Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]5([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH2:34][CH2:33]5)[CH:25]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.C(OCC)(=O)C>CN(C=O)C.[Pd]>[NH2:21][C:19]1[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]3([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:33][CH2:34]3)[CH:25]=2)=[CH:17][C:11]2[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH:20]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Reaction time: 8 h

Procedure:
2-(4-Fluorophenyl)-N-methyl-6-nitro-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide (83.3 mg, 0.152 mmol) undr N2 at r.t. was dissolved in DMF (2 ml) and then added ethyl acetate (10 mL). The mixture remained as a clear light brown solution. The mixture was added palladium (97 mg, 0.045 mmol, 5%/C), flushed with H2 using a balloon, and the mixture stirred under H2 for about 8 hr. The mixture was diluted with EtOAc, and filtered through a Whatman PTFE 45 uM disk. The filtrate was evaporated. The residue was titurated with 3×1 ml Et2O (the Et2O solution was removed by using a pipette), and the light orange solid product dried (64.4 mg, 82%). 1H NMR (500 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.32 (q, J=4.17, 1H), 7.94-7.89 (overlapping m, 3H), 7.97 (s, 1H), 7.62 (d, J=6.8, 1H), 7.58 (q, 1H), 7.34 (t, J=8.70, 2H), 7.29 (t, 1H), 7.28 (d, J=7.50, 1H), 7.23 (s, 2H), 7.227 (d, J=8.00, 1H), 7.17 (t, J=7.17, 1H,), 6.99 (s, 1H), 5.09 (s, 2H), 2.79 (appeared as d, J=3.97, 3H), 1.29 (appeared as d, 4H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XTERRA® MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=520.39, HPLC Rt=1.497 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].O>C1(C)C=CC=CC=1>[CH3:3][C:2]1[C:11]([CH3:10])=[N:1][C:2]2[C:11](=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[N:12]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc2nc(C)c(C)nc2c1

Procedure:
55.8 g (0.354 mole) of methyl 3,4-diaminobenzoate and 30.5 g (0.354 mole) of diacetyl are heated under reflux in 500 ml of toluene for 3 hours, using a water separator. The toluene is distilled off in vacuo and the residue is dissolved in ethyl acetate under the influence of heat, active charcoal being added, the active charcoal is separated off via a Seitz filter and the filtrate is concentrated to dryness.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18]>>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:13]2[CH:14]=[C:15]([O:19][CH3:20])[C:16]([O:17][CH3:18])=[C:11]([O:10][CH3:9])[CH:12]=2)[N:7]=1
Reactant: Cc1ccnc(Br)n1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: COc1cc(-c2nccc(C)n2)cc(OC)c1OC

Procedure:
2-Bromo−4-methylpyrimidine (1.5 g) and 3,4,5-trimethoxyphenylboronic acid (1.83 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[NH:29][N:28]=[N:27][N:25]=3)[CH:21]=[C:20]([Cl:26])[N:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)OC2CCN(c3cc(C#N)cc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(C(=O)OC2CCN(c3cc(-c4nnn[nH]4)cc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 120 °C

Procedure:
1-(6-Chloro-4-cyanopyridin-2-yl)piperidin-4-yl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate (Example 308, 64 mg, 0.154 mmol), sodium azide (12 mg, 0.185 mmol) and ammonium chloride (8.3 mg, 0.154 mmol) were dissolved in anhydrous DMF (2 ml) and the mixture was heated at 120° C. for 8 h. The mixture was filtered and purified my semi-preparative reverse phase HPLC eluting with CH3CN/H2O (0.1% TFA) (48 mg).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[OH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29]1)=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:1]1[CH2:3][C@H:2]1[CH2:4][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29]1)=[O:27]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: O=C(Cc1ccccc1O)N1CC[C@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1OC[C@@H]1CO1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
A mixture of (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (228 mg, 0.88 mmol), (3S)-1-[(2-hydroxyphenyl)acetyl]pyrrolidin-3-ol (196 mg, 0.88 mmol) and Cs2CO3 (344 mg, 1.05 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography/(0-3% methanol in dichloromethane) to give the subtitled compound (35 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][CH:19]=[C:18]1[C:13]=2[CH:14]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:15][CH2:16][CH2:17]1)C1C=CC=CC=1>CCO.[Pd]>[Si:24]([O:23][CH:14]1[C:13]2[C:18](=[CH:19][N:20]=[C:21]3[C:12]=2[CH:11]=[CH:10][C:9]([OH:8])=[CH:22]3)[CH2:17][CH2:16][CH2:15]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2cnc3cc(OCc4ccccc4)ccc3c21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CCCc2cnc3cc(O)ccc3c21
Yield: 89.1 %

