Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([O:7][CH3:8])=[O:6].Cl[C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[N:23]=[CH:24][C:17]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:22]1[C:18]2=[N:19][CH:20]=[N:21][C:16]([O:3][C@@H:4]([CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([O:7][CH3:8])=[O:6])=[C:17]2[CH:24]=[N:23]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: COC(=O)[C@@H](O)CCS(C)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCS(C)(=O)=O)Oc1ncnc2c1cnn2-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
Sodium hydride (58.7 mg, 1.47 mmol) was added to (S)-methyl 2-hydroxy-4-(methylsulfonyl)butanoate (Intermediate AA2) (120 mg, 0.61 mmol) in anhydrous THF (50 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (357 mg, 0.67 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to afford the product (160 mg, 61.6%). 1H NMR (400 MHz, CDCl3) δ 2.60-2.75 (2H, m), 3.01 (3H, s), 3.25-3.38 (2H, m), 3.82 (3H, s), 5.79-5.82 (1H, m), 7.44-7.54 (3H, m), 7.61-7.63 (1H, m), 8.34 (1H, s), 8.54 (1H, s); m/z (ES+) (M+H)+=425; HPLC tR=2.01 min.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[CH:16][S:15][C:14]=23)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33].[Cl-].[NH4+]>C1COCC1>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([S:7]([C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[C:16]([Sn:34]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:30][CH2:31][CH2:32][CH3:33])[S:15][C:14]=23)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccc(S(=O)(=O)c2ncn3ccsc23)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(=O)(=O)c3ccc(C)cc3)c2s1
Reaction time: 0.33 h
Yield: 43.3 %

Procedure:
A solution of 669 mg of 7-p-toluenesulfonylimidazo[5,1-b]thiazole in 65 ml of THF was cooled to −60° C. in an argon atmosphere. A 1.6 N n-butyllithium/n-hexane solution (2.5 ml) was added dropwise thereto at the same temperature. The mixture was stirred for 20 min. A solution of 1.25 g of tri-n-butylstannyl chloride in 10 ml of THF was added thereto, and the mixture was stirred at the same temperature for 40 min. A semisaturated aqueous ammonium chloride solution (150 ml) was added thereto, followed by extraction with 250 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1). The title compound (590 mg) was obtained from the fraction of Rf=0.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(F)cc1
Yield: 90 %

