Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:49]1[C:53]2[CH:54]=[CH:55][C:56]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)=[CH:57][C:52]=2[O:51][CH2:50]1>CN(C=O)C>[O:49]1[C:53]2[CH:54]=[CH:55][C:56]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)=[CH:57][C:52]=2[O:51][CH2:50]1
Reactant: Nc1cccc(-c2ccc3c(c2)OCO3)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3c(c2)OCO3)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 28.5 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Benzo[1,3]dioxol-5-yl-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.008 g of product in 29% yield: LCMS (ESI) m/z 402 (MH+).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:19]([O:21]CC)=O)[C:7]2[CH:12]=[N:11][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[N:9]=1.[NH2:24][CH2:25][C:26]1[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CCO.CCOC(C)=O.O>[Br:3][C:4]1[CH:5]=[C:6]([C:19]([NH:24][CH2:25][C:26]2[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=2[CH3:32])=[O:21])[C:7]2[CH:12]=[N:11][N:10]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:8]=2[N:9]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCOC(=O)c1cc(Br)nc2c1cnn2C1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCCCC2)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Aqueous NaOH (5 equivalent) was added to a solution of ethyl 6-bromo-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equivalent) in EtOH (10 times by volume) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Extraction was carried out using EtOAc; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was, then, dissolved in DMSO (10 times by volume) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (2 equivalents) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equivalents) was added to it and stirring was continued for 5 to 16 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water; brine; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography followed by ether wash to provide the desired intermediate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:10]([C:14]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([Cl:25])[CH:19]=3)[OH:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Bi]=O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:10]([C:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([Cl:25])[CH:19]=3)=[O:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(O)C(=O)c2cccc(-c3ccc(F)cc3)c2-c2cccs2)cc1Cl
Agent: O=[Bi]
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)C(=O)c2cccc(-c3ccc(F)cc3)c2-c2cccs2)cc1Cl
Yield: 69.5 %

Procedure:
The benzil was synthesized according to the procedure of Example 41, Step 3 using the benzoin of Step 2 (1.5 g, 4.8 mmol) and bismuth oxide (2.65 g, 5.3 mmol) in acetic acid (15 ml). There was obtained 1.45 g (98%) of the desired benzil as a crystalline solid: mp 124-126° C. Anal. Calc'd. for C15H10O2FClS (MW 308.77): C, 58.35; H, 3.26; S, 10.38. Found: C, 58.18; H, 3.09; S, 10.55.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[CH:11][CH:10]=[C:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:15]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13](=[O:14])[CH:12]=[CH:11][CH:10]=1)=[O:17])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)c1cccc(=O)n1Cc1ccccc1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccc(=O)n1Cc1ccccc1

Procedure:
Coupling of 1-benzyl-6-oxo-1,6-dihydro-pyridine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[N:19]=[CH:18][N:17]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:16]3[CH:21]=[C:20]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=4)[N:19]=[CH:18][N:17]=3)[CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Oc2cccc(C(F)(F)F)c2)ncn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(N2CCCCC2)cc1-c1cc(Oc2cccc(C(F)(F)F)c2)ncn1
Reaction time: 2 h

Procedure:
A solution of 4-(2-nitro-5-(piperidin-1-yl)phenyl)-6-(3-(trifluoromethyl)phenoxy)pyrimidine in a mixture of methanol and ethyl acetate was treated with 35 mg of 5% Pd/C and stirred for 2 h under a hydrogen atmosphere. The mixture was filtered and the solvent was evaporated. The residue was purified by chromatography to give the product as 170 mg of a yellow syrup.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[CH2:2][C:3]#[CH:4].Br[C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:18]=1.CCN(CC)CC>CN(C=O)C.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:17]2[N:18]=[C:14]([C:4]#[C:3][CH2:2][CH2:1][C:5]3[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=3)[C:8]#[N:9])[S:15][CH:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Brc1nc(-c2ccccc2)cs1
Reactant: C#CCCc1cccc(C#N)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cccc(CCC#Cc2nc(-c3ccccc3)cs2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.5 %

