Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:40](OC(=O)C)([F:42])[F:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:10]([O:17][CH:40]([F:42])[F:41])=[N:11]2
Reactant: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(F)cc3)c(C)c12
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(F)cc3)c(C)c12
Temperature: 70 °C
Reaction time: 120 h

Procedure:
A mixture of [8-fluoro-3-(4-fluorobenzyl)-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.48 g), N,N-dimethylformamide (6.0 mL), potassium carbonate (0.72 g) and acetic acid chlorodifluoromethyl ester (1.7 mL) was stirred at 70° C. for 5 days. The mixture was diluted with Water, extracted with ethyl acetate and the combined extracts washed with water and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:6 by volume), followed by washing with diethyl ether gave title compound as a white solid, 0.29 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]([OH:6])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:30]=[CH:29][C:28]=1[C:39]([NH:41][CH2:42][C:43]([CH2:49][NH2:50])([OH:48])[C:44]([F:47])([F:46])[F:45])=[O:40]>O1CCCC1.C(N(C(C)C)CC)(C)C>[NH2:26][C:27]1[N:31]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[N:30]=[CH:29][C:28]=1[C:39]([NH:41][CH2:42][C:43]([CH2:49][NH:50][C:4]([C:3]1[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6])([OH:48])[C:44]([F:47])([F:46])[F:45])=[O:40]
Reactant: O=C(O)c1c(Cl)cccc1C(F)(F)F
Reactant: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(C(=O)NCC(O)(CNC(=O)c2c(Cl)cccc2C(F)(F)F)C(F)(F)F)cnn1-c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of 2-chloro-6-(trifluoromethyl)benzoic acid (27 mg) in anhydrous tetrahydrofuran (1 ml) was added anhydrous dimethylformamide (5 μl) followed by a solution of oxalyl chloride in anhydrous tetrahydrofuran (1M, 0.13 ml). The solution effervesced and was stirred under nitrogen for 30 minutes. A solution of 5-amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (36 mg) in anhydrous tetrahydrofuran (1 ml) and diisopropylethylamine (65 μl) was added washed in with further tetrahydrofuran (0.5 ml). It was stirred under nitrogen for 16 hours, blown down, dissolved in dichloromethane (5 ml), washed with 2M hydrochloric acid (2 ml), blown down and purified on a silica SPE cartridge (5 g). Elution with dichloromethane followed by ethyl acetate:cyclohexane (1:5), (1:3), (1:2), (1:1) (4 times). Combination of the appropriate fractions and evaporation gave the title compound (50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2Cl)=O)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[NH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(Cl)cc1)c1cnccc1Cl
Solvent: CO
Solvent: O
Product: Clc1ccc(-c2n[nH]c3ccncc23)cc1
Reaction time: 3 h
Yield: 33 %

Procedure:
(4-Chlorophenyl)-(4-chloropyridin-3-yl)-methanone (3.88 g, 15.4 mmol) was dissolved in MeOH (20 mL) at room temperature and hydrazine hydrate (20 mL) was added. The reaction mixture was stirred for 3 h. The precipitate was filtered and purified by recrystallisation from PhMe/MeOH (˜4:1, ˜150 mL) to give 3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridine (1.16 g, 33.0%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH:13]([CH3:15])[CH3:14])[CH:6]=1)([CH3:4])[CH3:3].[CH2:16]=[O:17].[OH-].[K+].O>CCCCCC>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:8]([OH:12])=[C:9]([CH2:16][OH:17])[C:10]=1[CH3:11])([CH3:1])[CH3:3]
Reactant: C=O
Reactant: Cc1cc(O)c(C(C)C)cc1C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Product: Cc1c(C(C)(C)C)cc(C(C)C)c(O)c1CO
Temperature: 25 °C
Yield: 8.6 %

