Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]([C:24]([O:26]CC)=[O:25])=[C:9]([NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3)=[O:14])[S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:1]1([C:7]2[C:8]([C:24]([OH:26])=[O:25])=[C:9]([NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3)=[O:14])[S:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1c(C2CCCCC2)csc1NC(=O)Nc1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1ccc(F)c(F)c1)Nc1scc(C2CCCCC2)c1C(=O)O
Temperature: 100 °C
Reaction time: 17 h
Yield: 53.8 %

Procedure:
To a solution of 51 (0.2 mmol) in EtOH (2 ml) at room was added 1.0 N NaOH (aq.) (0.2 ml). The mixture was stirred at 100° C. for 17 hrs. The solvent was removed under vacuum. The residue was suspended in 1.0 N HCl (aq.) (2 ml) and extracted with ethyl acetate (3×5 ml). The combined organic layers were dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under vacuum to give the crude product which was purified using preparative HPLC to give 52 (40.9 mg). 1H NMR (DMSO-d6) δ 1.27 (m, 6H), 1.73 (m, 2H), 1.90 (m, 2H), 3.09 (m, 1H) 3.57 (s, 1H), 6.74 (s, 1H). 7.20 (m, 1H), 7.53 (m, 2H), 12.34 (s, 1H) ppm.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:26])[CH2:16][O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:12]=[CH:13][CH:14]=1>N1C=CC=CC=1>[C:1]([O:26][CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=1)[CH2:16][O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C(O)COCCN2CCOCC2)c1
Solvent: c1ccncc1
Product: CC(=O)OC(COCCN1CCOCC1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.65 ml of pyridine and 0.99 ml of acetic anhydride were added to 1 g of 1-(3-methylphenyl)-2-[2-(morpholin-4-yl)ethoxy]ethanol. The mixture was stirred for 3 hours at room temperature. The reaction mixture was subjected to distillation under reduced pressure to remove the solvent. To the residue were added 20 ml of ethyl acetate and 10 ml of water. The mixture was adjusted to pH 10 with potassium carbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/ethanol=30/1) to obtain 1 g of oily 1-acetoxy-1-(3-methylphenyl)-2-[2-(morpholin-4yl)ethoxy]ethane (compound No. 178).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].O1CCOCC1>[Cu]Br>[CH2:18]([O:17][C:11]([CH:12]([C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:13](=[O:14])[CH3:15])=[O:16])[CH3:19]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(O)c1ccccc1Br
Agent: [Cu]Br
Solvent: C1COCCO1
Product: CCOC(=O)C(C(C)=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cold (ice/water bath) stirred mixture of 2-bromobenzoic acid (20.1 g, 0.1 mol) and ethyl acetoacetate (13.01 g, 0.1 mol) in 1,4-dioxane (200 ml) sodium hydride (8 g, 0.2 mol, 60% dispersion in mineral oil) was added in small portions. After addition the cold bath was removed and the reaction mixture was allowed to stir at ambient temperature for 10 min. Copper (I) bromide (15.2 g, 0.106 mol) was added in portions and the obtained mixture was heated at reflux for 1 h. It was allowed to cool and stirred overnight at ambient temperature. The obtained green suspension was quenched with ethyl acetate (200 ml) and ice (300 g) and acidified with concentrated HCl (50 ml). The organic phase was washed with aq. 2 M HCl (2×100 ml) and brine, dried (Na2SO4) and evaporated in vacuo. The remaining mineral oil was removed by decantation after shaking with heptane (3×100 ml) and evaporation. Yield ca. 20 g, pale-yellow oil. The crude product was used in the next step without further purification. LC-MS (m/z) 205 ([M−CO2]+); tR=0.91. 1H NMR (500 MHz, DMSO-d6): mixture of at least 3 tautomers.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[O:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:17](I)[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+].C(#N)C>CCOCC>[CH2:1]([N:4]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[O:7][CH2:6]1)[CH2:17][CH2:18][CH3:19])[CH:2]=[CH2:3]
Reactant: CCCI
Reactant: C=CCNC1COc2cccc(OC)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: C=CCN(CCC)C1COc2cccc(OC)c2C1
Temperature: 47 °C
Reaction time: 120 h
Yield: 80.4 %

Procedure:
3-(N-Allylamino)-5-methoxychroman (1.3 g, 5.9 mmol) prepared analogous to example 26, n-propyl iodide (2.1 mL, 21 mmol), anhyrous K2CO3 (3.0 g, 21 mmol) and acetonitrile (5.5 mL) were stirred under N2 at 47° C. (oilbath temp) for five days until GC indicated complete reaction. Ether (40 mL) was added, the salts were filtered off by suction and the clear filtrate was concentrated in vacuo to afford 3-(N-allyl-N-n-propylamino)-5-methoxy chroman (1.24 g, 81% yield) as an oil. The base was precipitated from an ether solution by adding a slight excess of HCl (approx. 3M in ether). Crystallization of the crude HCl salt afforded colourless needles. Mp 117°-118° C.
