Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([OH:15])=O)=[C:5]2[OH:16].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CC(N(C)C)=O.O>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:13]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[OH:16])=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=3)=[O:15])=[CH:32][CH:31]=1
Reactant: O=C(O)c1cnc2cc(F)c(F)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(F)c(F)cc2c1O
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture of 0.5 g of 6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid from preparation No. 15 and 0.435 g of carbonyldiimidazole in 8 mL of anhydrous dimethylacetamide is stirred 4 h at 65° C. The reaction mixture is cooled to 25° C. and 2 drops of distilled water is added. After an additional 10 min 0.34 mL of 4-chlorobenzylamine is added. The mixture is stirred 26 h at 25° C. and then diluted with 10 mL of distilled water. After standing for an additional 30 min the precipitate is collected by filtration and washed with three 10 mL portions of distilled water. The solid is dried in a stream of air and then at 20 torr/120° C./3 days. The yield is 0.51 g (70%) of a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1)(=[O:3])[CH3:2].S(C1C=CC(C)=CC=1)(O[CH3:20])(=O)=O.[H-].[Na+]>C(#N)C>[C:1]([N:4]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1)[CH3:20])(=[O:3])[CH3:2]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)Nc1csc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N(C)c1csc(-c2ccccc2)n1

Procedure:
A mixture of 4-acetamido-2-phenylthiazole, prepared according to Example 1, and methyl tosylate in acetonitrile may be treated with sodium hydride to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([CH3:22])([OH:21])[CH3:20])[CH:15]=3)[CH:10]=[N:9]2)[C:5](Br)=[CH:4][N:3]=1.[C:24]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)(OC(C)(C)C)=O>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([CH3:22])([OH:21])[CH3:20])[CH:15]=3)[CH:10]=[N:9]2)[C:5]([C:34]2[CH:33]=[N:32][N:31]([CH3:24])[CH:35]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(O)C#Cc1ccc2cnn(-c3nc(N)ncc3Br)c2c1
Product: Cn1cc(-c2cnc(N)nc2-n2ncc3ccc(C#CC(C)(C)O)cc32)cn1

Procedure:
4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol (0.075 g) was reacted 1-Boc-4-pyrazoleboronic acid pinacol ester via General Procedure Suzuki Coupling to afford 9.5 mg of 4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-ol following reverse phase hplc purification. MS (Q1) 360. 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.76 (s, 1H), 7.46 (s, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.02 (s, 2H), 5.45 (s, 1H), 1.47 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:29])[CH2:27][CH3:28]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:29][CH2:26][CH2:27][CH3:28])=[O:20]
Reactant: CCCN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Product: CCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30953.6 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), propylamine (0.190 g, 3.21 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred for 6 hours at room temperature. After completion of the reaction, the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-propyl-3,4,5,6-tetrahydrophthalamide as white crystals (0,360 g, 30.9% yield).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([N:21]3C(=O)C4C(=CC=CC=4)C3=O)=[N:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([NH2:21])=[N:17]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccn(Cc2ccccc2OCc2ccccc2)n1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccn(Cc2ccccc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a solution of 2-[1-({2-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]-1H-isoindole-1,3(2H)-dione (4.83 g, approx 11.8 mmol) in THF (50 ml) was added hydrazine hydrate (2.86 ml, 59 mmol) and the solution was stirred overnight at ambient temperature. A white solid was filtered off and the filtrate dried over magnesium sulphate, filtered and evaporated to give an oil. The oil was applied to 100 g silica and purified using 0-100% ethyl acetate-cyclohexane to give the title compound as a pale yellow oil (1.66 g); LCMS: (System 3) MH+=280, tRET=0.96 min.
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].C(O)(C)C.Cl[CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>O>[CH2:17]([O:16][C:14]([CH2:13][C:12]1[N:2]=[C:1]([SH:3])[S:4][CH:11]=1)=[O:15])[CH3:18]
Reactant: NC(=S)[S-]
Reactant: CCOC(=O)CC(=O)CCl
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)Cc1csc(S)n1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
To 180.0 g (1.63 mols) of ammonium dithiocarbamate was added 1.5 liters of isopropyl alcohol, the mixture was stirred and then 268.9 g (1.63 mols) of ethyl 4-chloro-3-oxobutanoate was added dropwise to the mixture. After stirring the resultant mixture for 3 hours under refluxing, 300 ml of water was added to the reaction mixture, the mixture was cooled to room temperature and crystals formed were collected by filtration under a reduced pressure to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate to obtain 188 g (yield 57%) of 4-ethoxycarbonylmethyl-2-mercaptothiazole.
Reaction SMILES: Cl.O.[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1)[C:4]#[N:5]>[Fe].C(O)C>[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([NH2:13])[CH:7]=1)[C:4]#[N:5]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: N#CSc1ccc(N)c(N)c1
Reaction time: 0.06 h
Yield: 79 %

