Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][O:14][CH2:13][CH2:12][N:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:6][CH:5]=1.[Cl:23]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O.O>[Cl:23]/[C:3](/[C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:15][O:14][CH2:13][CH2:12][N:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:8][CH:9]=1)=[N:2]\[OH:1]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(C=NO)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(/C(Cl)=N/O)cc1
Temperature: 55 °C
Yield: 93.3 %

Procedure:
To a solution of tert-butyl (3R)-3-[4-[hydroxyiminomethyl]phenyl]morpholine-4-carboxylate 12 (5.57 g, 18.18 mmol) in DMF (33.06 mL) at 55° C. was added 1-chloropyrrolidine-2,5-dione (2.549 g, 19.09 mmol) and the resulting mixture heated at 55° C. for 20 mins. The reaction mixture was then cooled to rt and diluted with EtOAc (50 mL) and water (50 mL) and the organic layer separated. The aqueous later was extracted further with extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with water (3×50 mL) and brine (1×50 mL), dried over MgSO4, filtered and concentrated in vacuo to leave the product as a white foam (5.78 g, 89% yield); 1H NMR (400.0 MHz, DMSO) d 1.23 (9H, s), 3.37 (1H, m), 3.48 (1H, m), 3.75 (3H, m), 4.26 (1H, m), 5.01 (1H, s), 7.43 (2H, m), 7.78 (2H, m) and 12.40 (1H, s) ppm
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:8]1[O:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)([CH3:7])[CH3:6].CCN(CC)CC.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:25][S:22]([O:14][CH2:13][C:11]1[N:12]=[C:8]([C:5]([O:4][CH3:3])([CH3:7])[CH3:6])[O:9][CH:10]=1)(=[O:24])=[O:23]
Reactant: COC(C)(C)c1nc(CO)co1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(C)(C)c1nc(COS(C)(=O)=O)co1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(2-methoxypropan-2-yl)oxazol-4-yl)methanol (31 mg, 0.18 mmol) in dry CH2Cl2 (1.4 mL) was treated at 0° C. with Et3N (0.03 mL, 0.23 mmol) followed by DMAP (2.2 mg, 0.02 mmol) and Ms-Cl (0.02 mL, 0.23 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with water (10 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give 44 mg of crude (2-(2-methoxypropan-2-yl)oxazol-4-yl)methyl methanesulfonate as a yellow oil. LC-MS-conditions 07: tR=0.62 min, [M+H]+=250.00. A solution of this crude material (44 mg) in DMF (0.4 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (T. E. Eagles et al. Organic preparations and procedures 2 (2), 117-119, 1970; P. N. Neuman J. Heterocycl. Chem. 8, 51-56, 1971) (203 mg of a 9.6% solution in DMF, 0.17 mmol) in DMF (0.4 mL) pre-treated for 30 min with DIPEA (0.06 mL, 0.34 mmol) and the reaction mixture was stirred for 24 h at 50° C. Water (5 mL), followed by EA (5 mL) was added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.43. LC-MS-conditions 07: tR=0.72 min, [M]+=267.96.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][O:16][C:17](=O)[CH:18]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[C:17]([Cl:3])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc(=O)o[nH]2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(Cl)on2)cc1
Reaction time: 4 h

Procedure:
To 30 g of phosphorus oxychloride were added 7.4 g (39 mmol) of 3-(4-methoxyphenyl)isoxazol-5-one, followed by the dropwise addition of 4 g (40 mmol) of triethylamine. After completion of the dropwise addition, the reaction mixture was stirred at 120°-125° C. for 4 hours. The solvent was then distilled off under reduced pressure. Ice water (100 ml) was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried. Purification by silica gel column chromatography (solvent: hexane/ethyl acetate=10/1) gave the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:11]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[CH:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:7][C:8]=1[O:9][CH3:10].C(S([O-])(=O)=[O:41])CCCCCCCCCCC.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:11]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[CH:12][C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[O:14])=[CH:7][C:8]=1[O:9][CH3:10].[OH2:41]
