Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=2)[O:10][C:9]([C:20]2[N:25]=[CH:24][N:23]3[CH:26]=[CH:27][CH:28]=[C:22]3[CH:21]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:59][CH2:60][CH2:61][N:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>CN(C)C=O>[N:62]1([CH2:61][CH2:60][NH:59][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:20]2[N:25]=[CH:24][N:23]4[CH:26]=[CH:27][CH:28]=[C:22]4[CH:21]=2)=[CH:8][C:7]3=[N:6][O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:19])[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(C(=O)O)cc12
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(C(=O)NCCN3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
A suspension of 4-(tert-Butoxyimino)-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carboxylic acid methyl ester (example 115B) (170 mg, 0.43 mmol) in a mixture of tetrahydrofuran/methanol/water (2.0 ml/0.5 ml/0.5 ml) was treated with lithium hydroxide monohydrate (55 mg, 1.29 mmol) and heated at 60° C. for 2 hours. The solvents were removed and the residue was diluted with water, neutralized to pH 5-6 with a 1N solution of hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to dryness to give 4-(tert-Butoxyimino)-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carboxylic acid (135 mg, 84%) as a green solid. A solution of the previous carboxylic acid, (3-Dimethylamino-propyl)-ethyl-carbodiimide, hydrochloride (90 mg, 0.47 mmol), 1-Hydroxybenzotriazole hydrate (68 mg, 0.50 mmol) and triethylamine (250 μl, 1.80 mmol) in dimethylformamide (6.0 ml) was stirred at 0° C. for 1 hour then 4-(2-aminoethyl)-morpholine (52 μl, 0.40 mmol) was added. The mixture was stirred at room temperature for 18 hours. The volatiles were removed under vacuum and the residue taken into ethyl acetate, washed several times with a saturated solution of sodium hydrogenocarbonate, brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient ethyl acetate/methanol 0-8%) to yield the title compound as a yellow solid (137 mg, 78%).
Reaction SMILES: [C:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[N:13]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH:11]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([O:39]CC)=[O:38])[CH:32]=3)=[O:29])[C:10]2=[O:42])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.C(O)C.O.[OH-].[Li+]>O1CCCC1>[C:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[N:13]([C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[CH2:12][CH:11]([NH:27][C:28](=[O:29])[NH:30][C:31]3[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=3)[C:37]([OH:39])=[O:38])[C:10]2=[O:42])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3cccs3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc2c(c1)N(CC(=O)c1cccs1)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
1-[1-(2-Thenoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (0.67 g) was suspended in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (10 ml), aqueous lithiumhydroxide monohydrate (0.24 g) solution (10 ml) was added, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, weakly acidified with 1N hydrochloric acid, extracted with methylene chloride. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was suspended in a mixed solvent of methanol and ethyl acetate, crystals so precipitated were collected by filtration, to thereby obtain 0.48 g of the titled compound as white crystals (Yield: 78%).