Reaction SMILES: [C@@H]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.[CH2:21](Br)[CH:22]=[CH2:23].Cl.[OH-].[Na+]>CO.CS(C)=O>[NH2:18][C:17]1[NH:16][C:14](=[O:15])[C:13]2[N:12]([CH2:23][CH:22]=[CH2:21])[CH:11]=[N:10][C:20]=2[N:19]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: C=CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: C=CCn1cnc2nc(N)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 117.9 %

Procedure:
A mixture of guanosine (20 g, 0.071 mol), allyl bromide (14.7 ml, 0.169 mol) and anhydrous DMSO (100 ml) was stirred at rt, under nitrogen, for 18 hours. Concentrated HCl (50 ml of 37%) was added in one portion and the mixture stirred for 45 minutes then poured into MeOH (600 ml). The methanolic solution was neutralised with 2M NaOH (aq) solution and the resulting white precipitate collected by filtration. The white solid was dried under vacuum at 50° C. for 18 hours to afford the title compound (16 g crude, 119%). m/z 192.2[MH+].
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)O)=[N:8][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[CH2:28]([SH:30])[CH3:29].CCN(C(C)C)C(C)C>C1COCC1.N1C=CC=CC=1>[CH2:28]([S:30][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:7]1[NH:6][C:5]2[CH:22]=[CH:23][C:2]([F:1])=[CH:3][C:4]=2[N:8]=1)[CH3:29]
Reactant: CCS
Reactant: OC(c1ccc(OC(F)(F)F)cc1)c1nc2cc(F)ccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCSC(c1ccc(OC(F)(F)F)cc1)c1nc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
The compound of Example 1 (444 mg) was dissolved in THF (7 mL), and thionyl chloride (178 mg) and pyridine (247 mg) were added thereto. The mixture was stirred for 30 minutes at room temperature, and then ethanethiol (101 mg) and DIPEA (535 μL) were added thereto. The mixture was stirred for 1.5 hours at room temperature. After distilling off the solvent under reduced pressure, the residue was basified with a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (20% to 66% ethyl acetate/hexane), and thus the title compound (275 mg) was obtained as a colorless amorphous material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2O[C:9](=O)[NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[NH3:14]>C(N)=O>[F:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:14]=[CH:9][NH:8][C:7]2=[O:12]
Reactant: N
Reactant: O=c1[nH]c(=O)c2cc(F)ccc2o1
Solvent: NC=O
Product: O=c1[nH]cnc2ccc(F)cc12
Reaction time: 0.17 h

Procedure:
1. 3.62 g of 6-fluoro-2H-1,3-benzoxazine-2,4(1H)-dione are suspended in 15 ml of formamide. Gaseous ammonia is introduced while stirring during about 10 min. until the suspension is saturated and the mixture is stirred at room temperature for a further 1 h. Subsequently, the mixture is stirred at 125° C. (bath temperature) for 16 h. The solvent is then distilled off in a high vacuum. The residue is triturated in 50 ml of water and then cooled slightly. The resulting crystals are filtered off, washed with ice-cold water and dried over calcium chloride in a vacuum. 2.9 g of crude 6-fluoro-3H-quinazoline-4-one are obtained. The substance melts at 252°-255° C. after recrystallization from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3([OH:21])[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:22].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[N:34]=[C:35]=[O:36]>O1CCCC1>[CH2:19]([N:16]1[CH2:17][CH2:18][C:13]([C:11]2[S:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35]([NH:34][C:25]4[CH:26]=[C:27]([C:30]([F:31])([F:33])[F:32])[CH:28]=[CH:29][C:24]=4[F:23])=[O:36])=[C:3]([F:22])[CH:4]=3)=[CH:9][N:10]=2)([OH:21])[CH2:14][CH2:15]1)[CH3:20]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CCN1CCC(O)(c2ncc(-c3ccc(N)c(F)c3)s2)CC1
Solvent: C1CCOC1
Product: CCN1CCC(O)(c2ncc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)s2)CC1
Reaction time: 1 h

Procedure:
To an ambient solution of Example 8B (0.02 g, 0.062 mmol) in tetrahydrofuran (1 mL) was added 2-fluoro-5-trifluoromethylphenylisocyanate (0.010 g, 0.065 mmol). After 1 h, the mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min). The fractions containing the desired product were diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01 (t, J=7.1 Hz, 3H), 1.73 (br d, J=11.9 Hz, 2H), 2.08 (dt, J=11.9 and 3.7 Hz, 2H), 2.25-2.37 (m, 4H), 2.64-2.73 (m, 2H), 6.15 (s, 1H), 7.33-7.52 (m, 3H), 7.61 (m, 1H), 8.05 (s, 1H), 8.24 (m, 1H), 8.64 (m, 1H), 8.90 (s, 1H), 9.34 (s, 1H); MS (ESI) m/z 527 [M+H]+.
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].F[C:6]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:7]=1[C:8]#[N:9]>CO>[F:14][C:13]1[C:6]([O:3][CH3:2])=[C:7]([C:10]([F:15])=[CH:11][CH:12]=1)[C:8]#[N:9]
Reactant: N#Cc1c(F)ccc(F)c1F
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1c(F)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Methanol (600 mL) was treated portionwise with sodium (Alfa, 16.1 g, 0.702 gatoms, 1.05 equiv.). The sodium methoxide solution was cooled to room temperature and added dropwise to a solution of 2,3,6-trifluorobenzonitrile (Matrix, 105 g, 0.699 mol) in methanol (600 ml) at room temperature. After addition was complete the mixture was stirred for 1 hour at room temperature before removing the methanol under reduced pressure. The residue was partitioned between diethyl ether (500 ml) and water (500 mL). The organic layer was removed, dried over MgSO4, filtered and evaporated to give the crude product. This was purified by distillation using a 6″ vigreux column @ 20 mmHg, oil bath 160° C., head temp 120° C. to give the title compound as a white solid (108 g, 91%)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]4=[O:38])[CH2:24][CH2:23]3)=[O:21])[C:16](=[O:39])[N:15]([CH3:40])[CH2:14][C:13]=2[CH:41]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]4=[O:38])[CH2:24][CH2:23]3)=[O:21])[C:16](=[O:39])[N:15]([CH3:40])[CH2:14][C:13]=2[CH:41]=1
Reactant: [H][H]
Reactant: CN1Cc2cc(OCc3ccccc3)ccc2CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: [Pd]
Solvent: CO
Product: CN1Cc2cc(O)ccc2CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reaction time: 12 h

Procedure:
To a stirred solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid (8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide (187 mg, 0.34 mmol) in methanol (30 mL) followed by 10% palladium on carbon (30 mg) under nitrogen. The reaction mixture was brought to 1 atmosphere of hydrogen and stirred for 12 h. The catalyst was filtered and the solvent was evaporated to give 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid (8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide in quantitative yield.
Reaction SMILES: [C:1](=[O:8])([O-])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Si:9]([O:16][C@H:17]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[C@@H:18]1[NH:22][CH:21]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[NH2:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH:21]2[CH2:20][CH2:19][C@H:18]([C@H:17]([O:16][Si:9]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:10])[CH3:11])[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[N:22]2[C:1]([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:8])=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](c1cccc(Cl)c1)[C@H]1CCC(Cc2ccc(N)cc2)N1
Reactant: CC(C)(C)OC(=O)[O-]
Product: CC(C)(C)OC(=O)N1C(Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 33 mg (0.07 mmol) of 4-({(5R)-5-[(R)-([tert-butyl(dimethyl)silyl]oxy}(3-chlorophenyl)methyl]pyrrolidin-2-yl}methyl)aniline in 1 mL of anhydrous THF (from Step A) was added tert-butyl carbonate (15.3 mg, 0.07 mmol), followed by TEA (13 uL, 0.07 mmol) and the resulting solution stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was put directly on a preparative plate (500 uM) and eluted with 30% ethyl acetate in hexane to afford the title compound (25 mg, 78%). m/z (ES) 530, 532 (M, M+2)+, 430, 432 (M-Boc, M-Boc+2)+.