Reactant: CCCCCCCCCCCCS(=O)(=O)[O-]
Agent: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1OC
Agent: [Na+]
Product: O

Procedure:
63% benziothiazolinone, 2% dimethomorph, 6% sodium lignosulfonate, 3% sodium dodecyl sulfonate, 1% xanthan gum, 1% sodium carboxymethyl starch, complemented to 100% with attapulgite.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:9][N:10]=1>N1C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:7]=[N:6][C:5]([NH:2][NH2:3])=[N:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: NN
Reactant: Fc1ccc(-c2cnc(Cl)nn2)cc1
Solvent: c1ccncc1
Solvent: O
Product: NNc1ncc(-c2ccc(F)cc2)nn1
Temperature: 0 °C
Yield: 87.7 %

Procedure:
Hydrazine hydrate (0.28 mL, 0.0057 mol) was added to a suspension of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazine (400 mg, 0.002 mol) in pyridine (4 mL) at 0° C. and stirred at 0° C. until a precipitate formed. The mixture was then heated at 65° C. for 30 min. The solvent was evaporated under reduced pressure. The residue was triturated with water, filtered, and washed with water. The crystalline solid was collected and dried under high vacuum to give the desired product (360 mg, 91.9%). Analytical LCMS: (M+H)+=206.1.
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>C1COCC1.ClCCl>[CH3:3][O:4][C@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a glove box (O2 content≦2 ppm), a 50-ml stainless steel autoclave was charged with 1.99 mg of [Ru(η5-2,4-DMP)((R)—(S)—PPF—PtBu2)(NCMe)]BF4 (0.0023 mmol, S/C 1,000) and 5 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 2.5 ml of dichloromethane, 7.5 ml of THF and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.2% (>99.9% conversion) and an enantiomeric purity of 90%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19].O>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:18]([CH3:20])[CH3:19])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (8.00 g) in anhydrous DMF (50 ml) was added dropwise to a suspension of sodium hydride (1.08 g) in anhydrous DMF (200 ml), and the resulting mixture was stirred at room temperature for 80 minutes. To the reaction solution, 2-iodopropane (4.03 ml) was added, and the resulting mixture was stirred at room temperature for 2 hours. Sodium hydride (1.08 g) was added to the reaction solution and thereafter 2-iodopropane (4.03 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 6 hours. Water was added to the reaction solution and the resulting mixture was extracted twice with ethyl acetate. Organic layers were washed 4 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane-cyclohexane/ethyl acetate=50/1). The obtained solid was recrystallized from hexane to obtain N-(4-iodophenyl)-N-isopropylpyrimidin-2-amine (7.06 g). NMR (H1, CDCl3): δ 1.14(3H, s), 1.16 (3H, s), 5.12-5.19 (1H, m), 6.52 (1H, t, J=4.6 Hz), 6.88-6.92 (2H, m), 7.74-7.77 (2H, m), 8.29 (2H, d, J=4.6 Hz)
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][F:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:22]=1>N1CCCCC1.C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]#[C:28][C@:26]([C:23]4[N:22]=[C:21]([CH3:20])[O:25][N:24]=4)([OH:30])[CH3:27])[CH:10]=3)[C:6]([CH2:18][F:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(-n2nc(CF)c3ccc(Br)cc32)n1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(CF)nn(-c4ccnc(N)n4)c3c2)no1
