Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].S(Cl)([Cl:18])=O>>[ClH:18].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([Cl:1])=[O:15])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4]
Reactant: O=S(Cl)Cl
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (1.2 g) and thionyl chloride (15 ml) was stirred at room temperature for 3 hours. Thereafter, excess thionyl chloride was removed by distillation under reduced pressure. The residue was washed with anhydrous ethyl ether to obtain trans-4-guanidinomethylcyclohexanecarboxylic acid chloride hydrochloride (1.2 g) as colorless powder.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].OC1C(=O)[N:10]([CH2:21][CH2:22][O:23][CH3:24])[S:11](=[O:20])(=[O:19])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:6][C:1]1[C:2](=[O:3])[N:10]([CH2:21][CH2:22][O:23][CH3:24])[S:11](=[O:19])(=[O:20])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Solvent: ClCCl
Product: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Yield: 92.3 %

Procedure:
Oxalyl chloride (0.185 g, 1.46 mmol) was added dropwise to a solution of 4-hydroxy-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.250 g, 0.88 mmol) in DCM (15 mL). The mixture was refluxed for 2 days and then evaporated. The residue was dissolved in water and extracted 3 times with dichloromethane. The combined organic layers were washed 2 times with water, dried through a phase separator and evaporated to give the title compound (0.245 g, 92%) as a solid; 1H NMR (500 MHz, CD3OD): δ 7.94-7.97 (m, 2H), 7.58-7.67 (m, 3H), 3.94 (t, 2H), 3.70 (t, 2H), 3.38 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:33])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Temperature: 110 °C
Yield: 51.8 %

Procedure:
To a solution of 6-bromo-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (440 mg, 1.18 mmol) in 1,4-dioxane (3.6 mL) in a 10 mL CEM microwave test tube, there is added Lawesson's reagent (477 mg, 1.18 mmol). The resulting mixture is heated in a CEM microwave reactor at 110° C. for 40 min and cooled to rt. The solvent is removed in vacuo, and the residue is purified by flash chromatography column to give 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (238 mg, 52%). MS m/z 389 (M+H+).
Reaction SMILES: [CH2:1]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:2][CH2:3][C:4]#[CH:5].CN(C)CCN(C)C.C([Li])CCC.[CH2:26]1[O:28][CH2:27]1>O1CCCC1.O>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][CH2:1][CH2:2][CH2:3][C:4]#[C:5][CH2:26][CH2:27][OH:28]
Reactant: C1CO1
Reactant: C#CCCCOC1CCCCO1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OCCC#CCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a cooled solution (-20° C.) of tetrahydro- 2-(4-pentynyloxy)-2H-pyran (1) (16.8 g. 0.10 mole) and tetramethylethylene diamine (45.2 mL, 0.30 mole, distilled from CaH2 under nitrogen) in anhydrous tetrahydrofuran (100 mL. distilled from sodium/benzophenone under nitrogen) was added via syringe a solution of n-butyllithium (41.0 mL, 0.101 mole, 2.44 N in hexane). The mixture was allowed to warm to 0° C. over 30 minutes and stirred at 0° C. for 1 h followed by the addition, via cannula, of ethylene oxide (8 8 g, 0.20 mole, freshly condensed into an argon filled graduated cylinder). The solution was stirred at 0° C. for 1 h and then stored in a refrigerator (5° C.) for 3 days. The reaction mixture was poured into water (200 mL) and extracted with ether (1×200 mL, 2×50 mL). The organic layers were combined and washed with water (5×50 mL), saturated sodium chloride (50 mL), dried (MgSO4), and concentrated to provide 22.80 g of a crude amber oil which was chromatographed (ethyl acetate/hexane 1:1) to provide 12.09 g (59%) of the title compound: Rf =0.32 (ethyl acetate/hexane:1/1) 1H PMR (CDCl3); δ 4.60 (t, J=3 Hz, 1H), 3.85 (m, 2H), 3.67 (t, J=6 Hz, 2H), 3.50 (m, 2H), 2.71 (bs, 1H), 2.40 (m, 4H), 2.29 (m, 2H), 1.78 (m, 4H), 1.52 (m, 4H); 13C NMR (CDCl3): 98.9, 81.5, 77.1, 65.9, 62.2, 61.3, 30.7, 29.0, 25.5, 23.1, 19.5, 15.7 ppm; IR (CHCl3): 3600, 3460 cm-1 ; Analysis calculated for C13H20O3 : C, 67.89; H, 9.50; Found: C, 67.96; H, 9 79.