Procedure:
A mixture of 3-[5-(4-fluorophenyl)-4-isoxazolyl]propionic acid (3.68 g), conc. sulfuric acid (0.05 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-fluorophenyl)-4-isoxazolyl]propionate (3.50 g, yield 90%) was obtained as a pale yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). NMR (CDCl3) δ: 2.65 (2H, t, J=7.4 Hz), 2.98 (2H, t, J=7.4 Hz), 3.69 (3H, s), 7.12–7.28 (2H, m), 7.64–7.78 (2H, m), 8.22 (1H, s).
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.N(OC(C)(C)C)=O.[Cl:17]CCl>[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:17])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: ClCCl
Reactant: Nc1ncc(Br)nc1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(C)(C)ON=O
Product: Clc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dibromopyrazin-2-amine (1.00 g, 3.95 mmol) in dichloromethane 6.0 ml at 0° C. was added titanium tetrachloride (1 mol/l) in dichloromethane (3.95 mL, 3.95 mmol) then tert-butyl nitrite (1.05 mL, 7.91 mmol) was added dropwise. The reaction was warmed to RT then 1 more equivalent of TiCL4 was added and stirred for 1 h. The reaction was quenched with water and extracted with DCM. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was carried to next step. MS (ESI) m/z: 272.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([O:17]C)=[O:16])=[CH:12][S:13][CH:14]=1.[OH-].[K+]>C(O)C.O.O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([OH:17])=[O:16])=[CH:12][S:13][CH:14]=1
Reactant: COC(=O)c1cscc1Nc1ccc(I)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cscc1Nc1ccc(I)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
A mixture of methyl 4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylate (0.74 g, 1.96 mmol) in the solution of potassium hydroxide (0.3 g) in ethanol/water (4 ml/4 ml) was heated up to 60° C. and stirred at this temperature for 30 min. The mixture was cooled to room temperature, diluted with 4 ml of water and extracted with ether. The water layer was acidified with 1 N HCl to pH 2, the product precipitated and was filtered off, washed several times with water and dried in vacuo to afford 4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylic acid (0.59 g, 83%). 1H NMR (d6-DMSO): 13.20 (s, 1H), 9.13 (s, 1H), 8.35 (d, 1H), 7.62 (dd, 1H), 7.48-7.38 (m, 2H), 7.11 (s, 1H); MS (EI) for C11H7FINO2S: 362 (MH−).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([CH3:26])[CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)=[C:19]([CH3:26])[CH:18]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CSc1nc(Cl)c(C=O)c(NC(C)C)n1
Product: CSc1nc(NC(C)C)c(C=O)c(-c2ccc(F)cc2C)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methylphenylboronic acid to give the title compound 4-(4-fluoro-2-methyl-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 1.31 (d, 6H, J=5.7 Hz), 2.21 (s, 3H), 2.59 (s, 3H), 4.52 (m, 1H), 7.90-7.15 (m, 2H), 7.18-7.25 (m, 1H), 9.06 (br s, 1H), 9.50 (s, 1H). LC MS (m/e)=320 (MH+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[N:8]=1.Cl[CH2:23][C:24]#[N:25].C(N(CC)CC)C>CCO>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:23][C:24]#[N:25])[N:8]=1
Reactant: N#CCCl
Reactant: NCCCCCc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CCNCCCCCc1nccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(5-aminopentyl)pyrimidine (0.61 g.), chloroacetonitrile (0.17 g.) and triethylamine (0.23 g.) in EtOH (15 ml.) was heated under reflux for 7 hours. The solvent was evaporated and the residue was treated with sodium bicarbonate solution and extracted with EtOAc. The extract was dried (MgSO4) and evaporated to give an oil which was purified by medium pressure chromatography, eluting with 7.5% v/v MeOH in methylene chloride to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[5-cyanomethylaminopentyl]pyrimidine as a pale yellow solid which was used without further purification.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]([C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7].[C:18]([C:21]1[C:26]([NH2:27])=[C:25]([CH3:28])[C:24]([O:29][CH3:30])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:18]([C:21]1[C:26]([NH:27][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:6]([CH3:7])[CH3:8])[N:14]=2)=[O:17])=[C:25]([CH3:28])[C:24]([O:29][CH3:30])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(C)c1cccc(C(=O)O)n1
Reactant: COc1ccc(C(C)=O)c(N)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(C)=O)c(NC(=O)c2cccc(C(C)C)n2)c1C
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 125.2 %

Procedure:
POCl3 (0.88 mL, 9.53 mmol) was added at −25° C. drop wise over 5 min under nitrogen, to a stirred solution of 6-isopropylpyridine-2-carboxylic acid (106, 1.43 g, 8.66 mmol) and 6-acetyl-3-methoxy-2-methylaniline (1.55 g, 8.66 mmol) in dry pyridine (70 mL). The resulting solution was stirred at −10° C. for 2.5 h. Then, the reaction mixture was poured on ice, neutralized with aqueous sodium bicarbonate and extracted 3 times with AcOEt. The organic layers were combined, washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography (hexanes/AcOEt, 3:1) to give 3.54 g (72%) of the title compound 107: m/z=327 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][O:14]C(Cl)Cl.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([OH:12])=[CH:4][C:3]=1[CH:13]=[O:14]
Reactant: Oc1ccc(O)c2c1CCCC2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: O=Cc1cc(O)c2c(c1O)CCCC2
Yield: 60 %

