Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[C:28]([C:34]2([C:51]([F:54])([F:53])[F:52])[O:38][N:37]=[C:36]([C:39]3[N:40]4[C:44]([C:45]([C:48](O)=[O:49])=[CH:46][CH:47]=3)=[CH:43][CH:42]=[CH:41]4)[CH2:35]2)[CH:29]=[C:30]([Cl:33])[C:31]=1[F:32].Cl.[NH2:56][CH2:57][C:58]1[CH:69]=[CH:68][C:61]2[B:62]([OH:67])[O:63][C:64]([CH3:66])([CH3:65])[C:60]=2[CH:59]=1.Cl>CC#N>[Cl:33][C:30]1[CH:29]=[C:28]([C:34]2([C:51]([F:53])([F:54])[F:52])[O:38][N:37]=[C:36]([C:39]3[N:40]4[C:44]([C:45]([C:48]([NH:56][CH2:57][C:58]5[CH:69]=[CH:68][C:61]6[B:62]([OH:67])[O:63][C:64]([CH3:66])([CH3:65])[C:60]=6[CH:59]=5)=[O:49])=[CH:46][CH:47]=3)=[CH:43][CH:42]=[CH:41]4)[CH2:35]2)[CH:27]=[C:26]([Cl:25])[C:31]=1[F:32]
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CC1(C)OB(O)c2ccc(CN)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CC1(C)OB(O)c2ccc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(F)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)cc21
Reaction time: 0.08 h

Procedure:
HATU (350 mg, 0.92 mmol) can be added to CH3CN (5 mL) at 0° C. After stirring for 5 min, the mixture can be added to a solution of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.46 mmol), 5-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (157 mg, 0.69 mmol), and TEA (186 mg, 1.83 mmol) in CH3CN (8 mL). Then the solution can be stirred at rt for 2 h. The solution can be acidified with HCl (1 N) and extracted with EA. The combined organic layers can be washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue can be purified by prep-TLC to give the final title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[CH2:31][CH2:32][CH2:33][OH:34])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:35][O:36][CH2:37]OC>C[Si](I)(C)C.O>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=5)=[CH:18]4)=[CH:13][C:12]=3[CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COCOC
Reactant: COC(=O)c1ccc(-c2ccc3cc(CCCO)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Agent: C[Si](C)(C)I
Solvent: O
Product: COCOCCCc1cc2ccc(-c3ccc(C(=O)OC)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
541 mg (1.2 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxypropyl-2-naphthyl]benzoate and 5 ml of dimethoxymethane were introduced into a round-bottomed flask and 5 drops of trimethylsilyl iodide were added. The reaction mixture was stirred at room temperature for 24 hours, was poured into water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: O[Li].O.[Br:4][C:5]1[O:6][C:7]([C:14]([O:16]CC)=[O:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1.Cl>C1COCC1.O.CCOC(C)=O.O>[Br:4][C:5]1[O:6][C:7]([C:14]([OH:16])=[O:15])=[C:8]([C:10]([F:12])([F:11])[F:13])[N:9]=1
Reactant: CCOC(=O)c1oc(Br)nc1C(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1oc(Br)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
LiOH.H2O (0.64 g, 15.25 mmol) was added to a solution of ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate (A-2) (3.50 g, 12.2 mmol) in THF/H2O (20/5 mL) at 0° C. followed by stirring for 3 h at 0° C. The reaction mixture was diluted with EtOAc/H2O (25/25 mL) and neutralized with 1 M HCl (16 mL) at 0° C. The organic phase was separated, dried over MgSO4, filtered, and concentrated. The product was dried in vacuo to yield 2-bromo-4-trifluoromethyloxazole-5-carboxylic acid (A-38) as a white solid (2.80 g, 88% yield).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>>[CH2:15]([N:17]([CH2:18][CH3:19])[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1)[CH3:16]
Reactant: Clc1nc2ccnn2c2ncccc12
Reactant: CCNCC
Product: CCN(CC)c1nc2ccnn2c2ncccc12

Procedure:
2.04 g. of 5-chloropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine of Example 1c are added to 20 ml. of diethylamine. The solution is refluxed for 5 hours. The excess diethylamine is distilled off and the residue is treated with 5 ml. water and extracted three times with 10 ml. portions of ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered and evaporated to dryness. The residual N,N-diethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5-amine is recrystallized from ethyl acetate/petroleum ether, yield: 2 g. (83%); m.p. 102°.
Reaction SMILES: [ClH:1].C([NH:10][CH:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])(=O)C1C=CC=CC=1.C(O)C>O>[ClH:1].[NH2:10][CH:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]([OH:17])[C:13]([F:14])([F:15])[F:16]
Reactant: O=C(NC(Cc1ccccc1)C(O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC(Cc1ccccc1)C(O)C(F)(F)F