Procedure:
63 g. of iron powder are activated by heating with a mixture of 12 ml of 5N hydrochloric acid and 30 ml. of water on a water bath for half an hour, addition of 270 ml. of water and cooling the suspension to 45° C. follows. A hot solution of 58.5 g. of 4-thiocyanato-2-nitro-aniline and 180 ml of 96% ethanol is added under stirring to the suspension formed. The temperature of the reaction mixture rises slowly. When the temperature reaches 75° C. the reaction mixture is cooled with ice in order to maintain the internal temperature below 85° C. The exothermic stage of the reaction lasts for 3-4 minutes. The reaction mixture is then heated to boiling until no more starting material can be detected by means of thin layer chromatography (about 15 minutes). The warm reaction mixture is filtered, 225 ml. of hot water are added to the filtrate, the solution is clarified with activated charcoal, filtered until warm and the filtrate is allowed to crystallize slowly under stirring. The mixture containing crystals is stirred at 0° C. for 5-6 hours, the crystals are filtered off, washed with cold 25% ethanol and dried in vacuo. Thus 41,6 g. of 4-thiocyanato-1,2-diamino-benzene are obtained, yield: 79%, M.p.: 108°-110° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[NH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[N:12]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: Clc1ncc2[nH]ccc2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a stirred mixture of sodium hydride (12.5 g, 520 mmol, 60% in mineral oil) in anhydrous THF (300 mL) at 0° C. was added dropwise 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (40.0 g, 262 mmol) dissolved in anhydrous THF (200 mL). The reaction mixture was stirred at 0° C. for 15 min them SEMCl (52.5 g, 315 mmol) was added dropwise. The mixture was then stirred at RT for 1 h and then diluted with EtOAc. The organic layer was washed with water and brine, dried over (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography to afford 42 g (56.4%) of 2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine as an orange oil. A high-pressure tube charged with 2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine (2.23 g, 7.90 mmol), tributyl(1-ethoxyvinyl)stannane (3.7 g, 10.27 mmol), and Pd(PPh3)2Cl2 (200 mg) in degassed DMF (20 mL) under N2 was sealed and heated at 100° C. for 16 h. The reaction mixture was cooled, diluted with EtOAc, and filtered through a pad of Celite® to remove Pd solid. The filtrate was washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was dissolved in anhydrous THF (0.3 M), and 2N HCl (5.0 eq.) was added. The reaction mixture was stirred at RT under N2 for 16 h, poured into 10% aq. NaOH solution, and then extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography to afford 1.5 g (66%) of 1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethanone as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 7.66 (d, J=3.2 Hz, 1H), 6.89 (d, J=4.8 Hz, 1H), 5.60 (s, 2H), 3.49 (t, J=8.0 Hz, 2H), 2.88 (s, 3H), 0.901 (t, J=8.0 Hz, 2H), −0.053 (s, 9H); MS (ESI) m/z: 291 [M+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)=[CH:3][C:2]=1[O:1][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc([N+](=O)[O-])cn1

Procedure:
In the same method as in Example C1(v), the title compound (8.35 g, 98%) was obtained as an orange oil using N-(3-hydroxy-4-methylphenyl)-3-(trifluoromethyl)benzamide (6.00 g, 20.3 mmol), 2-chloro-5-nitropyridine (3.22 g, 20.3 mmol), potassium carbonate (8.43 g, 60.9 mmol) and N,N-dimethylformamide (150 mL) as starting materials. The title compound was used for the next reaction without further purification operation.
Reaction SMILES: [C:1]([NH:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:15]=[C:14]3B2OC(C)(C)C(C)(C)O2)=[N:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:40]1[N:45]=[C:44]([CH:46]2[CH2:48][CH2:47]2)[CH:43]=[CH:42][N:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([NH:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:15]=[C:14]3[C:40]2[N:45]=[C:44]([CH:46]3[CH2:48][CH2:47]3)[CH:43]=[CH:42][N:41]=2)=[N:9][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1nccc(C2CC2)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)(C)C)o4)ccc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(C4CC4)n3)c3cc(-c4nnc(NC(C)(C)C)o4)ccc32)cc1
Temperature: 120 °C
Yield: 24.4 %