Reaction SMILES: CC1C=CC(S[C:7]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=CC=1.CS[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.[CH3:30][OH:31]>>[CH3:30][O:31][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:25][CH:24]=1
Reactant: CSc1ccc(O)cc1
Reactant: CO
Reactant: Cc1ccc(Sc2cc(C(=O)O)ccc2C(=O)O)cc1
Product: COc1ccc(Oc2cc(C(=O)O)ccc2C(=O)O)cc1

Procedure:
2-(4-Methylthiophenoxy)terephthalic acid, m.p. 294°-296° from methanol, from 4-(methylthio)phenol.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15][C@@:16]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C@@H:20]1[CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=3[C@H:19]1[CH2:18][CH2:17]2.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.C1COCC1>[C:9]1([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1][C@H:24]2[CH2:23][CH2:22][C@H:21]3[C@H:20]4[C@H:19]([CH2:18][CH2:17][C@:16]23[CH3:15])[C:29]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=2[CH2:27][CH2:26]4)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NC(c3ccccc3)c3ccccc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A solution of aminodiphenylmethane (5.50 g) in methanol (100 ml) was stirred at room temperature. Added sequentially to this solution were glacial acetic acid (1.8 ml, 1.8 g), estrone methyl ether (8.52 g), sodium cyanoborohydride (2.3 g), and THF (80 ml). The mixture was stirred at room temperature for 8 days. Additional NaB(CN)H3 (1.5 g), amine (5.5 g), and acetic acid (1.8 g) were added after four days of the reaction time. Excess solvent was removed under reduced pressure and water (300 ml) was added to the solid residue. The mixture was made alkaline with 50% aqueous NaOH and was extracted with ether (3×). The extracts were dried (MgSO4), filtered, and concentrated, giving an oily residue. This crude product was chromatographed (500 g silica gel, 5% ethyl acetate-hexane, 350 ml fractions) on a gravity column. The desired product was eluted in fractions 4-7, and after recrystallization from methanol gave a first crop of crystals, mp 127° -129° C., and a second crop. A sample was recrystallized again from methanol and gave an analytical sample of the title compound, mp 127°-129° C. (PLA2, diabetes)
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([O:21][Si](C(C)C)(C(C)C)C(C)C)[CH:18]=[C:17]([CH3:32])[C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH:12]=1)[CH:10]=[O:11].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O.O>[OH:21][C:19]1[CH:18]=[C:17]([CH3:32])[C:3]([CH2:4][C:5]2[CH:6]=[CH:7][C:8]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH:12]=2)[CH:10]=[O:11])=[C:2]([CH3:1])[CH:20]=1
Reactant: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1ccc(Cc2c(C)cc(O)cc2C)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxymethoxy-benzaldehyde (1.4 g, 3.07 mmol) in THF (15 mL) was added TBAF (1 M, 3.68 mL) at 0° C. After stirring at r.t. for 2 h, the reaction mixture was diluted with EtOAc and water. The water layer was extracted with EtOAc and the combined organic extracts were dried (NgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate-hexanes; 1:9) to afford 5-(4-hydroxy-2,6-dimethylbenzyl)-2-methoxymethoxybenzaldehyde (590 mg, 64% for two steps): 1H NMR (200 MHz, CDCl3): δ 10.45 (s, 1H), 7.54 (s, 1H), 7.27 (m, 1H), 7.09 (m, 1H), 6.56 (s, 2H), 5.25 (s, 2H), 3.92 (s, 2H), 3.50 (s, 3H), 2.16 (s, 6H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:9); Rf=0.68.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:33])[C:25]1[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.Cl.CCOCC>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])=[O:33])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COc1ccccc1C(=O)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.7 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 mL). o-Anisoyl chloride (0.04 mL, 0.29 mmol) was added dropwise, and the reaction solution was stirred at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 24 (48 mg, 53% yield) as an off white solid. LC-MS (M+H=342, obsd.