Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][C:9]([Cl:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:19](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[C:11]([N:12]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH3:19])=[CH:10][C:9]([Cl:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCC2)c1Cl
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCCC2)c1Cl
Temperature: 80 °C
Yield: 93.3 %

Procedure:
To a stirred solution of methyl 2,5-dichloro-3-(cyclopentylamino)benzoate (0.275 g, 0.958 mmol) in acetonitrile (5 mL) was added cesium carbonate (0.622 g, 1.9 mmol) and methyl iodide (0.689 g, 4.78 mmol). The reaction mixture was heated at 80° C. for 18 h. On completion, the reaction was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to afford methyl 2,5-dichloro-3-(cyclopentyl(methyl)amino)benzoate (0.27 g, 93%).
Reaction SMILES: CNS(CCC1C=CC(N)=CC=1)(=O)=O.C(=O)(O)[O-].[Na+].II.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[CH3:31][NH:32][S:33]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[C:40]([I:45])[CH:39]=1)(=[O:35])=[O:34].[C:46](OC(=O)C)(=[O:48])[CH3:47]>ClCCl.CCCCCCC>[I:45][C:40]1[CH:39]=[C:38]([CH2:37][CH2:36][S:33](=[O:35])(=[O:34])[NH:32][CH3:31])[CH:43]=[CH:42][C:41]=1[NH:44][C:46](=[O:48])[CH3:47]
Reactant: CNS(=O)(=O)CCc1ccc(N)c(I)c1
Reactant: CC(=O)OC(C)=O
Agent: CNS(=O)(=O)CCc1ccc(N)cc1
Agent: II
Agent: O=C([O-])O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CNS(=O)(=O)CCc1ccc(NC(C)=O)c(I)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(4-aminophenyl)ethane sulfonic acid methylamide (50 g) in dichloromethane (500 ml), a 10% solution of sodium bicarbonate (500 ml) was added at 25° C. so as to obtain a biphasic reaction mass. Iodine crystals were added slowly maintaining the temperature below 30° C. The mixture was agitated at 25° C. for about an hour and cooled to 10-15° C. The excess of iodine content in the mixture was neutralized with saturated sodium metabisulphite solution and a solution of 2-(4-amino-3-iodo-phenyl)-ethanesulfonic acid methylamide (75 g) in dichloromethane (750 ml) was added followed by dropwise addition of 50% solution of acetic anhydride in dichloromethane (300 ml) maintaining the temperature of 25° C. The reaction mass was stirred for about 90 minutes and layers were separated. The organic layer was washed with water, dried and distilled under vacuum to obtain a residue. The residue was stirred in heptane (500 ml), filtered and dried under vacuum at 50-55° C. to obtain the title compound. (Yield: 85 g, HPLC Purity: 99%)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2Br)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([Sn](CCCC)(CCCC)/[CH:31]=[CH:32]\[CH2:33][OH:34])CCC>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2/[CH:31]=[CH:32]\[CH2:33][OH:34])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCC[Sn](/C=C\CO)(CCCC)CCCC
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2Br)ccc(Br)c1OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc(Br)c1OC
Temperature: 30 °C
Yield: 22.7 %

Procedure:
A mixture of methyl 3-bromo-6-(2-bromo-4-fluorobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 163, 0.916 g), 3-tributylstannyl-(Z)-prop-2-en-1-ol (prepared according to Webb et al, Tetrahedron, 2008, 64, 4778, 0.833 g) and tris(dibenzylideneacetone)dipalladium (0) (0.085 g) in toluene (12 ml) was degassed with argon. Tri-tert-butylphosphine (1M in toluene, 0.20 ml) was added and the mixture was again degassed then heated to 30° C. for 3 hours. After cooling, the mixture was diluted with ethyl acetate and filtered through a PTFE cone. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane containing 1% triethylamine with a gradient of 0-100%, to give (Z)-methyl 3-bromo-6-((4-fluoro-2-(3-hydroxyprop-1-enyl)benzenesulfonyl)methyl)-2-methoxybenzoate (0.198 g) as a yellow oil.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15]>C(Cl)Cl>[CH2:9]([O:8][P:1]([C:14](=[O:15])[CH:13]=[C:12]([CH3:17])[CH3:11])(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: CC(C)=CC(=O)Cl
Reactant: CCOP(OCC)OCC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(=O)C=C(C)C
Yield: 81.7 %