Procedure:
3-(But-3-yn-1-yl)benzonitrile (462 mg, 2.98 mmol) and 2-bromo-4-phenylthiazole (650 mg, 2.71 mmol) were taken in dry DMF (20 mL) and purged with nitrogen gas for 15 min. Et3N (1.9 mL, 13.5 mmol) was added to the reaction mixture, followed by a catalytic amount of copper iodide (51 mg, 0.27 mmol) and Pd(PPh3)4 (115 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 12 h and then quenched with water. The organic product was extracted with EtOAc, and the combined extracts were concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 15-20% EtOAc in petroleum ether) to get 3-(4-(4-phenylthiazol-2-yl)but-3-yn-1-yl)benzonitrile (430 mg, yield 50%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.92-7.90 (m, 2H), 7.59-7.52 (m, 3H), 7.47-7.33 (m, 5H), 3.04-2.99 (m, 2H), 2.83-2.78 (m, 2H). MS (ESI) m/z: Calculated for C20H14N2S: 314.09. found: 315.2 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=[CH:16][C:15]=2[N+:29]([O-])=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CC(O)=O>CO.[Zn]>[NH2:29][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[CH:19][C:14]=1[NH:13][C@@H:10]1[CH2:9][CH2:8][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ccc2[N+](=O)[O-])CC1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ccc2N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-N-isopropyl-4-(2-nitro-5-(2-(piperidin-1-yl)ethoxy)phenylamino)cyclohexanecarboxamide (350 mg, 0.809 mmol) in MeOH (4.0 mL) was added AcOH (0.463 mL, 8.09 mmol) and zinc (423 mg, 6.47 mmol), and the mixture was stirred at RT for 1 hour. The mixture was filtered through a pad of Celite® brand filter aid and evaporated to afford cis-4-(2-amino-5-(2-(piperidin-1-yl)ethoxy)phenylamino)-N-isopropylcyclohexanecarboxamide.
Reaction SMILES: S1C=CC(C2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8]C=2)=C1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH:27]=O>C(Cl)Cl.CO>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:8][CH:27]=1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: O=CCc1ccccc1Cl
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(Nc2ncc(-c3ccccc3Cl)s2)cc1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (2-chlorophenyl)-acetaldehyde. The title compound: ES-MS: 303.0 [M+H]+; single peak at tR=3.59 min (System 2); Rf=0.21 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: C1(S([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][CH:25]([OH:46])[CH2:26][N:27]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:28][CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C1COCC1.CO.O>[CH2:39]([N:27]([CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])[CH2:26][CH:25]([OH:46])[CH2:24][O:23][C:18]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:22]=2[CH:21]=[CH:20][CH:19]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2c1c1ccccc1n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 50 °C
Reaction time: 18 h

Procedure:
3.3 g of 1-(9-Benzenesulfonyl-9H-carbazol-4-yloxy)-3-{benzyl-[2-(2-methoxyphenoxy)-ethyl]-amino}-propan-2-ol (5.2 mmol) were dissolved in 33 ml THF/methanol (2:1). A solution of 1.1 g of sodium hydroxide in 1.7 ml of water was added in one portion. The mixture was stirred for 18 h at 50° C. The mixture was rotary evaporated (35° C./20 mbar). The residue was dissolved in 25 ml of toluene and 20 ml of water. The phases were separated and the toluene phase was washed 3 times with 25 ml of water. The organic phase was rotary evaporated (40° C./15 mbar) and the residue was crystallized with 9 ml ethanol. The product was filtered under suction and washed twice with 3 ml cold ethanol. The substance was dried at 50° C. for 12 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[O:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH3:33][Mg]Br.C(OCC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C@:29]([CH3:33])([OH:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: O=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A stirred solution of (3R,3aR,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (21.4 mg, 0.048 mmol) in THF (0.5 ml) was degassed (3×) and placed under nitrogen after being cooled to 0° C. in an ice bath. Methylmagnesium bromide 3.0 M in diethyl ether (0.16 ml, 0.480 mmol) was added to the reaction mixture. After 20 minutes, the reaction mixture was removed from the bath and allowed to warm to room temperature. After 1 hour, the reaction mixture was transferred via pipette into saturated aqueous NaHCO3 (15 ml) before being partitioned between EtOAc (30 ml) and water (15 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, washed with brine (1×15 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a colorless residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient followed by a 80% acetonitrile/water+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C25H22ClN3O4 463.13 observed m/e: 464.12 (M+H)+ (Rt 1.19/2 min); 1H NMR δ (ppm) (CD3OD): 8.00 (s, 1H), 7.74-7.78 (m, 4H), 7.71 (d, J=7.4 Hz, 2H), 7.49 (t, J=7.7 Hz, 2H), 7.39 (t, J=7.4 Hz, 1H), 5.60 (qt, J=5.1 Hz, 1H), 5.00 (t, J=5.2 Hz, 1H), 4.13-4.19 (m, 2H), 4.07 (d, J=4.8 Hz, 1H), 3.70 (d, J=8.1 Hz, 1H), 3.54 (d, J=8.1 Hz, 1H), 1.32 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]C)[CH2:6]1)=[O:4].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:19][C:2]([F:1])([F:18])[C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH2:6]1)=[O:4]
Reactant: COc1ccccc1C1CCN(C(=O)C(F)(F)F)C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(N1CCC(c2ccccc2O)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the title compound of Example 43 Step A (1.2 g, 4.4 mmol) in CH2Cl2 (15 mL) at 0° C. was added BBr3 (1M in CH2Cl2, 9.8 mL, 9.8 mmol). After warming to rt and allowing to stir for 18 h, sat'd NaHCO3 (aq.) was added slowly. The reaction was then extracted with CH2Cl2. The combined organic layers were dried and used in the next step without further purification. MS (ESI): mass calcd. for C12H12F3NO2, 259.2. m/z found, 260.1 [M+H]+. 1H NMR (CDCl3): 7.22-7.11 (m, 2H), 6.97-6.88 (m, 1H), 6.87-6.77 (m, 1H), 4.26-4.14 (m, 1H), 4.04-3.94 (m, 0.5H), 3.93-3.84 (m, 0.5H), 3.82-3.71 (m, 1H), 3.70-3.53 (m, 2H), 2.44-2.26 (m, 1.5H), 2.25-2.13 (m, 0.5H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Se](=O)=[O:12]>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH:1]=[O:12]
Reactant: Cc1nc2ccccc2s1
Reactant: O=[Se]=O
Product: O=Cc1nc2ccccc2s1
Yield: 41 %

