Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12](O)=[O:13])[CH:8]=[CH:9][CH:10]=1)(O)=[O:2].CSC.B>C1COCC1>[OH:2][CH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1cccc(CCO)c1
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a stirred solution of (3-carboxymethylphenyl)acetic acid (1.0 g, 5.15 mmol) in THF (100 mL) was added slowly borane dimethyl sulfide (2.3 mL, 30.9 mmol). The resulting solution was stirred overnight (˜18 hours) and then quenched by slowly adding 1N HCl (100 mL). The mixture was then extracted using EtOAc (3×100 mL) and the combined organic layers were washed with saturated NaCl (100 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to provide 750 mg of the title intermediate (87% yield), which was used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1)=[C:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1)=[C:8]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:7]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:6]2
Reactant: CCCCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 54.6 %

Procedure:
Methyl ether (116) (0.15 g, 0.32 mmol) was treated with BBr3 in CH2Cl2 to give the crude product as orange viscous oil, which was purified by reverse phase preparation HPLC on Agilent 1100 to afford 79 mg (54%) of the title compound (117) as a light yellow solid. mp 110-113° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.77 (t, J=6.8 Hz, 3H), 1.05-1.20 (m, 4H), 1.35-1.50 (m, 2H), 2.54 (t, J=7.8 Hz, 2H), 6.25 (d, J=16.0 Hz, 1H), 6.55 (d, J=8.8 Hz, 2H), 6.96 (dd, J1=9.0 Hz, J2=2.2 Hz, 1H), 7.08-7.15 (m, 3H), 7.17-7.27 (m, 3H), 7.33 (d, J=8.8 Hz, 2H), 7.48-7.57 (m, 2H), 7.59 (d, J=9.2 Hz, 1H). LCMS (ESI): m/z 451 (M−H)−. Anal. Calc for C30H28O4.0.25H2O: C, 78.84; H, 6.29. Found: C, 78.80; H, 6.14.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:25]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2F)cc1
Product: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)CC1

Procedure:
Using a method analogous to Method A with 2′,4′-difluorobiphenyl-4-sulfonyl chloride and methyl trans-4-aminocyclohexanecarboxylate, the title compound was obtained as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:29])(=[O:28])[N:11]=[C:12]1[NH:16][C:15](=[O:17])[C:14](=[CH:18][C:19]2[CH:27]=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=2)[S:13]1)=[O:4].O[Li].O>C1COCC1.O>[O:23]1[C:22]2[CH:26]=[CH:27][C:19]([CH:18]=[C:14]3[S:13][C:12](=[N:11][S:10]([C:9]4[CH:8]=[CH:7][S:6][C:5]=4[C:3]([OH:4])=[O:2])(=[O:28])=[O:29])[NH:16][C:15]3=[O:17])=[CH:20][C:21]=2[O:25][CH2:24]1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C1NC(=O)C(=Cc2ccc3c(c2)OCO3)S1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(=NS(=O)(=O)c2ccsc2C(=O)O)SC1=Cc1ccc2c(c1)OCO2