Reaction SMILES: [Cl:1]C1N(CC(OC(C)C)=O)C2C(C(CC)CC)=CC=C(Cl)C=2N=1.[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27](Cl)[CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[Br:24][C:25]1([Cl:1])[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH2:26]1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CC(=O)OC(C)C)c12
Reactant: Nc1ccc(Br)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: NC1=CCC(Cl)(Br)C=C1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of isopropyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (Reference Example 10; 1.33 g, 3.72 mmol), 4-bromo-2-chloroaniline (1.92 g, 9.31 mmol), p-toluenesulfonic acid monohydrate (707.6 mg, 3.98 mmol) and xylene (10.0 mL) was stirred at 150° C. for 2 hr. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give isopropyl {2-[(4-bromo-2-chlorophenyl)amino-4-chloro]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}acetate and 4-bromo-4-chloroaniline. The mixture was used for the next step without further purification.
Reaction SMILES: [C:1]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1>CN(C)C=O.C(OCC)(=O)C>[OH:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][NH:39][C:4]([CH2:3][CH2:2][C:1]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[O:7])=[O:6])=[CH:43][CH:44]=1
Reactant: NCCc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCCOC(=O)CCC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCOC(=O)CCC(=O)NCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
10.0 Gram (43.4 mmol) of 2-methacryloyloxyethyl succinate, 10.0 g (52.1 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 7.04 g (52.1 mmol) of 1-hydroxy-1H-benzotriazole were dissolved in 120 mL of N,N-dimethylformamide, and the resulting solution was cooled to 0° C. in a nitrogen stream and stirred for 0.5 hours. Subsequently, 5.95 g (43.4 mmol) of 4-(2-aminoethyl)phenol was added thereto, and the mixture was stirred at room temperature for 1 hour and further stirred at 60° C. for 4 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, three times with an aqueous saturated sodium hydrogencarbonate solution and twice with water and dried over sodium sulfate. The solvent was concentrated to obtain 14.0 g of 2-methacryloyloxyethyl 3-(4-hydroxyphenethylcarbamoyl)propanoate as a brown oil. Thereafter, 6.7 g (19.18 mmol) of this oil and 7.28 g (23.02 mmol) of 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl difluoride were dissolved in 100 mL of tetrahydrofuran (THF), and the resulting solution was cooled to 0° C. Thereto, 2.91 g of triethylamine was added dropwise over 0.3 hours, and the obtained reaction solution was stirred at 0° C. for 1 hour and further stirred at room temperature for 12 hours. Thereafter, 50 mL of triethylamine and 5.72 g (38.36 mmol) of trifluoromethanesulfonamide were added thereto, and the mixture was stirred at 50° C. for 4 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, twice with dilute hydrochloric acid and twice with water and dried over sodium sulfate. The solvent was concentrated, and the residue was purified by column chromatography (SiO2, ethyl acetate) to obtain 14.4 g of a brown oil. This brown oil was dissolved in 50 mL of methanol, and 5.64 g of triphenylsulfonium bromide was added thereto, followed by stirring at room temperature for 3 hours. After adding 200 mL of chloroform, the organic layer was washed with water, the solvent was concentrated, and the residue was purified by column chromatography (SiO2, ethyl acetate/methanol=6/1), as a result, 8.16 g of a brown transparent oily compound was obtained. 1H-NMR (300 MHz, CDCl3) δ 1.93 (s, 3H), 2.45 (t, 2H), 2.65 (t, 2H), 2.82 (t, 2H), 3.44 (q, 2H), 4.32 (bs, 4H), 5.58 (s, 1H), 6.08 (t, 1H), 6.11 (s, 1H), 7.15 (d, 2H), 7.23 (d, 2H), 7.62-7.79 (m, 15H), 19F-NMR (300 MHz, CDCl3) δ −78.7 (s, 3F), −107.8 (m, 2F), −112.4 (t, 2F), −118.0 (m, 2F).