Procedure:
The title compound was prepared from 2-methyl-1,3-benzothiazole (6h) and selenium dioxide using methods as described in the literature for similar compounds (Conte et al., 1967) in 41% yield.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:13]([F:24])[C:12]=3[Cl:25])=[CH:6][C:5]=12.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:24])[C:12]=3[Cl:25])=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccn3ncnc3c2)c(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Oc2ccn3ncnc3c2)c(Cl)c1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 25 ml flask was charged with tert-butyl 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloro-2-fluorobenzoate (0.060 g, 0.16 mmol) and dichloromethane (1.6 ml). The reaction was cooled to 0° C., and 2,2,2-trifluoroacetic acid (0.50 ml, 0.16 mmol) was added. The reaction was stirred for 20 minutes, then warmed to ambient temperature, stirred an additional 3 hours, and then concentrated to provide the desired product as a colorless oily residue.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N-:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:29]([C:26]1[CH:25]=[CH:24][C:23]([Br:22])=[CH:28][CH:27]=1)[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CN(C)c1ccc(C[N-]c2ccc(Br)cc2)cc1
Product: CN(C)c1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(Br)cc2)cc1
Yield: 99.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.57 g) and (4-bromophenyl)[(4-dimethylaminophenyl)methyl]amide (0.61 g) as starting materials, 5-benzyloxy-N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.14 g) was obtained. By the reaction and treatment in the same manner as in Example 133 using this compound, N-(4-bromophenyl)-N-[(dimethylaminophenyl)methyl]-5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.23 g) was obtained. melting point: 218-220° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.O1CCCCC1[O:20][NH:21][C:22](/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([C:36]2[CH:47]=[CH:46][C:39](COS(C)(=O)=O)=[CH:38][CH:37]=2)=[O:35])=[CH:28][CH:27]=1)=[O:23]>CN(C=O)C.C(Cl)Cl.O>[OH:20][NH:21][C:22](=[O:23])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](=[O:35])[C:36]2[CH:47]=[CH:46][C:39]([CH2:1][N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)=[CH:38][CH:37]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OCc1ccc(C(=O)/C=C/c2ccc(/C=C/C(=O)NOC3CCCCO3)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CN3CCNCC3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
N-Boc-piperazine (46 mg, 0.246 mmol) was added to a stirred mixture of methanesulfonic acid 4-((E)-3-{4-[(E)-2-(tetrahydro-pyran-2-yloxycarbamoyl)-vinyl]-phenyl}-acryloyl)-benzyl ester (prepared as described in Preparation 5, 100 mg, 0.206 mmol) and TEA (0.057 ml, 0.412 mmol) in DMF (1 ml) and DCM (1 ml). The resulting solution was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with AcOEt. The organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 99:1:0.2). The resulting product was dissolved in DCM and treated with HCl/Et2O for 4 h. The precipitate was filtered off and rinsed with DCM to give 42.6 mg of (E)-N-hydroxy-3-{4-[(E)-3-oxo-3-(4-piperazin-1-ylmethyl-phenyl)-propenyl]-phenyl}-acrylamide as its bis-hydrochloride salt.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:4]([NH:6][C@H:7]([C:20]([OH:22])=[O:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12](C2SC=CC=2)=[CH:11][CH:10]=1)=[O:5].[C:30]1(B(O)O)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[SH:1][CH2:2][CH:3]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:4]([NH:6][C@H:7]([C:20]([OH:22])=[O:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[CH:11][CH:10]=1)=[O:5]
Reactant: O=C(N[C@@H](Cc1ccc(-c2cccs2)cc1)C(=O)O)C(CS)Cc1ccccc1
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(N[C@@H](Cc1ccc(-c2cccc3ccccc23)cc1)C(=O)O)C(CS)Cc1ccccc1
Reaction time: 0.25 h