Procedure:
83 g (0.5 mol) of triethyl phosphite were added dropwise to a solution of 60 g (0.5 mol) of β,β-dimethylacrylic acid chloride in 200 ml of methylene chloride in the course of one hour. The reaction mixture was stirred for a further hour at 40° to 45° C.; the solvent was then distilled off under reduced pressure and the crude product which remained was purified by vacuum distillation. 90 g (82% of theory) of 1-oxo-3-methyl-2-butene-phosphonic acid diethyl ester of boiling point 72° C./0.01 mbar were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]1>CCOC(C)=O.CO.C(Cl)Cl>[CH3:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:15][CH2:14]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)c(C)cc1N
Reaction time: 8 h
Yield: 76.1 %

Procedure:
1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-(methylsulfonyl)piperazine (0.87 g, 2.64 mmol) was placed in a 100 mL high pressure vessel and dissolved in 60 mL of 1 to 1 to 1 EtOAc/MeOH/DCM. 5 wt % Platinum(sulfided)/C (1.03 g, 0.26 mmol) was added followed quickly by a rubber septum. The vessel was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (60 psi). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step B (0.602 g, 2.01 mmol, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.58 (s, 1H), 6.43 (s, 1H), 4.44 (s, 2H), 3.69 (s, 3H), 3.15-3.23 (m, 4H), 2.90 (s, 3H), 2.77-2.83 (m, 4H), 2.06 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30]([CH:32]4[CH2:34][CH2:33]4)=[O:31])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: CC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(Cl)cc1

Procedure:
Example 116 was prepared from 2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.15–7.95 (br, 1H), 7.63–7.44 (br, 1H), 7.39–7.12 (m, 7H), 6.85 (d, 1H, J=6.8 Hz), 3.74–3.55 (m, 1H), 3.45–3.22 (m, 2H), 3.22–3.12 (m, 1H), 3.12–3.00 (m, 1H), 2.66–2.40 (m, 3H), 2.29–2.09 (m, 2H), 1.92–1.63 (m, 6H), 1.64–1.51 (m, 1H), 1.47 (d, 3H, J=6.8 Hz), 1.18–0.98 (m, 2H), 0.91–0.74 (m, 2H); ESMS m/e: 468.2 (M+H)+; Anal. Calc. for (HCl salt) C27H35Cl2N3O2.0.28CHCl3: C, 60.91; H, 6.61; N, 7.81; Found: C, 60.66; H, 6.90; N, 8.19.
Reaction SMILES: [H-].[Na+].C(S)CC.[CH2:7]([C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37](C4C=CC([N+]([O-])=O)=CC=4)[N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[CH3:8].[ClH:47]>CCCCCC.CN1CCCC1=O.O>[ClH:47].[CH2:7]([C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[CH3:8]
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c2ccccc2n1
Agent: CCCS
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2ccccc2n1
Reaction time: 0.25 h
Yield: 64 %

Procedure:
Sodium hydride (50% dispersion in mineral oil; 0.091 g; 1.9 mmol) was washed with hexane, dried with a stream of nitrogen and covered with N-methylpyrrolidone (NMP) (5 ml). The mixture was cooled to below 10° C. and propanethiol (0.145 g; 1.9 mmol) was added slowly with stirring. After 15 minutes, a solution of 2-ethyl-4-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline (A) (0.5 g; 0.95 mmol) in NMP (10 ml) was added slowly maintaining the temperature of the reaction mixture below 10° C. The mixture was then stirred for 2 hours. Concentrated hydrochloric acid was added until the reaction mixture was pH2. Water (25 ml) was then added and the suspended white solid collected by filtration. The crude product was recrystallised from ethanol to give 2-ethyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride as a solid, in 64% yield; m.p. 178° -181° C.; NMR (d6 -DMSO): 1.53(3H, t), 3.30(2H, q), 5.65(2H, s), 7.25(2H, d), 7.50-7.75(6H, m), 7.80(1H, t), 7.90(1H, s), 8.00(1H, t), 8.35(1H, d), 8.50(1H, d).
Reaction SMILES: [CH3:1][S:2]([N:5]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[N:18]=2)[CH:15]=1)S(C)(=O)=O)(=[O:4])=[O:3].[OH-].[Na+]>C(O)C>[CH3:1][S:2]([NH:5][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=2)[CH:15]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)c1cn2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2nc(C(=O)O)cn2c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 54.2 %