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[N:39]2[N:40]=[CH:41][N:42]=[C:38]2[CH:37]=[CH:36][CH:35]=1)CCC>C1COCC1.[Cu]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>[N:42]1[CH:41]=[N:40][N:39]2[C:34]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[N:11]=[C:10]([CH2:12][N:13]5[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]5)[CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:35][CH:36]=[CH:37][C:38]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc2ncnn12
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4cccc5ncnn45)nc(N4CCOCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
2-(1-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (50 mg, 0.12 mmol) was dissolved in 2 mL of THF and treated with CuI (1.2 mg, 0.006 mmol) and 5-(tributylstannyl)-[1,2,4]triazolo[1,5-a]pyridine (65.4 mg, 0.16 mmol). The solution was sparged with bubbling nitrogen and tetrakis(triphenylphosphine)palladium (0) (7 mg, 0.006 mmol) was added. The mixture was heated in an Agilent microwave (140° C., 20 min). The solution was cooled to room temperature and concentrated. Purification by reverse phase HPLC gave 166 as a colorless solid. 1H NMR (400 MHz, DMSO) δ 8.52 (s, 1H), 8.21 (d, J=8.6 Hz, 1H), 7.99 (d, J=8.9 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.84-7.74 (m, 1H), 7.65 (d, J=7.0 Hz, 1H), 4.51 (s, 4H), 4.03 (s, 1H), 3.83-3.77 (m, 4H), 3.75 (s, 2H), 2.93 (d, J=11.1 Hz, 2H), 2.00 (t, J=11.2 Hz, 2H), 1.67 (d, J=11.4 Hz, 2H), 1.24 (overlapping m, 3H), 1.04 (s, 6H). LCMS: 489.2
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Br)cc2)cc1-c1c(Br)cnn1C
Yield: 72.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 4-bromophenyl isocyanate (0.022 g, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 5 (0.040 g, 0.08 mmol, 75%) as a white solid. LCMS m/z (%)=479 (M+H79Br79Br, 51), 481 (M+H79Br81Br, 100), 483 (M+H81Br81Br, 50). 1H NMR (400 MHz, acetone-d6) δ: 8.22 (s, 1H), 8.14 (s, 1H), 7.68 (dd, J=2.7, 9.0 Hz, 1H), 7.48-7.54 (m, 3H), 7.39-7.46 (m, 3H), 7.14 (d, J=9.0 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [CH3:1][Mg]Br.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[C:13](=[O:15])[CH3:14]>C1COCC1>[OH:15][C:13]([C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[OH:4])([CH3:1])[CH3:14]
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(O)c(C(C)(C)O)c1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a solution of methylmagnesium bromide (221 ml, 665 mmol) in 800 ml THF at 0° C. was added 1-(2-hydroxy-5-methoxy-phenyl)-ethanone (20.21 g, 302 mmol) in portions over 30 min. The mixture was allowed to warm to room temperature. After 16 h the mixture was quenched by the slow addition of 10% NH4Cl, carefully acidified to pH=1 (slow addition) with concentrated HCl and extracted with Et2O. The combined organics were washed with H2O, washed with brine, died over MgSO4, filtered and concentrated in vacuo to give 2-(1-hydroxy-1-methyl-ethyl)-4-methoxy-phenol (50.57 g, 100%) as a tan solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([O:13][CH2:14][C:15]([NH2:17])=[O:16])[CH:6]=[CH:5][C:4]1=2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>O1CCCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][CH2:2][CH:3]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:8]=[C:7]([O:13][CH2:14][C:15]([NH2:17])=[O:16])[CH:6]=[CH:5][C:4]2=3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: NCC1CCCc2cc(OCC(N)=O)ccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)COc1ccc2c(c1)CCCC2CNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