Procedure:
35 mg (0.08 mmol) of 3-(5-Benzo[1,3]dioxol-5-ylmethylene-4-oxo-thiazolidin-2-ylidenesulfamoyl)-thiophene-2-carboxylic acid methyl ester (Example 5) were dissolved in THF/water. 6 mg of LiOH.H2O were added, and the reaction was followed by TLC. After complete saponification the reaction medium was acidified to pH 3.5, where upon the desired compound precipitated. Washing and drying afforded 25 mg (70%) of 3-(5-Benzo[1,3]dioxol-5-ylmethylene-4-oxo-thiazolidin-2-ylidenesulfamoyl)-thiophene-2-carboxylic acid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[C:31]([N:39]=[C:40]=[S:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH:9]2[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C@H:3]([NH:2][C:40]([NH:39][C:31](=[O:38])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[S:41])[CH:19]([CH3:21])[CH3:20])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=S)NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of (R)-2-Amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (250 mg, 0.75 mmol) in DCM (2 mL) was added DIEA (175 μL, 1 mmol) followed by the dropwise addition of benzoylisothiocyanate (106 μL, 0.78 mmol). The reaction was stirred for 2 h at rt., acidified with 1 N aqueous HCl solution to pH 3 and then extracted with Et2O (3×10 mL). The extracts were combined, washed sequentially with sat. aqueous NaHCO3 solution (1×10 mL) and sat. aqueous NaCl solution (1×10 mL), dried (MgSO4), and the solvent removed to give (R)—N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamothioyl)benzamide (m/z, 458, M+1) as an oil (300 mg) in greater than 90% HPLC purity.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C(=NO)N)CC1.C[C:15]1(C)[NH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]2[CH:25]=[N:26][C:27](C(OCC)=O)=[C:16]12>C1COCC1>[CH:25]1[N:17]2[C:18]3[C:23]([N:24]=[CH:15][C:16]2=[CH:27][N:26]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3
Reactant: CCOC(=O)c1ncn2c1C(C)(C)Nc1ccccc1-2
Agent: CC(C)(C)[O-]
Agent: NC(=NO)C1CC1
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)ncc1cncn12
Reaction time: 0.17 h

Procedure:
Potassium tert-butoxide (1M in THF, 1.95 ml) is added to cyclopropylcarboxamide oxime (0.195 g) in THF (7 ml) at 0°. After 10 min ethyl 4,5-dihydro-4,4-dimethylimidazo[1,5-a]quinoxaline-3-carboxylate (XXXIII, EXAMPLE 94, 0.503 g) is added. The ice bath is removed after stirring for 10 min and the reaction is allowed to slowly warm to 20°-25°. After 2 hr DMF (4 ml) is added. When the reaction had stirred for a total of 7 hr, the solvents are removed under reduced pressure and the residue is partitioned between ethyl acetate and saline. The phases are separated, the organic phase is dried over magnesium sulfate and concentrated to give the title compound; mp 175°-179°; NMR (CDCl3): 1.10, 1.76, 2.18, 3.83, 6.79, 6.85, 7.13, 7.42 and 8.10 δ.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]([OH:17])[CH2:13][CH2:14][CH2:15][OH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].C(OCC)(=O)C>O1CCCC1.O>[CH2:3]([O:10][CH2:11][CH:12]([OH:17])[CH2:13][CH2:14][CH2:15][O:16][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCCC(O)COCc1ccccc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](OCCCC(O)COCc1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.96 g of sodium hydride (60 wt % in oil) was added to a solution of 5.0 g of 5-(benzyloxy)pentane-1,4-diol in 50 mL of tetrahydrofuran in a nitrogen atmosphere at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, 5.3 mL of triisopropylsilyl chloride was added dropwise to the reaction mixture at a temperature of 5° C. to 10° C. The reaction mixture was stirred at room temperature for 1 hour, and it was then added to a mixture of 100 mL of ethyl acetate and 100 mL of water. The organic layer was fractionated. The obtained organic layer was successively washed with 100 mL of a saturated sodium hydrogen carbonate aqueous solution, 100 mL of water and 100 mL of a saturated sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/5 to 1/5), so as to obtain 5.4 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-ol in the form of a colorless oily product.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[S:8][C:9]([Br:13])=[C:10]([Br:12])[CH:11]=1)=[O:6])C.[OH-].[Na+].C(O)(=O)C>O>[Br:12][C:10]1[CH:11]=[C:7]([C:5](=[O:6])[C:4]([OH:14])=[O:3])[S:8][C:9]=1[Br:13]
Reactant: CCOC(=O)C(=O)c1cc(Br)c(Br)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C(=O)c1cc(Br)c(Br)s1
Yield: 86 %