Procedure:
Ethyl 6-(N-(methylsulfonyl)methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxylate (0.412 mmol, 0.149 g) was dissolved in ethanol (10 ml) and cooled to 0° C. with an ice bath. NaOH 2 M solution (0.825 mmol, 0.412 ml) was added and stirred at 0° C. for 3.5 h after which the temperature was allowed to warm to RT. The stirring continued overnight. The temperature was raised to 50° C. and stirred for 5 h. The mixture was again stirred at RT overnight. Ethanol was evaporated and water was added. The pH was adjusted to 4 with 1 M HCl after which the product started to precipitate. The precipitate was removed by filtration and dried under vacuum. 0.057 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 3.05 (s, 3H), 7.22-7.29 (m, 1H), 7.60-7.66 (m, 1H), 8.49-8.53 (m, 1H), 8.55 (s, 1H), 9.81 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[C:10](Br)=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC.O>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[C:10]([C:24](=[O:26])[CH3:25])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Cn1cc(Br)c2cncnc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ncncc12
Temperature: 25 °C

Procedure:
A solution of (5-bromo-pyrrolo[2,3-d]pyrimidin-7-yl)-acetic acid tert-butyl ester (220 mg, 0.71 mmol), tri-butyl(1-ethoxyvinyl)tin (285 μL, 0.85 mmol) and tetrakis(triphenylphosphine) palladium (16.28 mg, 14.1 μmol) in toluene (7 mL) was heated at 110° C. for 72 h under argon atmosphere. The mixture was allowed to cool to RT, poured into water and extracted with EtOAc (×2). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH 94:6). TLC, Rf (CH2Cl2/MeOH 9:1)=0.54; MS (UPLC/MS): 276.3 [M+H]+, 320.4 [M+HCOO]−; tR (HPLC conditions f): 1.40 min.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[CH2:18]1[C:21]2([CH2:24][C:23](=O)[CH2:22]2)[CH2:20][O:19]1>C1COCC1>[CH2:18]1[C:21]2([CH2:24][C:23](=[CH:3][C:1]#[N:2])[CH2:22]2)[CH2:20][O:19]1
Reactant: O=C1CC2(COC2)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC2(COC2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (82 mg; 0.464 mmol) in THF (2 mL) at 0° C. under nitrogen was added potassium t-butoxide (0.51 mmol; 1M solution in THF) and the mixture was stirred at 0° C. for 1 hour. A solution of 2-oxaspiro[3.3]heptan-6-one (52 mg; 0.464 mmol) in THF (1 mL) was added. A precipitate formed and further THF (1 mL) was added to enhance the stirring. The reaction mixture was allowed to stir for 4 hours at ambient temperature. The reaction mixture was partitioned between saturated aqueous ammonium chloride (10 mL) and ethyl acetate (10 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×10 mL). The extracts were combined, dried (sodium sulfate), filtered and evaporated under reduced pressure. The material was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:2) to give the product as a colorless oil (20 mg).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])[O:27]C2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.O.[OH-].[Li+]>C1COCC1.CO>[C:35]([NH:34][C:26](=[O:27])[N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:23])[F:22])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:7]=1)[CH2:37][CH3:38])#[N:36]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NC#N
Temperature: 25 °C

Procedure:
[2′-(3-Cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester (0.100 g, 0.19 mmol) in THF (2 mL), MeOH (0.5 mL), and H2O (0.5 mL) was treated with lithium hydroxide (0.030 g, 0.71 mmol), and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [N:1]12[CH2:11][CH2:10][CH2:9][CH:8]=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]2.C(Cl)Cl.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>[Cl-]>[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:1][S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])[CH2:6]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C1=C2CCCCNN2CCC1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Yield: 54.3 %