Procedure:
A solution of Compound 225 (2.00 g, 4.77 mmol) in EtOH (80 mL) was hydrogenated over 10 percent Pd/C (1.00 g) under hydrogen atomsphere (ambient pressure) for four hours. The catalyst was removed by filtration through Celite with elution by 50 percent Et3N in THF (1.5 L). The combined filtrate was evaported in vacuo to provide Compound 141a (1.40 g, 89 percent): white crystalline solid; mp 248°-250° C. (dec., from MeOH-Et3N); Rf =0.48 (silica, 3.2 percent methanol in dicloromethane); IR (KBr) νmax 3400, 2929, 2857, 1622, 1619, 1611, 1477, 1404, 1249, 1238, 1212, 1088, 1034, 838, 773 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 9.99 (br s, 1 H, ArOH), 8.52 (s, 1 H, H6), 7.91 (d, J=9.0 Hz, 1 H, H1), 7.20 (d, J=2.4 Hz, 1 H, H4), 7.14 (dd, J=9.0, 2.4 Hz, 1 H, H2), 5.43 (s, 1 H, H10), 2.95-2.84 (m, 1 H, H7), 2.79-2.65 (m, 1 H, H7), 2.14-2.04 (m, 1 H, H8 or H9), 2.00-1.87 (m, 1 H, H8 or H9), 1.86-1.65 (m, 2 H, H8 or H9), 0.79 (s, 9 H, SiC(CH3)3), 0.00 (s, 3 H, SiCH3), -0.02 (s, 3 H, SiCH3); MS (FAB+) m/e (rel intensity) 330 (M+H, 100), 272 (14), 198 (9); HRMS for C19H28NO2Si (M+H), calcd 330.1889, found 330.1890. Anal. Calcd for C19H27NO2Si: C, 69.26; H, 8.26; N, 4.25. Found: C, 69.10; H, 8.17; N, 4.16.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:19][C:20]([NH2:22])=[NH:21]>C(O)C>[NH2:21][C:20]1[NH:22][C:10](=[O:12])[CH:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:19]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=C(O)O
Solvent: CCO
Product: Nc1nc(-c2ccccc2)cc(=O)[nH]1
Temperature: 80 °C
Yield: 89 %

Procedure:
Following the method of Jaeger (Liebigs. Ann. Chem. 1891, 262, 365), a mixture of 12.4 ml (72 mmol) ethyl benzoylacetate and 7.79 g (43.2 mmol) guanidine carbonate in 25 ml ethanol was heated at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and the resulting crystals collected by filtration and washed sequentially with ice-cold water and ethanol to afford 7.2 g (53%) 2-amino-6-phenyl-3H-pyrimidin-4-one as a white crystalline solid. EI-MS m/e (%): 187 (M+, 100).
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@@H:10]([CH2:12][OH:13])[C@H:8]([OH:9])[C@@H:6]([OH:7])[C@@H:4]1[NH2:5].C([O-])(O)=O.[Na+].F[C:20]1[C:28]2[C:24](=[N:25][O:26][N:27]=2)[C:23]([N+:29]([O-:31])=[O:30])=[CH:22][CH:21]=1>O.CO>[CH:21]1[CH:22]=[C:23]([N+:29]([O-:31])=[O:30])[C:24]2[C:28](=[N:27][O:26][N:25]=2)[C:20]=1[NH:5][C@@H:4]([C@H:6]([OH:7])[C@@H:8]([OH:9])[C@@H:10]([OH:11])[CH2:12][OH:13])[CH:3]=[O:2]
Reactant: N[C@@H]1C(O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])c1ccc(F)c2nonc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C[C@@H](Nc1ccc([N+](=O)[O-])c2nonc12)[C@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 37 °C
Reaction time: 2 h

Procedure:
In a brown flask, L-glucosamine hydrochloride (40.0 mg) and NaHCO3 (26.0 mg) were placed and dissolved in water (800 μl). A solution in which 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) (92.0 mg) was dissolved in methanol (4.0 ml) was added thereto, and under an argon atmosphere, the resulting mixture was stirred for 2 hours at a bath temperature of 37° C. Thereafter, the mixture was stirred at room temperature for an additional 40 minutes. Methanol was removed by concentration under reduced pressure, and the resulting precipitates (unnecessary substances derived from NBD-F) were removed by filtration. The precipitates were washed with water, and the filtrate and the washing solution were combined, followed by purification by HPLC. A target fraction was collected and lyophilized, whereby a target product was obtained (yield: 48.7 mg, yield ratio: 76%).
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.O.NN>C(O)C>[CH:16]1[C:3]2[CH2:2][CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=[CH:14][C:15]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)Cc1ccccc1S2
Agent: NN
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Reaction time: 5 h
Yield: 84.4 %