0.1 mol of 5-aminomethyl-5,6,7,8-tetrahydro-naphth-2-yl-oxyacetamide (Example 7), 0.11 mol of 4-chlorobenzenesulphonyl chloride and 0.11 mol of triethylamine are stirred in 200 ml of tetrahydrofuran at room temperature for 3 hours. The mixture is filtered, the filtrate is evaporated, the residue is taken up in CH2Cl2 and the mixture is washed with 1N HCl, saturated NaHCO3, 1N HCl and saturated NaCl solution, dried over Na2SO4 and evaporated. The residue is purified by flash chromatography over silica gel using CH2Cl2MeOH 5:1.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:6]=[C:7](/[CH:16]=[CH:17]/[C:18]([NH:20][CH:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)=[O:19])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[O:4]>C(O)C>[OH:4][CH2:3][C:5]1[CH:6]=[C:7](/[CH:16]=[CH:17]/[C:18]([NH:20][CH:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)=[O:19])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=Cc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(/C=C/c1ccc(-n2ccnc2)c(CO)c1)NC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.5 %

Procedure:
Sodium borohydride (2 mg) is added to an ethanol (1 mL) solution of (E)-3-(3-formyl-4-(1H-imidazol-1-yl)phenyl)-N-indan-1-ylacrylamide (17 mg) obtained in Example 437 and the reaction mixture was agitated for 30 minutes at room temperature. After the reaction solution was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: methanol-ethyl acetate system), and 1.8 mg of the title compound was obtained.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([S:13]([CH2:16][CH2:17][SH:18])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1[C:29]([C:30]([NH:32][CH2:33][C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:31])=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.CCCCCC>CN(C=O)C>[C:7]1([S:13]([CH2:16][CH2:17][S:18][C:20]2[C:29]([C:30]([NH:32][CH2:33][C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[O:31])=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(NCc1cccs1)c1cc2ccccc2nc1Cl
Reactant: O=S(=O)(CCS)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(NCc1cccs1)c1cc2ccccc2nc1SCCS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
112 mg (1.0 mmol) potassium tert-butylate were added to a solution of 202 mg (1.0 mmol) 2-(phenylsulfonyl)ethanethiol in DMF (6 ml) at 0° C. and the mixture was stirred for 10 min at 0° C. Then 303 mg (1.0 mmol) 2-chloro-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide (precursor VVV01) were added at 0° C. and the reaction solution was heated slowly to 50° C. and stirred for 16 h at this temperature. After cooling to RT it was diluted with EE and washed with a saturated aqueous NH4Cl solution. The aqueous phase was extracted with EE. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 4:1) with the residue yielded 326 mg (0.7 mmol, 70%) 2-[2-(phenylsulfonyl)ethylthio]-N-(2-thienyl-methyl)-3-quinoline carboxamide. MS: m/z 469.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1)#[N:2].[Br-].[Br-].[Br-].[Al+3].[Cl:19][C:20]([Cl:24])([Cl:23])[C:21]#[N:22]>>[Cl:19][C:20]([Cl:24])([Cl:23])[C:21]1[N:22]=[C:21]([C:20]([Cl:24])([Cl:23])[Cl:19])[N:22]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[N:2]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: N#Cc1ccc(SCCC(=O)O)cc1
Agent: [Al+3]
Agent: [Br-]
Product: O=C(O)CCSc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1

Procedure:
A solution containing 22 g of 3-(4-cyanophenylthio) propionic acid (106 mmol) and 2 g of aluminum tribromide (AlBr3) in 150 g of trichloroacetonitrile was dried at room temperature and bubbled with HCl. The solution was heated with a heat-gun in order to dissolve the starting materials remaining undissolved. The process of reaction was checked by TLC. The reaction product was formed gradually with the lapse of time. Then, the reaction was quenched after 24 hours and the reaction mixture was extracted with 1000 mL of diethyl ether. The resultant product was washed with deionized water and dried over anhydrous magnesium sulfate.