Procedure:
(4,5-Dibromothiophen-2-yl)-oxo-acetic acid ethyl ester (1.00 g, 2.92 mmol) was stirred in a mixture of 5 ml water and 1 N NaOH (3.65 ml, 3.65 mmol) at room temperature for 2 hours. The reaction was then poured into 2 N acetic acid, and extracted into 100 ml ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated under vacuum to provide (4,5-dibromothiophen-2-yl)-oxo-acetic acid (788 mg, 86%). MS (M−H)−: 312.73; 1H NMR (300 MHz, DMSO-d6) δ7.98 (s).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:24][N:25]([CH:33]=[O:34])[O:26]C2CCCCO2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C>O>[CH:1]1([CH2:6][C@H:7]([CH2:24][N:25]([CH:33]=[O:34])[OH:26])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1ncccn1)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1ncccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A mixture of (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-N-2-pyrimidinyl-3-pyrazolidinecarboxamide (20 mg, 0.042 mmol) in the solution of Acetic Acid (2 ml) and Water (0.500 ml) was stirred at 25° C. for overnight. The solvent was removed to give a residue. The residue was purified by RP-HPLC to give (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-2-pyrimidinyl-3-pyrazolidine carboxamide (9 mg, 0.023 mmol, 54% yield). MS (ES+) m/z 391.3 (MH+).
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:36])[C:7]2[C:12]([C:13]=1[C:14]1[S:18][C:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:22][CH2:21]3)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].BrP(Br)Br.C(Cl)Cl.[F:44][C:45]1[CH:46]=[C:47]([C:53]2[C:61]3[C:56](=[N:57][CH:58]=[N:59][C:60]=3[NH2:62])[NH:55][N:54]=2)[CH:48]=[C:49]([O:51][CH3:52])[CH:50]=1.C(=O)([O-])[O-].[K+].[K+].[Br-]>CN(C=O)C.CO.C(#N)C>[NH2:62][C:60]1[N:59]=[CH:58][N:57]=[C:56]2[N:55]([CH:2]([C:4]3[O:5][C:6](=[O:36])[C:7]4[C:12]([C:13]=3[C:14]3[S:18][C:17]([CH2:19][N:20]5[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)=[O:27])[CH2:24][CH2:25]5)=[CH:16][CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:54]=[C:53]([C:47]3[CH:48]=[C:49]([O:51][CH3:52])[CH:50]=[C:45]([F:44])[CH:46]=3)[C:61]=12
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2)s1
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccc(CN4CCN(C(=O)OCc5ccccc5)CC4)s3)c3ncnc(N)c23)c1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
benzyl 4-((5-(3-(1-hydroxyethyl)-1-oxo-1H-isochromen-4-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate (Intermediate B38, 903 mg, 1.790 mmol) was dissolved in 20 ml of dry then tribromophosphine 1M in DCM (2684 μl, 2.68 mmol) was slowly added. The mixture was stirred at r.t. The reaction was quenched by addition of 60 ml of NaHCO3 sat. sol. and extracted with DCM (100 ml). Phases were separated to leave a milky organic phase. 30 ml of ACN were added and the solution became clear. The mixture was concentrated to dryness to leave an off white solid. In a separate 30 ml vial, 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 510 mg, 1.969 mmol) and potassium carbonate (742 mg, 5.37 mmol) were suspended in 10 ml DMF and the mixture heated at 60 C for 15 min prior addition of the bromide dissolved in 5 ml of dry DMF. The reaction was stirred for a further hour at r.t. then the reaction was quenched with NaHCO3aq (40 ml) and extracted with DCM (80 ml) then concentrated to leave a brown solid that was purified by chromatography eluting with DCM:MeOH to give benzyl 4-((5-(3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate (460 mg, 0.617 mmol, 34.5% yield) as a brown solid.
Reaction SMILES: C(O[CH:5]([C:28]1[N:40]=[C:31]2[N:32]=[C:33]([CH3:39])[C:34]3[CH2:38][CH2:37][CH2:36][C:35]=3[N:30]2[N:29]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.C(#N)C.P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[CH3:39][C:33]1[C:34]2[CH2:38][CH2:37][CH2:36][C:35]=2[N:30]2[N:29]=[C:28](/[CH:5]=[C:6]3\[C@@H:7]4[N:11]([C:12]\3=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]4)[N:40]=[C:31]2[N:32]=1
Reactant: CC(=O)OC(c1nc2nc(C)c3c(n2n1)CCC3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1nc2nc(/C=C3/C(=O)N4C(C(=O)O)=CS[C@H]34)nn2c2c1CCC2
Temperature: 3 °C