Procedure:
Into a solution of 4.0 g of this product in pyridinemethylene chloride is added 8.39 g of diazabicyclo[5.4.0]undeca-7-ene. Subsequently, under cooling, a methylene chloride solution of 3.36 g of benzenesulfonyl chloride is added dropwise with stirring. After the reaction, water is added, and the organic layer is separated, followed by evaporation of the solvent. The residue is crystallized from an ethanol-n-hexane mixture, purified through silica gel column chromatography, and recrystallized from an ethyl acetate-n-hexane mixture to give 2.98 g of 5-amino-2-benzenesulfonylaminoindan.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](=[O:21])[CH2:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[Br:1][C:13]1[C:12](=[O:21])[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[O:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=O)CC(=O)C=Cc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc(-c2ccc(Cl)cc2)cc(=O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of bromine (7.06 ml) in chloroform (70 ml) was added dropwise to a stirred solution of ethyl 6-(4-chlorophenyl)-2,4-dioxo-hex-5-enoate (19.2 g) in chloroform (300 ml) at 5° to 10° C. The solution was stirred for 30 minutes at room temperature then evaporated to a yellow oil. This crude tribromide was dissolved in dimethylsulphoxide (150 ml), and 1,5-diazabicyclo[4.3.0]non-5-ene (16.9 g) was added at 20° to 25° C. The mixture was stirred for 30 minutes at room temperature then diluted with ice-water (300 ml) to precipitate a sticky brown solid. A solution of this crude product in chloroform was passed down a short column of silica-gel (100 g) and then evaporated. The residual solid was washed with ethyl acetate-petroleum ether 60°-80° C., then recrystallised from ethyl acetate-petroleum ether 60°-80° C. to give the title product as yellow needles (mp 146°-149° C.).
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.CCOCC.C([Li])CCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1.O>[C:2]1([B:28]([OH:33])[OH:29])[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-Bromopyrene (2.00 g, 7.12 mmol) was dissolved in anhydrous THF (150 ml) and anhydrous ether (150 ml). The light yellow solution was cooled to −78° C. in nitrogen. n-Butyllithium (4.9 ml, 7.83 mmol) was slowly dripped into the solution. At this time, the solution became murky. This mixture was kept at −78° C. for ten minutes, 0° C. for ten minutes, and then −78° C. for thirty minutes. Then, triisopropyl borate (4.93 ml, 21.36 mmol) was slowly dripped into the solution, and the mixture was kept at −78° C. for thirty minutes. Finally, the mixture underwent reaction at room temperature for 1.5 days. Next, water was added into the reaction mixture, and the resulting mixture was stirred vigorously for one hour. The water layer and the organic layer were separated, the water layer was then extracted by ethyl ether (2×25 ml), and the organic layer was water washed (2×50 ml). The combined organic solution was contact with MgSO4 to remove water, then filtered, and concentrated on a rotary evaporator to obtain a pyreneboronic acid solid product.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].I[CH3:16]>CN(C)C=O>[CH3:16][N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To a stirred suspension of sodium hydride (5.0 g; 167 mmol) in dimethylformamide (200 ml) at 0° C. under nitrogen was added 5-nitroindole (25 g; 154 mmol) in dimethylformamide. After stirring for 0.5 h, iodomethane (10.5 ml; 168 mmol) in dimethylformamide (50 ml) was added, and stirring was continued for 2 h. The reaction mixture was then quenched with water, and poured onto excess water with stirring. Filtration afforded the title compound (27.4 g; 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][CH:39]1[CH2:41][CH2:40]1)=[O:36]>CN(C=O)C>[CH:39]1([CH2:38][O:37][C:35]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([N:17]4[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]5[CH2:25][CH2:26][CH2:27][CH:18]45)(=[O:16])=[O:15])=[CH:12][CH:13]=3)=[CH:4][CH:3]=2)=[O:36])[CH2:41][CH2:40]1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Reactant: O=C(Cl)OCC1CC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1)OCC1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 2 mmol of cyclopropylmethyl chloroformate in 3 ml of DMF were added. The reaction solution was then stirred at RT for a further 6 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=3)[CH2:7]2)[C:5](=[O:18])[NH:4][C:3]1=[O:19].OS(O)(=O)=O.[CH3:25]O>>[CH3:1][N:2]1[C@@:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17][CH3:25])=[O:16])[CH:12]=3)[CH2:7]2)[C:5](=[O:18])[NH:4][C:3]1=[O:19]
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(C(=O)O)cc1C2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)C[C@@]1(C2)C(=O)NC(=O)N1C

Procedure:
To a stirred solution of 3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-5′-carboxylic acid (4.50 g, 17.3 mmol) in MeOH (500 mL) was added conc. H2SO4 (1 mL, 18 mmol) and the resulting mixture was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo to a volume of about 150 mL and then partitioned between saturated aqueous sodium bicarbonate (200 mL) and CHCl3 (500 mL). The aqueous layer was extracted further with CHCl3 (250 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness in vacuo to give the racemic product. Separation of the enantiomers was achieved by SFC on a ChiralPak AD-H column, eluting with CO2:i-PrOH-70:30, to give methyl (4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-5′-carboxylate, the title compound, as the first major peak, and methyl (4R)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-5′-carboxylate as the second major peak. MS: m/z=274.9 (M+1).