Procedure:
To 400 mg of (10,11-dihydro-11-oxo dibenzo[b,f]thiepin-2-yl)-acetic acid were added 20 ml of ethanol and 1 ml of hydrazine hydrate, and the mixture was refluxed with stirring under a dry atmosphere for 5 hours. After cooling, the solvent was removed by distillation under reduced pressure, and to the resulting mixture were added 20 ml of diethylene glycol and 4.0 g of sodium hydroxide. Thereafter, the resulting mixture was stirred under a dry atmosphere at 130° C. for 2 hours. After subsequent cooling, water was added to the mixture which was then washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was chromatographed over 18 g of silica gel and eluted with n-hexane/acetone (5/1) to obtain pale yellow crystals. These crystals were recrystallized from acetone/n-hexane to give 321 mg (yield: 84%) of (10,11-dihydro dibenzo[b,f]thiepin-2-yl)-acetic acid as colorless crystals having a melting point of 111°-112° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]#[N:9])[CH2:3]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>C1COCC1>[C:8]([C:4]1([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]1)#[N:9]
Reactant: CCCCCc1ccc(-c2ccc(CCBr)cc2)cc1
Reactant: CC1CCCC(C#N)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(CCC3(C#N)CCCC(C)C3)cc2)cc1

Procedure:
A mixture of 3.1 g of 3-methylcyclohexanecarbonitrile and 30 ml of THF has added to it at -78° a solution of lithium diisopropylamide (prepared from 3.3 g of diisopropylamine, 30 ml of THF and 19 ml of 1.6-molar butyllithium solution in hexane) and then a solution of 9.7 g of 1-bromo-2-(4'-pentylbiphenyl-4-yl)ethane in 30 ml of THF. Working up as in Example 1 gives 1-(1-cyano-3-methylcyclohexyl)-2-(4'-pentylbiphenyl-4-yl)ethane, m.p. 73°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([O:30]C)=O)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:36]([NH2:38])[CH3:37]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([NH:38][CH2:36][CH3:37])=[O:30])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCN
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Product: CCNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Yield: 76 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.53 mmol) was reacted with ethylamine to give the title compound as a white solid (195 mg, 76%); NMR Spectrum 1.04 (t, 3H), 1.65 (d, 3H), 3.14-3.20 (m, 2H), 5.16 (q, 1H), 5.71 (s, 2H), 7.01 (d, 1H), 7.04-7.12 (m, 3H), 7.36 (dd, 2H), 7.72-7.78 (m, 3H), 8.17 (s, 1H), 8.44 (m, 1H), 8.53 (s, 1H), 8.56 (s, 1H), 10.68 (br s, 1H); Mass spectrum MH+ 485.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].BrC[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: COc1ccc(CCBr)cc1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(OC)cc3)CC1)O2
Yield: 83.1 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) was alkylated using 1-(2-bromo-ethyl)-4-methoxy-benzene (0.16 ml, 1.5 mmol) as described in Example 56, Step A, giving (E)-3-{1′-[2-(4-methoxy-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (181 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([C:12]#[N:13])[C:3]=1[Cl:14].[OH-:15].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([Cl:14])=[C:4]([C:12]#[N:13])[C:5]([Cl:11])=[C:6]([Cl:10])[C:7]=1[C:8]([NH2:9])=[O:15]
Reactant: [OH-]
Reactant: N#Cc1c(Cl)c(Cl)c(C#N)c(Cl)c1Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(Cl)c(Cl)c(C(N)=O)c(Cl)c1Cl
Yield: 58.1 %

Procedure:
Tetrachloroterephthalonitrile (26.6 g, 0.1 mol) and ethanol (532 g) were mixed, and the resultant mixture was heated to 79° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (16 g) was added over six hours. Liquid chromatographic analysis revealed the reaction mixture contained 16.5 g of 2,3,5,6-tetrachloro-4-cyanobenzamide (yield 58%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C:10]([C:12]1[S:16][C:15]([C:17]([O:19]C)=O)=[CH:14][CH:13]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:22][NH2:23]>C(O)C>[C:1]([O:5][C:6](=[O:7])[CH2:8][NH:9][C:10]([C:12]1[S:16][C:15]([C:17]([NH:22][NH2:23])=[O:19])=[CH:14][CH:13]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)NCC(=O)OC(C)(C)C)s1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc(C(=O)NN)s1
Temperature: 25 °C
Yield: 71 %

Procedure:
Methyl 5-(tert-butoxycarbonylmethylcarbamoyl)thiophene-2-carboxylate (63 mg, 0.21 mmol) in ethanol (3.0 mL) was refluexed with heating with hydrazine monohydrate (0.13 mL) for 8 hours and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and water was added. The precipitated solid was collected by filtration, washed with water and dried to give 44 mg of the desired product (yield 71%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH3:19])[C@H:6]([OH:20])[C@@H:5]1[OH:21].Cl[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([CH2:24][CH2:23][N:2]([CH3:1])[CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH3:19])[C@H:6]([OH:20])[C@@H:5]1[OH:21])([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CCCl
Reactant: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 60 °C

