(C2COCCO2)ccn1
Temperature: 0 °C
Yield: 92 %

Procedure:
A mixture of 11.4 g. (57 mmoles) of 1-(2-chloro-4-pyridyl)-1-ethylenedioxyethane in 50 ml. of 98% hydrazine hydrate was heated to reflux for 15 hours. The mixture was cooled at 0° C. for 2 hours and the resulting precipitate was filtered and dried to give 10.3 g. (92%) of the desired compound. The analytical sample was recrystallized from toluene-cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].O.O[N:16]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:37][C:38]1([C:44]2[CH:45]=[C:46]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:47]=[CH:48][CH:49]=2)[CH:43]2[CH:39]1[CH2:40][NH:41][CH2:42]2.C(N(CC)CC)C>CN(C)C=O>[NH3:16].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:41]2[CH2:42][CH:43]3[CH:39]([C:38]3([C:44]3[CH:45]=[C:46]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:47]=[CH:48][CH:49]=3)[CH3:37])[CH2:40]2)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCc1ccc(Cl)c(Cl)c1
Reactant: On1nnc2ccccc21
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3ccc(Cl)c(Cl)c3)CC21
Product: N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.8 %

Procedure:
To a solution of 3-(3,4-dichlorophenyl)propanoic acid (35 mg, 0.16 mmol) in N,N-dimethylformamide (4 ml) was added 1-hydroxybenzotriazole monohydrate (26 mg, 0.17 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol). After stirring at room temperature for 5 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 52 mg, 0.17 mmol) and triethylamine (33 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 72 h before concentrating in vacuo. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml) and saturated brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The residue was purified by chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the title compound as a white foam (38 mg, 51%).
Reaction SMILES: C([O:8][C:9](=[O:36])[C@H:10]([CH2:33][CH2:34][CH3:35])[NH:11][C:12](=[O:32])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:31])[CH2:19][NH:20]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.[H][H].NCC(O)=O>CO.[Pd].O>[NH2:20][CH2:19][C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[C:12]([NH:11][C@H:10]([C:9]([OH:36])=[O:8])[CH2:33][CH2:34][CH3:35])=[O:32])=[O:31]
Reactant: [H][H]
Reactant: CCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: NCC(=O)O
Solvent: O
Solvent: CO
Product: CCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CN)C(=O)O
Reaction time: 18 h

Procedure:
Tripeptide 4 (0.308 g, 0.62 mmol) was dissolved in methanol (30 cm3). The reaction flask was flushed with nitrogen and 10 wt. % palladium on activated carbon (66 mg, 0.062 mmol) was added and the mixture was hydrogenated at 1 atmosphere of hydrogen. After 30 min a white solid precipitated. Water (15 cm3) was added to dissolve the solid and the reaction was stirred for 18 h. The reaction was filtered through Celite™ washed with methanol/water and the solvent removed to yield an oil which was contaminated with palladium. The filtration was repeated again and the solvent removed to yield a white sold which was suspended in methanol and placed in a freezer overnight. The solid was filtered, washed with ice-cold methanol and dried to yield GPNorval (0.142 g, 84%) as white flakes. GPNorval was shown to be a 78:22 trans:cis mixture of conformers by 13C NMR analysis (the ratio was estimated from the integration of the Proβ-C carbons at δ 29.4 and 31.6 and the Proγ-C carbons at δ 24.1 and 21.9 of the major and minor conformers respectively): [α]D −79 (c 0.1 in water); δH (300 MHz; D2O) 0.85 (3H, d, J 7.4, Eγ-CH3), 1.29 (2H, sextet, J 7.0, Eγ-H2), 1.53-1.75 (2H, m, Eβ-H2) 1.88-2.05 (3H, m, Proβ-HAHB, Proγ-H2) 2.09-2.27 (1H, m, Proβ-HAHB), 3.51-3.82 (4H, m, Proδ-H2, Glyα-H2), 4.09 (0.78H, dd, J 7.8 5.0, Eα-H), 4.14* (0.22H, dd, J 9 5.0, Eα-H) and 4.41 (1H, m, Proα-H); δC (75 MHz; D2O) 12.8* (CH3, Eγ-CH3), 12.9 (CH3, Eγ-CH3), 18.5 (CH2, Eγ-C), 18.7* (CH2, Eγ-C), 21.9* (CH2, Proγ-C), 24.1 (CH2, Proγ-C), 29.4, (CH2, Proβ-C), 31.6* (CH2, Proβ-C), 33.3* (CH2, Eβ-C), 33.8 (CH2, Eβ-C), 40.6 (CH2, Glyα-C), 46.8 (CH, Proδ-C), 47.5* (CH, Proδ-C), 55.1 (CH, Eα-C), 60.0* (CH, Proα-C), 60.4 (CH, Proα-C), 166.6 (quat., Gly-CO), 173.1 (quat., Pro-CON), 178.9* (quat., Eα-CO) and 179.0 (quat., Eα-CO); m/z (FAB+) 272.1641 (MH+.C12H22N3O4 requires 272.1610).
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C@@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([OH:51])=O)[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2].[CH3:55][NH2:56]>>[CH2:1]([O:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][NH:17][C@@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH:56][CH3:55])=[O:51])[CH2:15]2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(C)(C)C(=O)O)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: CN
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(C)(C)C(=O)NC)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1