Reaction SMILES: C([P:4]([CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:31])[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[O:18]2)=[C:13]([O:32][CH3:33])[CH:12]=1)([CH:6]([CH3:8])[CH3:7])=[O:5])(C)C.[N-]=[N+]=[N-].[Na+].CN(C)C=[O:41].C(OCC)(=O)C>O>[OH:5][P:4]([CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:31])[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[O:18]2)=[C:13]([O:32][CH3:33])[CH:12]=1)([CH:6]([CH3:7])[CH3:8])=[O:41]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc(=O)c3c(OC)cc(OCP(=O)(C(C)C)C(C)C)cc3o2)cc1OC
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2cc(=O)c3c(OC)cc(OCP(=O)(O)C(C)C)cc3o2)cc1OC
Temperature: 100 °C
Yield: 33 %

Procedure:
7-{(diisopropylphosphoryl)-methyloxy}-3′,4′,5-trimethoxyflavone (0.5 g, 0.99 mmol, produced in Step 1 of Example 6) and sodium azide (0.5 g, 7.69 mmol) were added dropwise to N,N-dimethylformamide (20 mL) and warmed at 100° C. for 8 hours. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 50 mL of water were added dropwise, followed by separation of the organic layer from the aqueous layer. 10 mL of conc. hydrochloric acid was added dropwise to the aqueous layer which was then extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then evaporated to afford 0.15 g (yield: 33%) of the title compound.
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.Cl.[CH3:12]O>>[ClH:1].[CH3:12][O:9][C:8](=[O:10])[CH2:7][C:5]1[N:4]=[CH:3][NH:2][CH:6]=1
Reactant: CO
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Product: COC(=O)Cc1c[nH]cn1

Procedure:
A solution of 1H-imidazole 4-acetic acid hydrochloride (4.00 g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature (RT) for 18 hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C@@:5]12[C:11]([CH3:13])([CH3:12])[C@@H:8]([CH2:9][CH2:10]1)[CH:7]=[C:6]2[C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]([CH3:30])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])=[CH:16][C:15]=1[O:31][CH3:32])=[O:4].[Li+].[OH-].O>CO.O>[CH3:32][O:31][C:15]1[CH:16]=[C:17]([C:22]([CH3:30])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])[CH:18]=[C:19]([O:20][CH3:21])[C:14]=1[C:6]1[C@:5]2([C:3]([OH:4])=[O:2])[C:11]([CH3:13])([CH3:12])[C@H:8]([CH:7]=1)[CH2:9][CH2:10]2
Reactant: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@@H]3CC[C@@]2(C(=O)OC)C3(C)C)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@@H]3CC[C@@]2(C(=O)O)C3(C)C)c(OC)c1
Yield: 26 %

Procedure:
Methyl ester 11a (HU-911) 0.103 g (0.233 mmol) and LiOH 0.111 g (4.66 mmol) in 2 ml of MeOH/H2O 3:1 were heated at 200° C. over 48 hrs in a screwed vial under air atmosphere. Water was added to the reaction mixture and extracted several times with ether. Organic phases were collected, dried over MgSO4 and concentrated in vacuo. The product was purified by preparative TLC (hexane/ethyl acetate) to give yellow solid 0.026 g (26%). mp 101-102° C.; 1H NMR (300 MHz, CDCl3) δ ppm 6.46 (s, 2H), 6.32 (d, J=3.40 Hz, 1H), 3.71 (s, 6H), 2.46 (t, J=3.44 Hz, 1H), 2.38-2.44 (m, 1H), 1.80-2.03 (m, 1H), 1.53-1.58 (m, 2H), 1.26 (s, 6H), 1.16-1.24 (m, 7H), 1.14 (s, 3H), 1.03-1.12 (m, 3H), 1.00 (s, 3H), 0.85 (t, J=6.74 Hz, 3H). Exact mass calculated for C28H42O4 m/e 428.29. found 428.98. Anal. calcd. for C28H42O4: C, 75.66; H, 9.41. Found: C, 75.50; H, 9.48.