Procedure:
A mixture of 4-(1,1-dimethylethyl)-2-(1-methylethyl)-5-methylphenol (103.2 g, 0.5 mol), 40% formaldehyde solution (375 mL, 5 mol), potassium hydroxide (49.5 g, 0.75 mol) and poly(ethylene glycol) avg. M.W. 300 (1 g) was heated at reflux for 24 hour. The mixture was cooled to 25° C. and water (1 L) and hexane (700 mL) were added. The aqueous layer was extracted with hexane (2×100 mL). The combined organic extracts were washed with water (3×100 mL), brine (2×100 mL) and dried (Na2SO4). Evaporation of solvents and crystallization of the residue from hexane gave 10.2 g (8.6% yield) of 5-(1,1-dimethylethyl)-6-methyl-3-(1-methylethyl)-2-hydroxy benzenemethanol, mp 143°-146° C.; 1H-NMR (CDCl3)δ 1.25 (6H, d, J=7 Hz), 1.40 (9H, s), 2.31 (3H, s), 3.0-3.6 (1H, m), 4.85 (2H, s), 7.01 (1H, s), 7.23 (1H, s); IR (CHCl3)νmax 3550, 3350, 2940, 1575, 1470, 1360 cm-1 ; M m/e 236, 218, 206, 203, 191, 161, UVλmax (ethanol) 224 nm (ε=6690), 287 nm (ε=2480).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@H:17]([CH3:19])[NH:16][C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[Cl:51][C:52]1[S:56][C:55]([CH:57]=[CH:58][C:59](O)=[O:60])=[CH:54][CH:53]=1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@H:17]([CH3:19])[N:16]([C:59](=[O:60])[CH:58]=[CH:57][C:55]4[S:56][C:52]([Cl:51])=[CH:53][CH:54]=4)[C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(O)C=Cc1ccc(Cl)s1
Reactant: C[C@@H]1N[C@@H](C)CN(Cc2ccc3c(N)ncnc3c2)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1C(=O)C=Cc1ccc(Cl)s1
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of (3S,5S)-1-(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (42 mg, 0.147 mmol), major epimer from EXAMPLE 88, Part D, in 2 mL of DMF is added TBTU (52 mg, 0.162 mmol), triethylamine (0.02 mL, 0.162 mmol) and 3-(5-chloro-thiophen-2-yl)-acrylic acid (28 mg, 0.15 mmol), EXAMPLE 25. After stirring for two hours, the reaction mixture is directly purified by reverse phase HPLC (10-70% ACN/H2O). The product (35.5 mg, 36%) is isolated as a yellow solid with a melting point of 116-120° C. C22H22ClN5O2S: MS m/z: 456, 458. Anal. calcd. for C22H22ClN5O2S.C2HF3O2: C, 50.57; H, 4.07; N, 12.29. Found: C, 46.48; H, 3.64; N, 11.04.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: CCCCCCCCCCCCN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
In 1 ml of DMF, 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine was dissolved, and then 1.30 g (7.0 mmol) of dodecylamine was added dropwise thereto over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 745 mg (yield: 63.4%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5](I)=[CH:4][N:3]=1.[CH3:18][C:19]1[N:24]=[C:23]([S:25][CH3:26])[N:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[N:20]=1.[F-].[Cs+].O1CCOCC1>O.[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>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([C:21]2[N:20]=[C:19]([CH3:18])[N:24]=[C:23]([S:25][CH3:26])[N:22]=2)=[CH:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)nc(SC)n1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(Cl)ncc2-c2nc(C)nc(SC)n2)cn1
Temperature: 140 °C
Yield: 46.3 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (181 mg, 0.499 mmol), 2-methyl-4-(methylthio)-6-(tributylstannyl)-1,3,5-triazine (215 mg, 0.499 mmol), copper(I) iodide (19 mg, 0.100 mmol), cesium fluoride (250 mg, 0.998 mmol), tetrakis(triphenylphosphine)palladium(0) (57.7 mg, 0.050 mmol) and dioxane (3 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 30 min. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give 2-chloro-N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (87 mg, 0.231 mmol, 46.4% yield). 1H NMR (300 MHz, CDCl3) δ 11.82 (s, 1H); 9.48 (s, 1H); 8.37 (s, 1H); 8.08 (dd, J=9.28, 1.97 Hz, 1H); 6.83 (d, J=9.06 Hz, 1H); 3.96 (s, 3H); 2.67 (s, 3H); 2.64 (s, 3H). m/z (ESI, +ve ion) 376.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[Cl-].[Al+3].[Cl-].[Cl-]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH:9]=[CH2:10])=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)c1ccc(F)cc1