Procedure:
According to general procedure D, 1.0 mmol of 3-[(2R,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl) -phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid are reacted with methylamine (8M in EtOH) to afford the title compound which is identified based on its Rf value.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH:52]1([CH2:59][CH2:60][NH2:61])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=[CH:53]1>ClCCl.CN(C)C=O>[CH:52]1([CH2:59][CH2:60][NH:61][C:15](=[O:17])[C@H:14]([CH3:18])[C@H:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[O:19][CH3:20])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=[CH:53]1
Reactant: NCCC1C=CC=CC=C1
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@H]([C@@H](C)C(=O)NCCC1C=CC=CC=C1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
To a solution of #11 (3.57 g, 12.4 mmol, 1 eq.) in dichloromethane (100 mL, 0.1 M) and N,N-dimethylformamide (4 mL) was added HATU (5.36 g, 13.7 mmol, 1.1 eq.). After 20 minutes, triethylamine (5.20 mL, 37.3 mmol, 3 eq.) was added, followed by #62 (1.68 g, 12.4 mmol, 1 eq.), and the mixture was stirred for 18 hours. The reaction was concentrated in vacuo and the residue was taken up in ethyl acetate and washed with water (50 mL). The aqueous layer was back-extracted with ethyl acetate (3 times) and the combined organic layers were dried, filtered, and concentrated in vacuo to provide a brown oil, which was purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to provide #63 (2.95 g, 59% yield) as a viscous oil. LC-MS: m/z 405.4 [M+H+], 427.4 [M+Na+], retention time=0.75 minutes; 1H NMR (400 MHz, CDCl3), presumed to be a mixture of rotamers: δ 6.63-6.68 (m, 2H), 6.16-6.23 (m, 2H), 5.19 (br dd, J=9.0, 5.8 Hz, 2H), 3.51-3.63 and 3.71-3.90 (2 br multiplets, total 3H), 3.42 (s, 3H), 3.18-3.29 and 3.34-3.47 (2 br multiplets, total 3H), 2.27-2.45 (br m, 1H), 1.6-2.00 (m, 7H), 1.47 and 1.50 (2 br s, total 9H), 1.16-1.29 (br m, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.[F:51][C@H]1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][C@H:24]([F:51])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: F[C@H]1CCNC1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC[C@H](F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-3-fluoropyrrolidine hydrochloride and isolated as light-yellow solid (16.5 mg, 90%). MS (m/e): 389.4 (MH+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[I-].[O:22]=[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[N:24]1[CH2:33][CH2:34][N:35]([C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[C:36](N1C=C[N+](C)=C1)=[O:37]>C(Cl)Cl>[O:32]=[C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:22])[N:24]1[CH2:33][CH2:34][N:35]([C:44]1[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=1)[C:36]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:37]
Reactant: C[n+]1ccn(C(=O)N(CCN2C(=O)c3ccccc3C2=O)c2ccc(F)cc2)c1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Agent: [I-]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCN(C(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a 50 mL round-bottomed flask was added (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (80 mg, 290 μmol), 1-((2-(1,3-dioxoisoindolin-2-yl)ethyl)(4-fluorophenyl)carbamoyl)-3-methyl-1H-imidazol-3-ium iodide (151 mg, 290 μmol, from step 3), CH2Cl2 (2 mL). The reaction mixture was stirred at 40° C. for 48 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give (R)—N-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)-phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide. MS (ESI pos. ion) m/z: 588 (M+1).
Reaction SMILES: [NH2:1][C:2](=[N:6][OH:7])[CH2:3][S:4][CH3:5].[Cl:8][CH2:9][C:10](Cl)=[O:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:1][C:2](=[N:6][O:7][C:10]([CH2:9][Cl:8])=[O:11])[CH2:3][S:4][CH3:5]
Reactant: CSCC(N)=NO
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSCC(N)=NOC(=O)CCl
Reaction time: 1 h
Yield: 61.5 %