Reaction SMILES: C[N:2]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH2:3][CH2:4][CH2:5][NH:6]C.[C:13]1([C:19]#[C:20][C:21]([OH:23])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[S:9]1[CH:10]=[CH:11][N:12]=[C:8]1[NH:2][CH2:3][CH2:4][CH2:5][NH:6][C:21](=[O:23])[C:20]#[C:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNCCCN(C)c1nccs1
Reactant: O=C(O)C#Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(C#Cc1ccccc1)NCCCNc1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
440 mg (2.37 mmol) N1,N3-dimethyl-N1-(thiazol-2-yl)propane-1,3-diamine was dissolved, together with 347 mg (2.37 mmol) 3-phenyl propiolic acid, 412 μl (2.37 mmol) DIPEA and 761 mg (2.37 mmol) TBTU, in THF (30 ml), and stirred for 2 h at RT. The reaction solution was concentrated in vacuo and the residue was taken up by chloroform, washed with water and brine, dried over MgSO4 and concentrated in vacuo. CC (DCE/EtOH 10:1) was carried out on the residue, yielding 314 mg (1.00 mmol, 42%) N-(3-((thiazol-2-yl)amino)propyl)-3-phenylpropiolamide. MS [MH+] 314.1
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH2:22]([NH:29][C:30]([NH2:32])=[S:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:32]=[C:30]([NH:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:31][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)NCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-c2sc(NCc3ccccc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 69.2 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.415 g, 1.12 mmol) in isopropanol (12 mL) in a 25 mL round bottom flask was added N-benzyl thiourea (0.186 g, 1.12 mmol). The solution was heated to reflux (30 hours), cooled to room temperature and let stand for 7 days. The resulting suspension was concentrated in vacuo. The resulting residue was suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), dried over sodium sulfate, filtered and reconcentrated in vacuo yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole as a pale yellow solid (0.34 g, 69%): mp 112° C. 1H NMR (CDCl3 400 mHz δ7.74 (d, J=8.56 Hz, 2H), 7.43-7.25 (m, 10H), 6.92 (t, J=8.56 Hz, 2H), 4.33 (s, 2H), 3.02 (s, 3H). MS (EI-thermospray): m/z 439 (MH+). HRMS Δ=1.6 mmu.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[CH3:18][O-:19].[Na+]>CN(C)C=O.CO>[CH3:18][O:19][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 120 °C

Procedure:
First, the intermediate 2-methoxy-9,10-anthraquinone was prepared. A solution of 2-chloro-9,10-anthraquinone (10.08 g, 42 mmol) in 100 mL of N,N-dimethylformamide was treated with 25 mL of 25% sodium methoxide in methanol. The stirred reaction mixture was heated in a 120° C. oil bath for 6 h under nitrogen, then cooled to ambient. The product was precipitated into aqueous HCl (0.5 M, 250 mL), collected, washed with water and dried. The product was purified by recrystallization from a mixture of toluene and heptane to provide 1.6 g (16%) of a light yellow solid. This intermediate was characterized by 1H NMR: (300 MHz, CDCl3) δ 4.00 (s, 3H), 7.28 (d, 1H), 7.29 (d, 1H), 7.70 (m, 2H), 8.26 (s, 1H), 8.30 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[CH:4][N:3]=1.B([C:23]1[CH:34]=[CH:33][C:26]([CH2:27][C@@H:28]([C:30]([OH:32])=[O:31])[NH2:29])=[CH:25][CH:24]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:29][CH:28]([CH2:27][C:26]1[CH:33]=[CH:34][C:23]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[CH:4][N:3]=2)=[CH:24][CH:25]=1)[C:30]([OH:32])=[O:31]
Reactant: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(Cc1ccc(-c2cc(OC(c3ccccc3)C(F)(F)F)ncn2)cc1)C(=O)O
Temperature: 120 °C
Yield: 11500.3 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with 4-chloro-6-(2,2,2-trifluoro-1-phenyl-ethoxy)-pyrimidine (30 mg, 0.1 μmol), 4-borono-L-phenylalanine (32 mg, 0.16 mmol), 1 ml of acetonitrile and 0.6 ml of water. Aqueous sodium carbonate (0.42 ml, 1M) was added to above solution followed by 10 mol percent of POPd2 (dihydrogen di-μ-chlorodichlorobis(di-tert-butylphosphinito-κP)dipalladate. The reaction vessel was sealed and heated to 120° C. for 30 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep-LC to give 4.8 mg of 2-amino-3-{4-[6-(2,2,2-trifluoro-1phenyl-ethoxy)-pyrimidin-4-yl]-phenyl}-propionic acid, yield 11%. 1H-NMR (400 MHz, CD3OD): δ 3.20 (m, 1H), 3.40 (m, 1H), 4.25 (t, 1H), 6.82 (dd, 1H), 7.43 (m, 5H), 7.57 (s, 1H), 7.60 (m, 2H), 8.10 (d, 2H), 8.75 (s, 1H).