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(5-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (200 mg, 0.31 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and phosphate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 15 mg, 13%; as yellow crystals; mp 250° C. (Dec); (M+H+Na) 378. 1H NMR (DMSO-d6) δ 6.80 (s, 1H), 6.76 (s, 1H), 6.25 (s, 1H), 3.24 (m, 2H), 2.96 (m, 2H), 2.49 (s, 3H), 2.25 (m, 2H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.O>CN(C)C=O>[C:13]([C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])=[CH:10][CH:11]=1)([OH:15])=[O:14]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)/C=C\C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
One molar equivalent of maleic anhydride and p-amino benzoic acid are dissolved in N,N-dimethylformamide (DMF), and the mixture stirred at room temperature for five hours under nitrogen atmosphere. The resulting solution is poured into a sufficient water to precipitate crude N-(4-carboxyphenyl)maleamic acid. This is filtered, dried, and recrystallized three times from water to obtain pure N-(4-carboxyphenyl)maleamic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([S:10](Cl)(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[NH2:16][C:17]1[CH:25]=[C:21]([C:22]([OH:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1>O1CCOCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([S:10]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([OH:26])=[C:21]([CH:25]=3)[C:22]([OH:24])=[O:23])(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: C1COCCO1
Product: Cc1c(S(=O)(=O)Nc2ccc(O)c(C(=O)O)c2)sc2ccc(Cl)cc12
Yield: 79 %

Procedure:
A solution of 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (22 mg, 0.075 mmol) and 5-aminosalicylic acid (17 mg, 0.112 mmol) in aqueous dioxane (800 μL, 4:1 dioxane/water) was shaken at 35° C. for 5 days. The product was purified by reversed phase chromatography (ACE C8, 4 μm, 21×50 mm, flow 25 ml/min, gradient: 0.1% TFA in water/MeCN over 6 minutes). The title compound was obtained in 79% yield (23.6 mg). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.41-2.43 (m, 3 H) 6.87 (d, J=8.79 Hz, 1 H) 7.20-7.25 (m, 1 H) 7.53 (dd, J=2.93, 1.46 Hz, 1 H) 7.56 (dd, J=8.79, 1.95 Hz, 1 H) 8.00 (d, J=1.95 Hz, 1 H) 8.06 (d, J=8.79 Hz, 1 H) 10.45 (s, 1 H). MS (ESI+) m/z 398 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH3:23])[N:15]=[C:14]([NH:24][CH3:25])[N:13]=2)[CH:9]=[C:8](F)[C:5]=1[C:6]#[N:7])[CH3:2].CCO.CCN(C(C)C)C(C)C.[NH2:39][NH2:40]>O>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH3:23])[N:15]=[C:14]([NH:24][CH3:25])[N:13]=2)[CH:9]=[C:8]2[C:5]=1[C:6]([NH2:7])=[N:39][NH:40]2)[CH3:2]
Reactant: CCOc1cc(-c2cc(N3CCC[C@H]3C)nc(NC)n2)cc(F)c1C#N
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O
Product: CCOc1cc(-c2cc(N3CCC[C@H]3C)nc(NC)n2)cc2[nH]nc(N)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
In a sealable tube, 2-(ethyloxy)-6-fluoro-4-{2-(methylamino)-6-[(2R)-2-methyl-1-pyrrolidinyl]-4-pyrimidinyl}benzonitrile (87 mg, 0.245 mmol), EtOH (5 mL), Hunig's base (0.046 mL, 1.469 mmol), and hydrazine anhydrous (0.043 mL, 0.245 mmol) were added, and the yellow suspension mixture was heated at 100° C. overnight in an oil bath. After overnight, there was a yellow solution as well as a little amount of white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was purified by flash column chromatography. The fractions containing product were combined, and the solvent was removed under reduced pressure to afford the title compound (48 mg) as a white solid. LC-MS (ES) m/z=368 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.21 (d, J=6.1 Hz, 3H), 1.44 (t, J=7.0 Hz, 3H), 1.66 (m, 1H), 2.02 (m, 3H), 2.82 (d, J=4.8 Hz, 3H), 3.56 (m, 1H), 4.12-4.24 (q, J=7.1 Hz, 2H), 4.99 (s, 2H), 6.19 (s, 1H), 6.32-6.51 (m, 1H), 6.87-6.98 (m, H), 7.41-7.56 (m, 1H), 11.50 (s, 1H).
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[NH3:12]>>[C:1]([NH2:12])(=[O:11])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: N
Product: NC(=O)C(O)c1ccccc1