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting with methyl ester of N-[(1,1-dimethylethoxy) carbonyl]-O-[(trifluoromethyl) sulphonyl]-L-tyrosine (prepared as indicated in Stage 1 of Example 10), 10 ml of toluene, 282 mg of naphthalene boronic acid and 169.7 mg of sodium bicarbonate, the solution is agitated for 15 minutes, then 94.77 mg of 5-tetrakis (triphenylphosphine) is added. In this way 165.7 mg of expected product is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH2:25]Cl)[N:19]=[CH:18]3)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:34][CH2:35][C@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH2:25][N:37]2[CH2:38][CH2:39][CH2:40][C@@H:36]2[CH2:35][OH:34])[N:19]=[CH:18]3)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1CCCN1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCC[C@@H]2CO)c1
Temperature: 90 °C
Yield: 16.9 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1-(2-chloroethyl)-1H-indazol-5-yl)pyridin-2(1H)-one (0.15 g, 0.40 mmol) in DMF (2.1 mL) was added Cs2CO3 (0.64 g, 2.0 mmol) and (R)-2-hydroxymethylpyrrolidine (0.78 mL, 7.9 mmol). The reaction mixture was heated at 90° C. for 3 h. The reaction mixture was cooled and diluted with H2O (25 mL) and was extracted with EtOAc (3×20 mL) The organic extracts were washed with brine (2×20 mL), dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, Hexanes/EtOAc/9:1 MeOH/NH4OH, 1:1:0 to 9:9:2) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.2 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (30 mg, 17%) as a clear film. 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.67 (s, 1H), 7.49-7.46 (m, 1H), 7.42-7.36 (m, 6H), 7.30-7.26 (m, 1H), 6.09-6.08 (m, 2H), 5.06 (s, 2H), 4.50-4.49 (m, 2H), 3.47-3.45 (m, 1H), 3.39-3.37 (m, 1H), 3.28-3.19 (m, 2H), 2.88-2.86 (m, 1H) 2.69 (br s, 1H), 2.60-2.45 (br s, 1H), 2.39-2.38 (m, 1H), 1.86-1.70 (m, 4H); ESI MS m/z 445 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]12[NH:15][C:14](=[O:16])[NH:13][C:12]1=[O:17].[N+:18]([O-])([OH:20])=[O:19]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:18]([O-:20])=[O:19])[CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]12[NH:15][C:14](=[O:16])[NH:13][C:12]1=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C1NC(=O)C2(CCNc3ccc(Cl)cc32)N1
Product: O=C1NC(=O)C2(CCNc3c([N+](=O)[O-])cc(Cl)cc32)N1
Temperature: 0 °C
Yield: 98 %

Procedure:
5.00 g. (0.0199 mol) of 6'-chloro-1',2',3',4'-tetrahydro-spiro(imidazolidine-5,4'-quinoline)-2,4-dione, formula (V), prepared as described in U.S. Pat. No. 4,235,911, was added to 500 ml of concentrated nitric acid precooled to 7° C. measured internally. After one minute the reaction mixture was poured into 4 liters of ice water and extracted with 2×1 liter of ethyl acetate. The combined organic layers were washed with 1 liter of water, dried over magnesium sulfate, filtered and concentrated to a yellow solid. The solid was slurried in ether/hexane (1/3) filtered and dried in vacuo to provide 5.8 g. (98%) of the title product, m.p. 271° to 274° C. dec.