Temperature: 66 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine (70 mg, 0.21 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.02 mmol), copper(I) iodide (3 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (90 mg, 0.41 mmol). The reaction mixture was warmed to 66° C. for 2 hr, re-treated with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (45 mg, 0.20 mmol) and warming continued at 66° C. for a further 1 hr. Following cooling to RT, the reaction mixture was concentrated in vacuo, DCM (10 mL) was added and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished a brown oil which was suspended in acetonitrile and concentrated in vacuo. The residue was slurried in diethyl ether (0.5 mL) to which was introduced acetonitrile until a fine cream precipitate resulted. Filtration furnished the title compound as a cream solid: 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 2.62 (3H, s), 5.85 (2H, d, J=47.45 Hz), 6.82 (1H, s), 6.95-7.23 (3H, m), 7.43 (1H, dd, J=8.28, 1.18 Hz), 7.98 (1H, d, J=8.20 Hz), 8.33 (1H, d, J=5.36 Hz), 8.94 (1H, s); LC-MS: m/z=+394.00 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[O:21])[CH2:15][CH2:14]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)#[N:2].C[Si]([N:38]=[N+:39]=[N-:40])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:38]1[C:1]([CH2:3][CH2:4][C:5]2([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([N:19]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=4)[C:20]([C:22]4[O:23][CH:24]=[CH:25][CH:26]=4)=[O:21])[CH2:15][CH2:14]3)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)=[N:2][N:40]=[N:39]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCC#N)CCCCC3)CC2)nc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCc4nnn[nH]4)CCCCC3)CC2)nc1

Procedure:
To a solution of N-[1-[2-[1-(2-cyanoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl) -2-furancarboxamide (355 mg) dissolved in toluene (2 mL) were added trimethylsilylazide (0.21 mL) and di-n-butyltin oxide (19.7 mg). The solution was heated under reflux for 11 hours. Trimethylsilylazide (0.42 mL) and di-n-butyltin oxide (98.0 mg) were further added to the solution and it was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure (by azeotropic distillation with methanol). The resulting residue was purified by chromatography (silica gel, chloroform:methanol=80:20) to give the title compound (385 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20]>>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:12]1[CH:13]=[CH:14][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[N:11]1
Reactant: O=[N+]([O-])c1ccc(-c2cc[nH]n2)cc1
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCn1ccc(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 3 using 3-(4-nitrophenyl)-1H-pyrazol (2.4 mmol) and 2-chloro-N,N-dimethylethanamine hydrochloride provided the title compound. ESMS [M+H]+: 261.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:25])[CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([CH:23]=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:26](Cl)(=[O:30])[C:27](Cl)=[O:28].[CH3:32][OH:33].