=342).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:15]=[C:16]([C:33](=[O:43])[C:34]([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)=[O:35])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:44]([O-:47])([O-])=O.[K+].[K+].CN([CH:53]=[O:54])C>>[CH2:1]([O:13][C:14]1[CH:15]=[C:16]([C:33](=[O:43])[C:34]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:54][CH2:53][C:8]3([CH3:9])[CH2:44][O:47][CH2:7]3)=[CH:40][CH:41]=2)=[O:35])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)C(=O)c2ccc(O)cc2)cc1OCCCCCCCCCCCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCCCCOc1ccc(C(=O)C(=O)c2ccc(OCCCCCCOCC3(C)COC3)cc2)cc1OCCCCCCCCCCCC
Temperature: 80 °C
Yield: 52 %

Procedure:
A mixture of JYC-I-146-A (1.46 g, 2.5 mmol), JYC-I-43-A (0.72 g, 2.7 mmol), and K2CO3 (0.68 g, 4.9 mmol) in 30 mL of DMF was refluxed at 80° C. overnight and then heated at 150° C. for additional 3 h. The reaction mixture was quenched with a saturated NH4Cl aqueous solution and extracted with CH2Cl2. The organic phase was washed with H2O and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give brown oil. The crude product was purified by column chromatography (silica gel, hexanes:ethyl acetate=6:1 (v/v)) to give a yellow solid (0.99 g, 52%). 1H NMR (300 MHz, CDCl3, δ): 7.89 (d, J=8.8 Hz, 2H), 7.54 (d, J=2.0 Hz, 1H), 7.41 (dd, J=8.3 Hz, 2.0 Hz, 1H), 6.91 (d, J=9.3 Hz, 2H), 6.82 (d, J=8.8 Hz, 1H), 4.47 (d, J=5.9 Hz, 2H), 4.32 (d, J=5.9 Hz, 2H), 3.98-4.05 (m, 6H), 3.443 (t, J=6.3 Hz, 2H), 3.437 (s, 2H), 1.80 (m, 6H), 1.59 (m, 2H), 1.27 (s, 3H), 1.20-1.50 (m, 40H), 0.85 (t, J=6.6 Hz, 6H). 13C {1H} NMR (75 MHz, CDCl3, δ): 193.73, 193.45, 164.35, 154.99, 149.30, 132.28, 126.19, 126.08, 126.03, 114.61, 112.31, 111.60, 80.13, 76.04, 71.36, 69.20, 69.07, 68.26, 39.88, 31.86, 29.65, 29.61, 29.57, 29.54, 29.41, 29.30, 29.03, 28.93, 28.88, 25.94, 25.87, 25.74, 22.63, 21.32, 14.05. HRMS-FAB (m/z): [M]+ calcd for C49H7O7, 778.5748; found, 778.5740. Anal. Calcd for C49H78O7: C, 75.54; H, 10.09. Found: C, 75.44; H, 10.20.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10](Cl)=[CH:9][C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)=[O:4].[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([F:27])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>ClC1C=CC=CC=1Cl.CCOC(C)=O>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:10]2[C:5]([C:3]([OH:2])=[O:4])=[N:6][N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[CH:9]=2)=[C:22]([F:27])[CH:21]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COC(=O)c1nn(-c2ccccc2)c(=O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Clc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1nn(-c2ccccc2)c(=O)cc1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a mixture of 4-chloro-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methyl ester (0.250 g, 0.944 mmol) in 1,2-dichlorobenzene (3.8 mL) was added 4-bromo-2-fluoro aniline (0.561 g, 3.78 mmol), and cesium carbonate (0.615 mg, 1.89 mmol). The reaction mixture was heated to reflux. After 1 hour, the reaction mixture was cooled to room temperature. Water was added and the mixture was diluted with EtOAc. The aqueous layer was separated, acidified with 10% HCl solution, and extracted with EtOAc. The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and triturated to give 0.153 g (43%) of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.O.[NH2:15][NH2:16]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10](=[N:15][NH2:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1CCN(c2ccncc2)CC1
Solvent: CCO
Solvent: O
Product: NN=C1CCN(c2ccncc2)CC1

Procedure:
A solution of 1-(4-pyridyl)-4-piperidone (3.52 g) and hydrazine hydrate (1.25 q) in ethanol (50 ml) was stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue obtained was crystallized from ether to obtain [1-(4-pyridyl)-4-piperidinylidene]hydrazine (3.51 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([N:22]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17](=[O:21])[CH2:18][C:19]#[N:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([Mg]Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[NH2:20][C:19]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[CH:18][C:17](=[O:21])[C@@H:16]([N:22]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#CCC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: Br[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: NC(=CC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 23B (19.0 g, 40.1 mmol) in THF (48 mL) was treated dropwise with a solution of benzyl magnesium bromide (120 mL, 1 M in ether) at 0° C. The mixture was allowed to warm to 25° C. and was stirred for 16 hours. The reaction was cooled to 0° C. and quenched with 10% citric acid, followed by partitioning between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the crude product (23.2 g), which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([NH2:9])=[N:7][O:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[NH:30][C:29]([C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:28][CH:27]=3)=[CH:22][CH:21]=2)O1.C([O-])(O)=O.[Na+].O.CCOC(C)=O>COCCOC.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>[NH2:9][C:6]1[C:5]2[CH:10]=[CH:11][C:2]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[NH:30][C:29]([C@@H:31]5[CH2:35][CH2:34][CH2:33][N:32]5[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:28][CH:27]=4)=[CH:24][CH:25]=3)=[CH:3][C:4]=2[O:8][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: Nc1noc2cc(Br)ccc12
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(N)noc4c3)cc2)[nH]1
Temperature: 70 °C
Reaction time: 12 h
Yield: 26.8 %

Procedure:
A mixture of 6-bromobenzo[d]isoxazol-3-amine (1.78 g, 8.36 mmol), (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (3.95 g, 8.99 mmol), Pd(Ph3P)4 (0.42 g, 0.364 mmol) and NaHCO3 (1.93 g, 23.0 mmol) was suspended in DME (60 mL) and H2O (20 mL) and the solution was degassed by evacuating and back-filling with N2 (repeated 5 times). The mixture was then heated at 70° C. overnight. LCMS indicated the reaction to be incomplete. A further portion of Pd(Ph3P)4 (0.10 g, 0.087 mmol) was added and heating continued for a further 12 h. The cooled reaction mixture was poured into H2O/EtOAc and the layers separated. The aq layer was extracted with EtOAc (×2) and the combined org layers were washed (H2O, brine), then dried (Na2SO4) and concentrated. The residue was purified by BIOTAGE® (TLC 5:4.5:0.5 hexane:EtOAc:MeOH) solvent A was 1:1 hex:EtOAc and solvent B was 20% MeOH in EtOAc to afford a red-orange foam (1.0 g). This material was purified by prep HPLC (CH3CN—H2O—NH4OAc) giving a light yellow foam (404.4 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ 11.85-12.21 (m, 1H), 7.85 (app t, J=8.0, 8.6, 2H), 7.72-7.73 (m, 4H), 7.54-7.60 (m, 2H), 6.41 (s, 2H), 4.76-4.83 (m, 1H), 3.54 (s, br, 1H), 3.31-3.37 (m, 1H, partially obscured by H2O), 2.14-2.25 (m, 1H), 1.79-2.04 (m, 3H), 1.40, 1.15 (s, 9H, rotamers). LCMS: Anal, Calcd. for C25H27N5O3: 445; found: 446 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[O:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:45][CH2:46][C:47]1[C:48]([OH:55])=[N:49][C:50]([CH3:54])=[CH:51][C:52]=1[CH3:53]>ClCCl>[OH:55][C:48]1[C:47]([CH2:46][NH:45][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[CH:2]([CH3:1])[CH2:3][O:4][C:5]=3[CH:10]=2)=[O:13])=[C:52]([CH3:53])[CH:51]=[C:50]([CH3:54])[N:49]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC1COc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc3c(c2)OCC3C)c(O)n1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of 3-methyl-2,3-dihydrobenzofuran-6-carboxylic acid (100 mg, 0.56 mmol) in dichloromethane (50 mL) was added 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.5 mmol), triethylamine (32 mg, 0.7 mmol), stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.4 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL), dried over sodium sulphate, concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give the product N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-3-methyl-2,3-dihydrobenzofuran-6-carboxamide (75 mg, 43%) as white solid. LRMS (M+H+) m/z: calcd 367.23. found 367. HPLC Purity (214 nm): 97%. 