Procedure:
A mixture of 4a (500 mg, 1.69 mmol), ethyl 3-chloropropionate (270 mg, 1.97 mmol), DIEA (109 mg, 0.14 mL, 0.84 mmol), and DMF (5 mL) was heated at 60° C. for 2 days. Starting material remained but since the solution was getting darker, heating was stopped. The reaction mixture was concentrated to dryness. The product was purified by column chromatography (7:1:0.1 chloroform:methanol:NH4OH) to give a sticky solid: yield 210 mg (31%); MS m/z 395 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.11 (bs, 2H, 6-NH2), 5.74 (d, 1H, H-1′, J1′,2′=5.6 Hz), 5.33 (bd, 1H, OH-2′), 5.16 (bd, 111, OH-3′), 5.12 (bdd, 1H, H-2′, J1′,2′=5.6 Hz, J2′,3′=5.5 Hz), 4.21 (bdd, 1H, H-3′, J2′,3′=5.5 Hz, J3′,4′=4.3 Hz), 4.01 (q, 2H, OCH2CH3), 3.91-4.00 (m, 1H, H-4′), 2.70-2.77 (m, 1H, 5′-CH2), 2.54-2.66 (m, 3H, 5′-CH2, CO—CH2), 2.53 (s, 3H, 8-CH3), 2.38 (t, 2H, N(CH3)—CH2), 2.16 (bs, 3H, N—CH3), 1.15 (t, 3H, OCH2CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 2-(4-amino-1H-indazol-1-yl)-2-(4-chlorophenyl)butanoate (1.0 g, 2.9 mmol) and NMM (0.9 g, 8.7 mmol) in DCM (10 mL) was added MsCl (0.4 g, 3.2 mmol) dropwise, Then the mixture was stirred at room temperature overnight. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (50 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: PE/EA=4/1) to afford the title compound as a yellow solid. LC/MS m/z=422.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](Cl)=[O:29])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[OH:12][C:3]1[C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[CH:26]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1cccc(-c2ccncc2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2cccc(-c3ccncc3)c2)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-4-yl)benzoic acid (1.5 g, 7.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum giving 1.5 g of crude 3-(pyridin-4-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (950 g, 5.8 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) was added crude 3-(pyridin-4-yl)benzoyl chloride (1.5 g, 7 mmol) portion wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 2-hydroxy-3-(3-(pyridin-4-yl)benzamido)benzoate as a yellow solid (1.8 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: N.O1CCOCC1.C([N:10](CC)CC)C.[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C@@H:27]2[C:32]([C:33]#[N:34])=[C:31]([CH3:35])[N:30]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:29](=[O:46])[NH:28]2)=[C:21]([S:23](Cl)(=[O:25])=[O:24])[CH:22]=1)#[N:16]>C(#N)C>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C@@H:27]2[C:32]([C:33]#[N:34])=[C:31]([CH3:35])[N:30]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:29](=[O:46])[NH:28]2)=[C:21]([S:23]([NH2:10])(=[O:25])=[O:24])[CH:22]=1)#[N:16]
Reactant: CCN(CC)CC
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: N
Solvent: C1COCCO1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(N)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
At room temperature, a 0.5 M solution of ammonia in dioxane (25.79 ml, 12.9 mmol; 10 eq.) and triethylamine (130 mg, 1.3 mmol; 1 eq.) were added to 5-cyano-2-{(4S)-5-cyano-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (3.10 g, content 20%, 1.29 mmol), and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure, water/acetonitrile (˜10:1) was added to the residue and the solution was lyophilized. The substance obtained was dissolved in acetonitrile and then purified by preparative HPLC (column: Waters Sunfire C18, 5 μm; column dimensions: 250 mm×20 mm; detection: 240 nm; temperature: 28° C.; flow rate: 25 ml/min; injection volume: 500 μl; mobile phase: acetonitrile/0.2% trifluoroacetic acid 45:55). The title compound was obtained as a solid (0.155 g, 26% of theory).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=O.OS(O)(=O)=O>O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:9]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH3:11])[C:8]([OH:13])=[O:12])=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
To a cooled mixture of phenol (9.4 g, 0.1 mol), pyruvic acid (4.4 g, 0.05 mol), and water was added concentrated H2SO4 (4.5 mL, 18.0 g) dropwise with stirring. After 15 minutes the ice bath was removed and the reaction was warmed to room temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl ether/water (200 ml 1:1) and the layers were separated. The organic layer was extracted with saturated aqueous NaHCO3. The aqueous extract was then acidified, extracted with ethyl ether, dried over MgSO4, filtered, and concentrated in vacuo to give 2,2-bis(4-hydroxyphenyl)propionic acid (6.2 g) as a colorless sticky oil.