Procedure:
To a 5 mL glass microwave tube containing N-tert-butyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (357.8 mg, 0.667 mmol) was added 2-bromo-4-cyclopropylpyrimidine (153 mg, 0.767 mmol) (CombiPhos Catalysts Inc.), potassium phosphate (425 mg, 2.001 mmol) (Sigma-Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (19.08 mg, 0.040 mmol) (Strem), and Pd2(dba)3 (18.32 mg, 0.020 mmol) (Strem). The tube was purged with argon, the solids were treated with Dioxane (3.0 mL) and Water (0.300 mL), the tube was sealed, and the contents were heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 min. The mixture was treated with H2O and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 5-60% EtOAc in Hex) affording N-tert-butyl-5-(3-(4-cyclopropylpyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (86.2 mg, 0.163 mmol, 24.45) as an off-white foam. MS (ESI, pos. ion) m/z: 529.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:29][CH2:28][C:27](=[N:32][OH:33])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CO
Product: ON=C1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1

Procedure:
A mixture of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-piperidin-4-one 7A-96 (75 mg, 0.17 mmol) and hydroxylamine hydrochloride (11.9 mg, 0.17 mmol) in methanol (0.3 ml) was stirred overnight at room temperature. The reaction was then extracted from saturated aqueous sodium bicarbonate, the combined organic layers were dried (Na2SO4) and concentrated to afford title compound 32A-1 (75 mg, 97%) as a solid: +ESI MS (M+1) 453.4; 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.28 (s, 1H), 7.70 (dd, J=7.7, 1.5 Hz, 1H), 7.53–7.41 (m, 5H), 7.31 (d, J=8.7 Hz, 2H), 4.45–4.18 (v br s, 4H), 2.61 (t, J=6.0 Hz, 2H), 2.39 (t, J=5.8 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=N)[O:10][CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[SH:8].O.S(=O)(=O)(O)[OH:16]>C(O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[SH:8])[C:9]([O:10][CH2:11][CH3:12])=[O:16]
Reactant: CCOC(=N)c1ccc(S)c(Br)c1
Reactant: O=S(=O)(O)O
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(S)c(Br)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethyl 3-bromo-4-mercaptobenzenecarboximidate (3.00 g) was dissolved in ethanol (100 ml), and water (10 ml) and then concentrated sulfuric acid (10 ml) were added dropwise thereto at 0° C. and stirred overnight at room temperature. Zinc (1 g) was added to the reaction system and the resulting mixture was stirred at room temperature for 2 hours to induce the production of a monomer. After the zinc powder was removed by filtration through Celite, the ethanol was distilled off under reduced pressure, followed by extraction with ethyl acetate, and the organic layer was washed with water (×4). The organic layer was dried over anhydrous sodium sulfate and then concentrated to obtain ethyl 3-bromo-4-mercaptobenzoate (2.58 g) as a light-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([Cl:12])=[C:14]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)=[O:9]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)c1cc(Br)ccc1O
Yield: 37.4 %

Procedure:
Using 5-bromosalicylic acid and 4-chloro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22](Br)[S:21]2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9](=[O:10])[N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[S:21]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Reactant: OB(O)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(-c3ccccc3)sc2n1)c1ccccc1
Yield: 6 %

Procedure:
Compound A24 was synthesized from compound 12a (0.053 mmol) and phenylboronic acid (0.16 mmol), following the procedure as described for compound A1, to give compound A24 as a white solid in 6% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.40 (s, 9H), 1.82-1.91 (m, 1H), 2.01-2.13 (m, 1H), 2.35-2.42 (m, 1H), 3.13-3.21 (m, 1H), 3.77-3.84 (m, 1H), 4.70-4.72 (m, 1H), 5.46 (d, J=7.08 Hz, 1H), 6.04 (d, J=7.08 Hz, 1H), 7.31-7.46 (m, 11H), 7.63 (s, 1H), 7.89 (s, 1H), 9.88 (brs, 1H); and MS (ESI, EI+) m/z=546.23 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH2:6][CH:7]=[CH:8][CH2:9][PH:10](=[O:14])[O:11][CH2:12][CH3:13].[CH3:21][C:22]1([CH3:38])[C:26]([CH3:28])([CH3:27])[O:25][B:24]([C:29]2[CH:30]=[N:31][N:32]([CH2:34]CCO)[CH:33]=2)[O:23]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH2:6][CH:7]=[CH:8][CH2:9][PH:10](=[O:14])[O:11][CH2:12][CH2:13][CH2:34][N:32]1[CH:33]=[C:29]([B:24]2[O:25][C:26]([CH3:28])([CH3:27])[C:22]([CH3:38])([CH3:21])[O:23]2)[CH:30]=[N:31]1
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Reactant: CCO[PH](=O)CC=CCc1ccc([N+](=O)[O-])c(OC)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CC=CC[PH](=O)OCCCn2cc(B3OC(C)(C)C(C)(C)O3)cn2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.3 %