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[S:9](=[O:26])(=[O:25])[CH2:10][C:11]3[C:15]([C:16]([OH:18])=O)=[N:14][N:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:12]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCOC(C)=O.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C1COCC1>[CH3:1][O:2][C:3]1[C:8]2[S:9](=[O:26])(=[O:25])[CH2:10][C:11]3[C:15]([C:16]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[O:18])=[N:14][N:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:12]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: COc1cccc2c1S(=O)(=O)Cc1c(C(=O)O)nn(-c3ccccc3)c1-2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc2c1S(=O)(=O)Cc1c(C(=O)N3CCOCC3)nn(-c3ccccc3)c1-2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 6-methoxy-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide (0.20 g, 0.54 mmol) in THF (20 mL) is added triethylamine (0.20 mL, 1.63 mmol) followed by 50% propane phosphonic acid anhydride in EtOAc (0.70 mL, 0.347 g, 1.09 mmol). The reaction mixture is cooled to 0° C. and then morpholine (0.049 g, 0.59 mmol) is added and the reaction mixture is stirred overnight at room temperature. The solvent is removed under reduced pressure and the residue is diluted with EtOAc. The organic layer is washed with 10% NaHCO3 then brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography (eluent 1 to 2% MeOH in DCM) to afford the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.59-7.58 (m, 3H) 7.46-7.42 (m, 3H) 7.25 (d, J=8.60 Hz, 1H), 6.35 (d, J=7.92 Hz, 1H), 4.82 (s, 2H), 3.95 (br, 2H), 3.90 (s, 3H), 3.65 (br, 4H), 3.59 (br, 2H). MS (ESI+): 440.0. HPLC (max plot) 96.0%; Rt 4.81 min.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[F:21])[NH2:17]>C(O)C>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc(F)c(F)c2)C1=O
Yield: 49.2 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 3,4-difluoroaniline (0.442 mL; 4.36 mmol) in ethanol (3 mL). 1-(3,4-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid 0.172 g (70%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:13][C:9]2=[N:10][N:11]=[N:12][C:8]2=[CH:7][CH:6]=1)=[O:4].[CH3:14]I>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[N:11][N:10]([CH3:14])[C:9]=2[CH:13]=1)=[O:4]
Reactant: COC(=O)C1=CC=C2N=NN=C2C1
Reactant: CI
Product: COC(=O)c1ccc2nnn(C)c2c1

Procedure:
Benzotriazole-6-carboxylic acid methyl ester is reacted with methyl iodide, yielding the title compound (in addition to the isomeric 2-methyl-2H and 3-methyl-3H compounds).
Reaction SMILES: C([Si](C)(C)OC(CC1C=CC=CC=1)CCC1NC(=O)CC1)(C)(C)C.[CH2:25]([O:27][C:28](=[O:62])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]2[C:42](=[O:43])[CH2:41][CH2:40][CH:39]2[CH2:44][CH2:45][CH:46]([O:54][Si](C(C)(C)C)(C)C)[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:31][CH:30]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:62])[C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][N:38]2[C:42](=[O:43])[CH2:41][CH2:40][CH:39]2[CH2:44][CH2:45][CH:46]([OH:54])[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:33][CH:34]=1)[CH3:26]
Reactant: CCOC(=O)c1ccc(OCCN2C(=O)CCC2CCC(Cc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Product: CCOC(=O)c1ccc(OCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Yield: 100.2 %

Procedure:
Analogous to the procedure described for Compound 1A, Step E, 4-(2-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-ethoxy)-benzoic acid ethyl ester (66.4 mg, 0.122 mmol) was deprotected to provide 4-{2-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-ethoxy}-benzoic acid ethyl ester (52 mg) after purification by radial chromatography (CH2Cl2 to 2% MeOH in CH2Cl2). 1H NMR (CDCl3) δ 7.94 (m, 2H), 7.31-7.16 (m, 5H), 6.83 (m, 2H), 4.30 (q, 2H), 4.12 (m, 2H), 3.90 (m, 1H), 3.76 (m, 2H), 3.38 (m, 1H), 2.80 (m, 1H), 2.64 (m, 1H), 2.33 (m, 2H), 2.10 (m, 1H), 1.69-1.37 (m, 6H), 1.34 (t, 3H).