Procedure:
Fluorobenzene (0.5 mL), acryloyl chloride (0.23 g), and aluminium chloride (0.33 g) were treated in the same manner as described in Example 1 to obtain the title compound (90 mg).
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.Cl[Ti](Cl)(Cl)Cl.C1COCC1>[CH2:22]([NH:29][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=3)[CH:5]=[CH:4][C:3]1=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3=O)cc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3NCc2ccccc2)cc1
Reaction time: 72 h
Yield: 11.6 %

Procedure:
Combine 4-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-benzamide (Intermediate 26, 120.0 mg, 0.43 mmol), Benzylamine (70 uL, 0.64 mmol), THF (3 mL), and Ti(OiPr)4 (0.2 mL, 0.68 mmol) at 0° C. Stir the reaction for 12 hours allowing it to come to room temperature and then add TiCl4 (0.7 mL, 0.68 mmol) at 0° C. After reaction stirs for 3 hours, add BH3SMe2 at room temperature. After the reaction stirs for 72 hours, add 1N NaOH aq (6 mL) at room temperature. Upon addition, a precipitate forms. Allow the reaction to stir for an additions 12 hours, centrifuge, and decant off aqueous and organic layers. Separate the organic layer and concentrate. Add the organic mixture to a 2 g SCX column, wash with MeOH, and elute with 1N NH3 MeOH. Purify using reverse phase chromatography (5% to 95% 0.001% TFA buffer in acetonitrile/water) to afford 19.4 mg, 0.05 mmol (12% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.7-1.8 (2H, m), 1.9-2.1 (3H, m), 2.6-2.9 (2H, m), 3.8-4.0 (3H, m), 6.7-6.9 (2H, m), 6.9-7.0 (2H, m), 7.2-7.5 (6H, m), 7.7-7.9 (2H, m); MS m/z 284 (M of SM+3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]([OH:15])[CH2:13][OH:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:16][C:17]1[CH:18]=[CH:19][C:20](B2OC(C)(C)C(C)(C)O2)=[C:21]([CH:24]=1)[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.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.C1(C)C=CC=CC=1>[C:22]([C:21]1[CH:24]=[C:17]([CH3:16])[CH:18]=[CH:19][C:20]=1[C:2]1[CH:11]=[C:10]([CH:12]([OH:15])[CH2:13][OH:14])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1)#[N:23]
Reactant: COC(=O)c1cc(Br)cc(C(O)CO)c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C#N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(C)cc2C#N)cc(C(O)CO)c1

Procedure:
A mixture of methyl 3-bromo-5-(1,2-dihydroxyethyl)benzoate (100 mg, 0.36 mmol), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (130 mg, 0.54 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.035 mmol), potassium carbonate (75 mg, 0.54 mmol), N,N-dimethylformamide (0.5 mL), and toluene (1 mL) under nitrogen was subjected to microwave irradiation at 110° C. for 1 h. After cooling, the mixture was diluted with water (5 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash column to afford the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][Si:5]([CH3:15])([CH3:14])[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Br>C(N(CCCC)CCCC)CCC.O>[CH3:4][Si:5]([CH3:15])([CH3:14])[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][C:1]#[N:2]
Reactant: C[Si](C)(C)c1cccc(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: C[Si](C)(C)c1cccc(CC#N)c1
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of KCN (5.5 g, 84 mmol), m-trimethylsilylbenzylbromide (5.31 g, 21.8 mmol), tributylamine (0.11 g, 0.59 mmol) and water (12.5 cm3) was stirred overnight. The product was extracted with dichloromethane (3×30 cm3), the extract was filtered through a silica plug (5g) and the solvent was removed under reduced pressure. The residue was distilled to give the product (2.27 g, 55%) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: COc1ccccc1B(O)O
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: COc1ccccc1-c1ccc(Cn2ccnc2)cn1