Procedure:
To a solution of 1,4-dihydroxy-5,6,7,8-tetrahydronaphthalene (1.640 g, 0.010 mol) in dichloromethane (50 ml) was added titanium tetrachloride (5.69 g, 0.03 mol). Then 1,1-dichlorodimethyl ether (1.73 g, 0.015 mol) was added dropwise under vigorous stirring and the reaction mixture stirred for another 3 h at room temperature. Finally 5% hydrochloric acid (10 ml) was added under ice-cooling. The organic phase was separated and the residual aqueous phase repeatedly extracted with ether. The combined organic phases are washed with saturated saline solution, dried over sodium sulfate and evaporated under vacuum. The residue was crystallized from benzene or alternatively submitted to flash chromatography on silica gel with benzene/ethylacetate 85:15 to afford pure title compound in about 60% yield (1.080 g), mp 145° C.
Reaction SMILES: [NH3:1].[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13]([C:15]1[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29](OC)=[O:30])[CH2:23][CH2:22]3)[CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:9]2>CO>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13](=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([NH2:1])=[O:30])[CH2:23][CH2:22]3)[N:20]=1)[CH2:9]2
Reactant: N
Reactant: COC(=O)CCN1CCN(c2cccc(C(=O)NC3C4CC5CC(C4)CC3C5)n2)CC1
Solvent: CO
Product: NC(=O)CCN1CCN(c2cccc(C(=O)NC3C4CC5CC(C4)CC3C5)n2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
7N ammonia in methanol (2 ml) was added into methyl 3-(4-(6-(adamantan-2-ylcarbamoyl)pyridin-2-yl)piperazin-1-yl)propanoate (94 mg, 0.22 mmol), and then the resulting mixture was stirred at room temperature for 48 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (10% MeOH/MC), to obtain 54 mg of colorless oil (60%). MS (ESI): 412 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][C:13]=2[CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:6]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[CH:14][C:13]=2[CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:6]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Product: COC(=O)Cc1cccc(Oc2ccc(-c3cccnc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 7, Step 1, using the following starting materials: {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester and 3-pyridineboronic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([NH:19][CH:20]=[O:21])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH3:22][O:23][C:24]1[C:29]([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH:17]([NH:19][CH:20]=[O:21])[CH3:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COc1ncccc1B(O)O
Reactant: CC(NC=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Product: COc1ncccc1-c1cccc(-n2cnc3cc(C(C)NC=O)ccc32)c1
Yield: 77 %

Procedure:
This was prepared analogously from N-{1-[1-(3-bromo-phenyl)-1H-benzoimidazol-5-yl]-ethyl}-formamide and 2-methoxypyridine-3-boronic acid in 77% yield. LC-ESI-HRMS of [M+H]+ shows 373.1666 Da. Calc. 373.166451 Da. dev. 0.4 ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[Cl:9].CC1(C)C(C)(C)OB([C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])O1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:23]([O:22][C:20]([C:19]1[C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[Cl:9])=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:24]
Reactant: Cc1ccc(Br)c(Cl)c1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccccc1-c1ccc(C)cc1Cl
Temperature: 110 °C
Reaction time: 2 h
Yield: 126 %

Procedure:
Under an argon atmosphere, 4-bromo-3-chlorotoluene (200 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (376 g), toluene (1000 ml), water (1000 ml), tripotassium phosphate (412 g) and dichlorobis(triphenylphosphine)palladium(II) (14 g) were added to a reaction vessel and the mixture was stirred at 110° C. for 2 hr. The reaction mixture was cooled to room temperature. The insoluble material was filtered off, and washed with water (500 ml) and toluene (500 ml). The filtrate was partitioned in a separatory funnel. The organic layer was washed twice with water (1000 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (337 g). The obtained residue was directly used for the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N12CCCN=C1CCCCC2.[OH-].[Na+]>CN(C)C=O>[CH2:13]([O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C=O)c(O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(O)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
2,4-Dihydroxy-5-methoxybenzaldehyde (6.0 g), benzyl bromide (9.7 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (8.6 g) in N,N-dimethylformamide (30 ml) were heated at 100° C. under nitrogen for 5 hours. After cooling to room temperature, 1 N NaOH was added and the mixture washed with ethyl acetate. The water phase was acidified with HCl and the precipitate was filtered.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[F:11][C:12]1[CH:41]=[CH:40][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:41][CH:40]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(O)Cn1ccnn1
Reactant: COc1cccc(C[C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Agent: Cl
Product: COc1cccc(C[C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)N(C(=O)Cn3ccnn3)C2)c1
Yield: 91 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide, gave Compound 68, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide (176 mg, 91%). 1H-NMR (400 MHz, CDCl3): σ 8.95 (s, 1H), 7.78 (s, 1H), 7.75 (s, 1H), 7.43 (d, 2H), 7.00 (t, 2H), 6.93-6.89 (m, 4H), 6.79-6.88 (m, 4H), 5.27 (d, 1H), 5.15 (d, 1H), 4.78 (d, 1H), 4.80 (d, 1H), 3.81 (s, 3H), 3.67 (dd, 1H), 3.27 (t, 1H), 3.07-2.88 (m, 2H), 2.66-2.61 (m, 2H), 1.77-1.69 (m, 1H). MS (EI) for C29H28FN5O4. found 530.2 (MH+).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([N:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.N12CCCN=C1CCC[CH2:27][CH2:26]2.C(Br)C>C1C=CC=CC=1>[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([N:7]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:26][CH3:27])=[O:13])=[CH:15][CH:16]=2)=[CH:5][CH:6]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C(=O)O)cc2)cc1
Solvent: CCBr
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(N(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Yield: 75.5 %