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 2H), 7.12-7.11 (m, 1H), 6.10 (s, 1H), 4.72-4.66 (m, 1H), 4.46 (s, 2H), 4.11-4.05 (m, 1H), 3.56-3.53 (m, 1H), 2.35 (s, 3H), 2.24 (s, 3H), 1.31 (d, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:5]1[CH2:21][OH:22].Cl[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C>[CH3:3][N:4]1[C:8]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:5]1[CH2:21][O:22][CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: Cn1c(CO)nc(-c2ccccc2)c1-c1ccncc1
Reactant: CCOP(=O)(CCl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: CCOP(=O)(COCc1nc(-c2ccccc2)c(-c2ccncc2)n1C)OCC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 80% NaH in mineral oil (0.013 g, 0.452 mmol) in DMF at 0° C. was added 1-methyl-2-hydroxymethyl-4-phenyl-5-[4-pyridinyl]imidazole (0.100 g, 0.377 mmol) in DMF. The resulting bright yellow solution was stirred at 0° C. for 0.5 h when diethyl chloromethylphosphonate (0.070 mL, 0.452 mmol) dissolved in 0.079 mL of HMPA was added. The resulting mixture was stirred at 0° C. for 15 min and then warmed to rt. After 5 h, the solution was partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 50:1 CH2Cl2/MeOH. The title compound was obtained as a light amber oil (0.088 g, 56%): ESMS (mnz): 416 (M++H).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:9]=2)=[CH:6][C:5]([CH:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH3:35])=[CH:4][N:3]=1.[S:42]1[C:46]2[CH:47]=[CH:48][C:49]([NH2:51])=[CH:50][C:45]=2[N:44]=[CH:43]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C1COCC1>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:51][C:49]3[CH:48]=[CH:47][C:46]4[S:42][CH:43]=[N:44][C:45]=4[CH:50]=3)=[N:3][CH:4]=[C:5]([CH:34]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[CH3:35])[CH:6]=2)[N:9]=1
Reactant: Nc1ccc2scnc2c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCOCC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2ccc3scnc3c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.1 %

Procedure:
A mixture of 4-(2-fluoro-5-(1-morpholinoethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.300 g, 0.537 mmol) and benzo[d]thiazol-5-amine (0.202 g, 1.343 mmol) in THF (10 mL) was chilled to 0° C. in an ice bath. Then sodium bis(trimethylsilyl)amide (1.0 M solution in THF, Aldrich; 2.148 mL, 2.148 mmol) was added into the mixture via syringe. After the addition, the ice bath was removed and the mixture was allowed to stir under an inert atmosphere for 1 h. The reaction mixture was diluted with water (30 mL) and the organic layer was extracted with chloroform (3×20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. This gave the crude bis-PMB protected product as a tan oil. This crude material was treated with trifluoroacetic acid (1.8 mL) and trifluoromethanesulfonic acid (0.2 mL). The reaction mixture was placed into a pre-heated bath (70° C.) and allowed to stir under inert atmosphere for 10 min. The mixture was removed from the heat source and allowed to cool to ambient temperature. The mixture was concentrated in vacuo. The crude residue was diluted with DCM (10 mL), and then sodium carbonate (1.5 g) was added to the mixture with stirring. The mixture was filtered and concentrated in vacuo. The crude was purified by reverse phase HPLC (Varian, 5-70% acetonitrile in water with trifluoroacetic acid as additive 0.1% v/v in each solvent) to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(1-morpholinoethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.015 g, 0.033 mmol, 6.23% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ 12.24 (s, 1H) 9.36 (s, 1H) 8.92 (s, 1H) 8.75 (s, 1H) 8.36 (s, 1H) 8.06 (d, J=8.61 Hz, 1H) 7.92 (s, 1H) 7.82 (d, J=8.61 Hz, 2H) 3.57 (s, 4H) 3.29-3.46 (m, 1H) 2.50 (d, J=7.82 Hz, 5H) 2.34 (s, 2H) 1.36 (d, J=6.46 Hz, 3H). m/z (ESI, +ve ion) 449.1 (M+H)+.