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:32][O:33][C:26](=[O:30])[C:27]([C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]2[CH2:24][CH:12]([N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[CH3:25])[CH2:13][CH2:14][C:15]=12)=[O:28]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C1CCc2cc3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Reactant: CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(=O)c1c2n(c3ccccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a 0° C. solution of (+/−) 4-fluoro-N-methyl-N-(6,7,8,9-tetrahydropyrido [1,2-α]indol-7-yl)benzenesulfonamide from Step 11 in CH2Cl2 (0.1 M) was added oxalyl chloride (2 equiv.) and the mixture was stirred for 1 h at 0° C. MeOH (20 equiv.) was added, the resulting mixture was stirred at rt for 1 h, and then poured into aqueous NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried with MgSO4 and concentrated under vacuum to afford the crude title compound (100%) as a yellow solid. The material was used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=[CH:4][C:3]=1[NH2:20].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([NH:20][C:3]2[CH:4]=[C:5]([O:8][CH2:9][C:10]3[C:11]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:17]=[CH:18][CH:19]=3)[CH:6]=[CH:7][C:2]=2[Br:1])=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Nc1cc(OCc2ccc3ccccc3c2)ccc1Br
Solvent: ClCCl
Product: S=C(Nc1cc(Cl)cc(Cl)c1)Nc1cc(OCc2cccc3ccccc23)ccc1Br
Yield: 37.6 %

Procedure:
A solution of 2-bromo-5-(2-naphthylmethoxy)phenylamine (100 mg, 0.3 mmol) and 3,5-dichlorophenylisothiocyanate (60 mg, 0.3 mmol) in 10 mL of dichloromethane was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and the residue recrystallized from ethyl acetate/hexane to give 60 mg of product in (38%) yield as a white solid: mp 149-151° C. 1H NMR (400 MHz, Me2SO-d6) δ5.56 (s, 2H); 7.02 (dd, 1H, J=3.0, 8.9); 7.29 (d, 1H, J=3.0); 7.35 (t, 1H, J=1.8); 7.49-7.69 (m, 7H); 7.93-7.99 (m, 2H); 8.07-8.10 (m, 1H); 9.78 (s, 1H); 10.10 (s, 1H). Anal. Calcd for C24H17BrCl2N2OS: C, 54.16; H, 3.22; N, 5.26; S, 6.02; Cl, 13.32; Br, 15.01. Found: C, 54.17; H, 3.32; N, 5.28; S,6.10; Cl, 13.31; Br, 15.00.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:8]=[C:9]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)[S:10][CH:11]=1.O.[NH2:20][NH2:21]>O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:8]=[C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:17])[NH:20][N:21]=2)[S:10][CH:11]=1
Reactant: O=C(O)CCC(=O)c1cc(Cc2ncc[nH]2)cs1
Reactant: NN
Solvent: O
Product: O=C1CCC(c2cc(Cc3ncc[nH]3)cs2)=NN1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 5.6 g of 4-[4-(1-imidazolylmethyl)-thien-2-yl]-4-oxobutyric acid, 1.1 g hydrazine hydrate and 50 ml water was stirred for 2 hours at 90° C. After cooling, the precipitated solid was filtered off, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(#N)C.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>CCOC(C)=O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:25]=[CH:24][C:23]([O:27][CH3:28])=[O:26])[N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccn(S(=O)(=O)c3ccccn3)c2c1
Reactant: C=CC(=O)OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COC(=O)C=Cc1cc2ccc(C)cc2n1S(=O)(=O)c1ccccn1
Temperature: 110 °C
Yield: 30.8 %

Procedure:
In a sealed tube, 44 (9.60 g, 35.2 mmol), copper (II) acetate monohydrate (14.05 g, 70.4 mmol), and PdCl2(CH3CN)2 (0.91 g, 3.5 mmol) were placed under a nitrogen atmosphere. Acetonitrile (60 mL) was added followed by methyl acrylate (9.52 mL, 105.6 mmol). The mixture was heated at 110° C. for 20 h, allowed to reach rt, diluted with EtOAc, and washed with water and brine. The combined organic layers were dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with a linear gradient ranging from 0 to 20% EtOAc-hexanes to provide 3.86 g (30%) of product 45 as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 3.81 (s, 3H), 6.39 (d, J=16 Hz, 1H), 6.97 (s, 1H), 7.06-7.08 (m, 1H), 7.39 (d, J=8 Hz, 1H), 7.40-7.45 (m, 1H), 7.84-7.90 (m, 1H), 7.94-7.96 (m, 1H), 8.06 (dt, J=1, 8 Hz, 1H), 8.42 (d, J=16 Hz, 1H), 8.52-8.54 (m, 1H). LC-MS (CI): m/z 357.1 [(M+H)+ C18H16N2O4S requires 356.08].