Procedure:
A suspension of (3-methoxy-4-nitrobenzyl)prop-2-en-1-ylphosphinic acid (Compound 37E, 241 mg, 0.888 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 224 mg, 0.888 mmol) in 1,2-Dichloroethane (19 mL) and DIPEA (0.928 mL, 5.33 mmol) was charged with (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (1387 mg, 2.665 mmol). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (20 mL). The organic layer was washed with NaHCO3 (10 mL), washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a yellow oil. The crude material was purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a light yellow oil. The material was re-purified on a Teledyne ISCO Combiflash® Rf system using 1:1 DCM-EtOAc/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a light yellow solid (189.6 mg, 42%). 1H NMR (CDCl3, 400 MHz): δ=7.81-7.87 (m, 2H), 7.71 (s, 1H), 7.11 (s, 1H), 6.92 (d, J=7.8 Hz, 1H), 5.73-5.86 (m, 1H), 5.19-5.32 (m, 2H), 4.27 (t, J=6.4 Hz, 2H), 3.90-4.04 (m, 5H), 3.20 (d, J=16.2 Hz, 2H), 2.61 (dd, J=7.6, 17.4 Hz, 2H), 2.15-2.25 (m, 2H), 1.33 (s, 12H). MS (ESI): m/z 506.63 [M+H]+. UPLC: tR=1.23 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [P:1]12([S:13]P3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH2:15]([CH:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:19][OH:20])[CH2:16][CH3:17]>C1(C)C=CC=CC=1>[CH2:15]([CH:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:19][O:20][P:1](=[S:2])([O:20][CH2:19][CH:18]([CH2:15][CH2:16][CH3:17])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[SH:13])[CH2:16][CH3:17]
Reactant: CCCCCC(CO)CCC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CCCCCC(CCC)COP(=S)(S)OCC(CCC)CCCCC
Temperature: 75 °C
Reaction time: 2 h

Procedure:
0.2 mol of diphosphorus pentasulfide (44 g) was suspended in 300 ml of toluene and heated to 75° C. Then 0.8 mol of 2-propylheptanol (127 g) was added dropwise with evolution of gas over a period of 1 h. The reaction mixture was stirred at 75° C. for a further 2 hours. A clear solution was obtained. The conversion was >95% (determined by means of acid-base titration).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:35]=[CH:34][CH:33]=[CH:32][C:6]=1[CH2:7][N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[N:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9]1)=[O:4].Cl>O1CCOCC1>[O:13]=[C:12]1[C:11]2([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[N:10]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][N:8]1[CH2:7][C:6]1[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To tert-butyl 3-(2-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.12 g, 0.25 mmol) was added 4M solution of HCl in dioxane (2.5 mL). After stirring at room temperature for 90 minutes, the reaction mixture was concentrated in vacuo to obtain methyl 2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1([C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[C:19]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:18]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1([C:17]2[CH:29]=[CH:28][C:20]([C:21]([OH:23])=[O:22])=[C:19]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:18]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(-n2cnc3ccccc32)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-n2cnc3ccccc32)cc1Nc1ccc(F)cc1

Procedure:
Trifluoroacetic acid 7.5 mL solution of tert-butyl 4-(1H-benzimidazol-1-yl)-2-(4-fluoroanilino)benzoate 0.16 g was stirred at room temperature for 1 hour and 30 minutes. The solvent was removed under reduced pressure, ethyl acetate was added to the obtained residue, and solid matter was filtrated to give 4-(1H-benzimidazol-1-yl)-2-(4-fluoroanilino)benzoic acid trifluoroacetate 99 mg of a yellow solid.