Procedure:
Synthesized using 2-methoxyphenylboronic acid (190 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Yellow solid. Yield: 210 mg, 0.79 mmol, 94%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.85 (s, 3H), 5.17 (s, 2H), 6.95 (brs, 1H), 7.00 (dd, J=8.5, 0.6 Hz, 1H), 7.08 (dt, J=7.6, 1.1 Hz, 1H), 7.12 (s, 1H), 7.38 (ddd, J=8.5, 7.6, 1.9 Hz, 1H), 7.44 (dd, J=8.5, 2.2 Hz, 1H), 7.60 (s, 1H), 7.77 (dd, J=7.6, 1.9 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 8.60 (d, J=1.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.2, 55.6, 111.4, 119.1, 121.1, 125.2, 128.3, 129.5, 130.2, 130.3, 131.1, 134.6, 137.3, 148.2, 156.4, 157.0; MS (ESI): m/z=266.28 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[S:6][CH2:7][C:8]1[CH2:9][S:10][C@@H:11]2[CH:18]([NH:19][C:20](=[O:37])[C:21]([C:23]3[N:24]=[C:25]([NH:28][C:29]([O:31][C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:30])[S:26][CH:27]=3)=[O:22])[C:17](=[O:38])[N:12]2[C:13]=1[C:14]([OH:16])=[O:15].[OH-].[Na+].[BH4-].[Na+]>CO.O>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[S:6][CH2:7][C:8]1[CH2:9][S:10][C@@H:11]2[CH:18]([NH:19][C:20](=[O:37])[CH:21]([OH:22])[C:23]3[N:24]=[C:25]([NH:28][C:29]([O:31][C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:30])[S:26][CH:27]=3)[C:17](=[O:38])[N:12]2[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: CCC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C)(C)OC(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1

Procedure:
To a solution of 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (3.1 g.) in methanol (30 ml.) was added 1 N sodium hydroxide aqueous solution (5.2 ml.) under ice-cooling and stirring. To the mixture was dropwise added a solution of sodium borohydride (0.074 g.) in water (2 ml.) over 10 minutes, and the mixture was stirred for 30 minutes at the same temperature. After the reaction, the reaction mixture was concentrated under reduced pressure. To the residue were added water and ethyl acetate, and the aqueous layer was separated. The aqueous layer was adjusted to pH 5 to 6 with 10% hydrochloric acid and then washed with ethyl acetate. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and then treated with activated charcoal. After distillation of the solvent from the ethyl acetate layer, the remaining residue was pulverized in diethyl ether, collected by filtration and then dried to give pale yellow powder of 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (2.2 g.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:34][C:35]([C@@H:37]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:61]([O:63][CH2:64][Cl:65])=[O:62]>N1C=CC=CC=1.C(OCC)(=O)C>[C:61](=[O:62])([O:63][CH2:64][Cl:65])[O:47][C@H:18]([C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([N:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:19][C@@H:20]([NH:34][C:35](=[O:36])[C@H:37]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:42][C:43]([O:44][CH3:45])=[O:46])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCCl
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)OCCl)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a solution of the product from Example 111 (0.050 g, 0.062 mmol) in pyridine (0.60 mL) at room temperature was added chloromethyl chloroformate (0.007 mL, 0.079 mmol), and the mixture was stirred for 30 minutes. Additional chloromethyl chloroformate (0.007 mL) was added and the reaction was stirred for 30 minutes. The reaction was diluted with ethyl acetate and washed with dilute NaHCO3 and brine. The organic was dried over MgSO4, filtered and evaporated to give the title compound (0.047 g, 84% yield), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([O:11][CH2:12]/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:5](=[O:7])[C:4]1[C:8]([O:11][CH2:12]/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15])=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)[CH3:30]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(F)cc1C(=O)O
Product: CCN1CCCC1CNC(=O)c1cc(F)ccc1OC/C=C(\C)CCC=C(C)C
Yield: 84 %