Reaction SMILES: ClS(N=C=O)(=O)=O.COC1C=CC(CO)=CC=1.[CH3:18][O:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][O:25][C:26]([NH:28][S:29](Cl)(=[O:31])=[O:30])=[O:27])=[CH:22][CH:21]=1.[CH3:35][O:36][C:37]1[CH:73]=[CH:72][C:40]([CH2:41][O:42][C:43]([N:45]2[CH2:49][C@@H:48]([S:50][C:51]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:47][C@H:46]2[CH2:70][NH2:71])=[O:44])=[CH:39][CH:38]=1.C(N(CC)CC)C>ClCCl>[CH3:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:41][O:42][C:43]([N:45]2[CH2:49][C@@H:48]([S:50][C:51]([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:47][C@H:46]2[CH2:70][NH:71][S:29](=[O:31])(=[O:30])[NH:28][C:26]([O:25][CH2:24][C:23]2[CH:33]=[CH:34][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[O:27])=[O:44])=[CH:72][CH:73]=1
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN)cc1
Reactant: COc1ccc(COC(=O)NS(=O)(=O)Cl)cc1
Agent: COc1ccc(CO)cc1
Agent: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)NS(=O)(=O)NC[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc(OC)cc2)cc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
To a solution of chlorosulfonyl isocyanate (3.95 ml: 45.4 mmole) in dichloromethane (70 ml), p-methoxybenzyl alcohol (5.66 ml: 45.4 mmole) is added at -50° C. The mixture is stirred at -50° C. for 15 minutes. The resulting solution of p-methoxybenzyloxycarbonylsulfamoyl chloride is added to a solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-aminomethyl-4-tritylthiopyrrolidine (obtained in the above Steps 6 or 8) (12.21 g: 22.7 mmole) and triethylamine (6.38 ml: 45.6 mmole) in dichloromethane (300 ml) at -78° C., and the mixture is stirred for 10 minutes, successively washed with dilute hydrochloric acid and brine, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-p-methoxybenzyloxycarbonylsulfamoylaminomethyl-4-tritylthiopyrrolidine (16.31 g). Yield: 91.6%. NMR δ(CDCl3) ppm: 3.78(s, 3H), 3.81, 3.83(2×s, 3H), 4.98, 4.89(ABq, J=12 Hz, 2H), 5.09, 5.03(ABq, J=12 Hz, 2H). IR ν (CHCl3) cm-1 : 3390, 1740, 1685.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH:3]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH3:13])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[N:37]#[C:38]Br.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>O1CCOCC1.O.O.O1CCOCC1>[CH3:31][C:2]([CH3:30])([CH3:1])[CH:3]([C:20]1[CH:21]=[CH:22][C:23]([C:24]2[O:25][C:38]([NH2:37])=[N:27][N:26]=2)=[CH:28][CH:29]=1)[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH3:13])=[CH:8][CH:9]=1
Reactant: CCC(Oc1ccc(C(c2ccc(C(=O)NN)cc2)C(C)(C)C)cc1)c1ccccn1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC(Oc1ccc(C(c2ccc(-c3nnc(N)o3)cc2)C(C)(C)C)cc1)c1ccccn1
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
Crude 3d (40.0 mg, 0.0967 mmol) was suspended in dioxane/water (1.3 mL of a 3:1 mixture) and cooled to approximately 5° C. A solution of aqueous sodium bicarbonate (22.0 mg, 0.237 mmol) in water (150 μL) was added followed by a solution of cyanogen bromide (15.0 mg, 0.142 mmol) in dioxane (100 μL). After 5 min, the reaction mixture was warmed to ambient temperature and aged for approximately 1 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate/brine (1:1) and extracted twice with DCM. The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (isocratic elution; 80% EtOAc/hexanes as eluent) afforded the title compound 3e. m/z (ES) 443 (M)+. 1HNMR (500 MHz, CDCl3): δ 1H NMR (500 MHz, CDCl3) δ 8.61 (t, 1H, J==2.6 Hz), 7.79 (d, 2H, J=8.8 Hz), 7.66 (m, 1H), 7.48 (d, 2H, J=8.7 Hz), 7.40 (d, 1H, J=7.7 Hz), 7.25 (d, 2H, J=8.7 Hz), 7.20 (m, 1H), 6.81 (d, 2H, J=8.7 Hz), 5.5-5.8 (bs, 2H), 5.18 (t, 1H, J=6.9 Hz), 3.67 (s, 1H), 2.0 (m, 2H), 1.05 (t, 3H, J=7.3 Hz), 1.0 (s, 9H).