Procedure:
1-Amino-1-hydroxyimino-2-methylthioethane (11.32 g, 94.2 mmol) was suspended in dry chloroform (60 mL) under nitrogen. A solution of chloroacetyl chloride (7.5 mL, 94.2 mmol) in chloroform (20 mL) was added dropwise. After stirring for 1 hour, a solution of triethylamine (15.8 mL, 113 mmol) in chloroform (20 mL) was added dropwise. The reaction mixture was stirred for 15 minutes, then washed with water (2×70 mL), dried over sodium sulfate, concentrated in vacuo, and dried under vacuum to yield 11.4 g (62% yield) of 1-amino-1-((chloromethyl)carbonyloxy)imino-2-methylthioethane, as a brown semi-solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH3:17])=[CH:12][C:13]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][C:11]([CH3:17])=[CH:12][C:13]=1[C:14](=[O:16])[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([Cl:18])[CH:20]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)O)c(NC(=O)OC(C)(C)C)s1
Reactant: Nc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)Nc2cccc(Cl)c2)c(NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.3 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-5-methyl-thiophene-3-carboxylic acid (1.16 g, 4.49 mmol) in dimethylformamide (50.00 ml) was treated with 3-chloro aniline (0.86 g, 6.73 mmol), DIPEA (1.74 g, 13.47 mmol) and TBTU (2.16 g, 6.73 mmol) and stirred at room temperature for 48 h. The volatiles were evaporated and the residue purified by flash chromatography (heptane/ethyl acetate), to yield [3-(3-chloro-phenylcarbamoyl)-5-methyl-thiophen-2-yl]-carbamic acid tert-butyl ester (0.45 g, 27%) as a yellow solid, MS (ISP): m/e=368.6 (M+H+)
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH3:36][O:37][CH2:38][CH2:39][NH2:40].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][NH:40][CH2:39][CH2:38][O:37][CH3:36])=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: COCCN
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COCCNCc1ccc2c(c1)cc(-c1cc(OC)c(OS(C)(=O)=O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 55.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (1.02 g, 2.66 mmol) was dissolved in acetonitrile (13.0 mL), and the solution was treated with 2-methoxyethylamine (3.47 mL, 39.9 mmol), acetic acid (2.28 mL, 13.3 mmol) and sodium triacetoxyborohydride (2.82 g, 39.9 mmol), followed by purification by flash column chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(2-methoxyethylaminomethyl)indol-2-yl]isoindolinone (0.83 g, 56%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.O>[CH2:32]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:11][C:12]1=[O:16])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CN(c2ccc([N+](=O)[O-])cn2)CCN1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CN(c2ccc([N+](=O)[O-])cn2)CCN1Cc1ccccc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution of 4-(5-nitropyridin-2-yl)piperazin-2-one (B-13) (365 mg, 1.64 mmol) in DMF (6 mL) was added, dropwise, 1.0 M sodium bis(trimethylsilyl)amide solution in THF (1.8 mL, 1.8 mmol), followed 1 min later by benzyl bromide (215 μL, 1.8 mmol), also dropwise. After 1 h, the reaction mixture was poured into water and extracted with EtOAc. The extract was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (eluant: gradient of EtOAc in hexanes) to give 1-benzyl-4-(5-nitropyridin-2-yl)piperazin-2-one (B-14) (329 mg, 64% yield). MS (M+1): 313.2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].CC(N(C)C)=O.[CH3:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.[Cu]I>[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=2)[NH2:5])[CH:24]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 140 °C
Reaction time: 48 h
Yield: 66.7 %

Procedure:
3-Bromo-5-(trifluoromethyl)aniline (0.2 mL, 1.43 mmol) was stirred in a solvent of dimethylacetamide (10 mL). The reaction solution was added with 4-methyl-1H-imidazole (0.35 g, 4.26 mmol), K2CO3 (0.20 g, 5.23 mmol), Cu (0.022 g, 0.346 mmol) and CuI (0.068 g, 0.115 mmol), and stirred for about 2 days at 140° C. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.23 g, 67%).