Procedure:
In a manner identical to Example 15, 3-fluoro-6-geranyloxybenzoic acid (1.46 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.68 g (84%) of the aimed compound.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C@H:5]1[O:10][C@:9]2([O:15][C@@H:14]3[CH2:16][CH:17]=[C:18]([CH3:41])[C@@H:19]([OH:40])[C@@H:20]([CH3:39])[CH:21]=[CH:22][CH:23]=[C:24]4[CH2:25][O:26][C@@H:27]5[C@H:32]([OH:33])[C:31]([CH3:34])=[CH:30][C@@H:29]([C:35]([O:37][C@@H:12]([CH2:13]3)[CH2:11]2)=[O:36])[C@:28]45[OH:38])[CH:8]=[CH:7][C@@H:6]1[CH3:42])[CH3:4].CCC([C@H]1[O:52][C@]2(O[C@@H]3CC=C(C)[C@@H](O[C@@H]4O[C@@H](C)[C@H](O)[C@@H](OC)C4)[C@@H](C)C=CC=C4CO[C@@H]5[C@H](O)C(C)=C[C@@H](C(O[C@@H](C3)C2)=O)[C@]45O)C=C[C@@H]1C)C>>[CH3:1][CH2:2][CH:3]([C@H:5]1[O:10][C@:9]2([O:15][C@@H:14]3[CH2:16][CH:17]=[C:18]([CH3:41])[C@@H:19]([OH:40])[C@@H:20]([CH3:39])[CH:21]=[CH:22][CH:23]=[C:24]4[CH2:25][O:26][C@@H:27]5[C@H:32]([OH:33])[C:31]([CH3:34])=[CH:30][C@@H:29]([C:35]([O:37][C@@H:12]([CH2:13]3)[CH2:11]2)=[O:36])[C@:28]45[OH:38])[CH2:8][C@H:7]([OH:52])[C@@H:6]1[CH3:42])[CH3:4]
Reactant: CCC(C)[C@H]1O[C@]2(C=C[C@@H]1C)C[C@@H]1C[C@@H](CC=C(C)[C@@H](O)[C@@H](C)C=CC=C3CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Reactant: CCC(C)[C@H]1O[C@]2(C=C[C@@H]1C)C[C@@H]1C[C@@H](CC=C(C)[C@@H](O[C@H]3C[C@H](OC)[C@@H](O)[C@H](C)O3)[C@@H](C)C=CC=C3CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Agent: CCC(C)[C@H]1O[C@@]2(C[C@@H]3C[C@@H](C/C=C(\C)[C@@H](O)[C@@H](C)/C=C/C=C4\CO[C@@H]5[C@H](O)C(C)=C[C@@H](C(=O)O3)[C@]45O)O2)C[C@H](O)[C@@H]1C
Agent: CCC(C)[C@H]1O[C@]2(C=C[C@@H]1C)C[C@@H]1C[C@@H](C/C=C(\C)[C@@H](O)[C@@H](C)/C=C/C=C3\CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Agent: CCC(C)[C@H]1O[C@]2(C=C[C@@H]1C)C[C@@H]1C[C@@H](C/C=C(\C)[C@@H](O[C@H]3C[C@H](OC)[C@@H](O)[C@H](C)O3)[C@@H](C)/C=C/C=C3\CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Product: CCC(C)[C@H]1O[C@@]2(C[C@@H]3C[C@@H](CC=C(C)[C@@H](O)[C@@H](C)C=CC=C4CO[C@@H]5[C@H](O)C(C)=C[C@@H](C(=O)O3)[C@]45O)O2)C[C@H](O)[C@@H]1C

Procedure:
13β-14a-hydroxy, avermectin B1a aglycone→13β-14a-hydroxy, avermectin B1a monosaccharide