Procedure:
Following Example 10 and replacing the salicylic acid with mandelic acid (1 cmole; 1.521 g) the result is a solution of the corresponding acid chloride which, when treated with ammonia gives mandelamide.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:50]([O:51][Si](C(C)(C)C)(C)C)[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:59]([CH3:61])[CH3:60])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:50]([OH:51])[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:59]([CH3:60])[CH3:61])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Yield: 100.6 %

Procedure:
18.7 mg of compound (45) was stirred together with 218 μl of dry tetrahydrofuran and 32.7 μl of 1M tetrabutylammonium fluoride-tetrahydrofuran solution at room temperature for 4 hours. The reaction solution was concentrated in vacuo to give the crude reaction product. It was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×20 cm) and eluted with n-hexane-ethyl acetate (8:1) to give 16.3 mg of compound (46) as a colorless oily substance.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[C:17]=2[CH3:25])[NH:12]1)=[O:10])[CH3:7].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:6]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[C:17]=2[CH3:25])[N:12]1[C:3](=[O:4])[CH2:2][Cl:1])=[O:10])[CH3:7]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(OC)c(C)c2C)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(OC)c(C)c2C)N1C(=O)CCl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Chloroacetyl chloride (1.7 mL, 21.5 mmol) To a solution of cis-5-(4-methoxy-2,3-dimethylphenyl)pyrrolidine-2-carboxylic acid ethyl ester (16.56 mmol) and Et3N (3.5 mL, 24.8 mmol) in CH2Cl2 (80 mL) at 0° C. The reaction mixture is stirred at 0° C. for 15 min and then at room temperature for 45 min. The mixture then poured into half-saturated aq. NaHCO3 (100 mL) and extracted with EtOAc. The extract is further washed with water (1×50 mL) and brine (1×50 mL). The aqueous washes are reextracted once with EtOAc, and the combined extracts are dried over Na2SO4, and concentrated. The crude material is used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 7.90 (d, J=8.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 5.30 (dd, J=7.6, 3.6 Hz, 1H), 4.53 (t, J=8.0 Hz, 1H), 4.37-4.21 (m, 2H), 3.81 (s, 3H), 3.77, 3.65 (ABq, J=13.2 Hz, 2H), 2.50-2.41 (m, 1H), 2.26 (s, 3H), 2.24-2.14 (m, 1H), 2.19 (s, 3H), 2.09-2.00 (m, 1H), 1.96-1.89 (m, 1H), 1.35 (t, J=7.2 Hz, 3H). Electrospray MS: m/z 354 [M+1].