Procedure:
4-(Di-p-tolylamino)benzoic acid (69.7 g, 0.22 mol) dissolved in benzene (500 mL), was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (38 mL, 0.25 mol), followed by the addition of ethyl bromide (33 mL, 0.44 mol). The reaction was filtered to remove salts, washed with saturated ammonium chloride until neutral (1.5 L), washed with water, washed with brine, and dried over magnesium sulfate. The solvent was removed at 40° C. and the residual crystalline solid was washed with cold ethanol to give ethyl 4-(di-p-tolylamino)benzoate (57.4 g, 76% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:52][CH3:53])([C:31]2[NH:32][N:33]=[C:34](/[CH:36]=[CH:37]/[C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=3)[N:35]=2)[CH2:28][CH2:29]O)=[CH:23][CH:22]=1>C(Cl)(Cl)(Cl)Cl.C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([O:52][CH3:53])[C:31]3[N:32]([N:33]=[C:34](/[CH:36]=[CH:37]/[C:38]4[CH:43]=[CH:42][C:41]([N:44]5[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]5)=[C:40]([O:50][CH3:51])[CH:39]=4)[N:35]=3)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1
Reactant: COc1cc(/C=C/c2n[nH]c(C(CCO)(OC)c3ccc(F)cc3)n2)ccc1-n1cnc(C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(/C=C/c2nc3n(n2)CCC3(OC)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 1.9 %

Procedure:
Triphenylphosphine (22 mg) was added to a suspension of 3-(4-fluorophenyl)-3-methoxy-3-(5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-2H-[1,2,4]triazol-3-yl)propan-1-ol (38 mg) in carbon tetrachloride (2 mL) and THF (2 mL), and the reaction solution was heated under reflux for seven hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and a saturated sodium bicarbonate solution were added to the resulting residue, and the organic layer was separated. The organic layer washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system), again purified with silica gel column chromatography (elution solvent: ethyl acetate-methanol system) and then purified by LC-MS. After concentrating the target fraction, ethyl acetate and a saturated sodium bicarbonate solution were added to the residue, and the organic layer was separated. The organic layer washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 0.69 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[C:20]1[S:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[C:3]([C:20]2[S:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc(Br)s1
Product: Cc1cc2c(cc1-c1ccc(C=O)s1)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to Example 3(b), by reaction of 4.2 g (17 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid with 2.17 g (11.3 mmol) of 5-bromo-2-thiophenecarboxaldehyde, 2.1 g (60%) of the expected aldehyde are obtained, with a melting point of 130-5° C.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[N:6][CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:9]1[CH2:10][CH:11]=[C:12]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:13][CH2:14]1
Reactant: Fc1nccnc1I
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1nccnc1C1=CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a glass microwave vial was added 2-fluoro-3-iodopyrazine (1.6485 g, 7.36 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.319 g, 11.04 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.413 g, 0.589 mmol), and sodium carbonate (3.90 g, 36.8 mmol) in DME (19.63 mL) and water (4.91 mL) to stir at 80° C. overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with water, sat NaCl, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide 2-(3,6-dihydro-2H-pyran-4-yl)-3-fluoropyrazine. MS (ESI, pos. ion) m/z: 181.1.