Procedure:
12 N Hydrochloric acid is added to a suspension of (2RS, 3RS)-3-benzoylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane (3.00 g, Reference compound No. 31-1), ethanol (60 ml) and water (60 ml), and the mixture is refluxed for one day. After standing, the reaction mixture is concentrated under reduced pressure, diethyl ether is added to the resulting residue, and the whole is extracted with water. The extract is concentrated under reduced pressure to give the titled reference compound (1.58 g).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([CH:21]=[C:22]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:23]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.CO.O>[C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([CH:21]=[C:22]([N:24]2[CH:29]=[C:28]([F:35])[C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:23]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: F[B-](F)(F)F
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Solvent: CO
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-n2cc(F)c(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 90 °C
Yield: 29 %

Procedure:
The fluorination procedure was performed as described in Lal, G S, et al. J. Org Chem., 60:7340-7342 (1995). The product from Example 13A, Part B (0.42 g, 1.26 mmol) and Selectfluor™ (0.672 g, 1.9 mmol) were combined in a mixture of acetonitrile (8 mL) and methanol (1 mL) and heated at 90° C. under N2 for 5 h. The solution was diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, concentrated and purified by column chromatography on silica gel to give the title compound (0.138 g, 29%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][O:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:5]23)[CH:10]=1.Br[C:27]1[C:28]([O:34][CH3:35])=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.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].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:35][O:34][C:28]1[C:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][O:12][CH2:13][CH2:14][N:7]4[C@H:6]4[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:5]34)[CH:10]=2)=[CH:32][C:31]([CH3:33])=[CH:30][N:29]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: COc1ncc(C)cc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ncc(C)cc1Nc1cc2c3c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N3CCOC2
Temperature: 50 °C
Yield: 89 %

Procedure:
A solution of tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4] oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)Carboxylate from Example 56, Part B (968 mg, 2.81 mmol), 3-bromo-2-methoxy-5-methylpyridine (515 mg, 2.55 mmol), and NaOt-Bu (404 mg, 4.20 mmol) in anhydrous toluene (40 mL) was stirred under an argon atmosphere in a sealable test tube. The mixture was degassed with argon at 85° C. for 30 min then cooled to 50° C. Tris(dibenzylideneacetone)dipalladium(0) (62 mg, 67 μmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (84.0 mg, 135 μmol) were added; the reaction was sealed and heated at 85° C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc, filtered through a bilayer pad of diatomaceous earth and silica gel, and concentrated. Purification of the residue by flash column chromatography (silica gel, 10-50% EtOAc/hexanes) provided tert-butyl (7bR,11aS)-6-(2-methoxy-5-methyl-3-pyridinyl)amino-1,2,7b, 10,11,11 a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate (1.16 g, 89%). A solution of the intermediate in CH2Cl2 (20 mL) at −10° C. was treated with TFA (6 mL) and stirred for 1 h. Upon concentration in vacuo, the residue was partitioned between a 1:1 solution of CH2Cl2/satd NaHCO3 (100 mL). The aqueous phase was extracted with CH2Cl2 (4×75 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography [silica gel, 5-50% (80:18:2 CHCl3/MeOH/concd NH4OH)/CH2Cl2]and trituration with CH2Cl2/Et2O/hexanes provided the title compound of Example 172 (590 mg, 65%) as a tan solid: mp 122-124° C.; 1H NMR (300 MHz, CDCl3) δ 7.40 (s, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.77 (s, 1H), 5.84 (br s, 1H), 4.75 (d, J=14.1 Hz, 1H), 4.58 (d, J=14.1 Hz, 1H), 4.3414.16 (m, 1H), 4.01 (s, 3H), 3.89-3.69 (m, 1H), 3.58-3.39 (m, 1H), 3.38-3.13 (m, 2H), 3.11-2.99 (m, 1H), 2.98-2.85 (m, 2H), 2.81-2.68 (m, 1H), 2.61-2.42 (m, 1H), 2.19 (s, 3H), 2.01-1.77 (m, 3H); ESI MS m/z 367 [C21H26N4O2+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(C)CNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)CN(c1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a mixture of 1.70 g (0.0082 mole) of (rac)-2-methyl-3-phenylamino-propanoic acid ethyl ester, 1.7 g (0.0088 mole) of 2,4-dichloro-5-nitro-pyrimidine and 60 mL of ethyl acetate, was added 4.24 mL (0.0246 mole) of N,N-diisopropylethylamine. The mixture was stirred at room temperature for 2 hours, and then washed with successively with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (80:20) to give 2.99 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-phenyl-amino]-2-methyl-propanoic acid ethyl ester (IV-51) as yellow oil.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])[CH:2]=1.NC1[S:15][C:16]2C=C[CH:20]=[CH:19][C:17]=2N=1>C(#N)C>[S:15]1[C:16]2[CH:17]=[CH:19][CH:20]=[CH:9][C:10]=2[N:11]=[C:12]1[NH:8][C:6]([N:3]1[CH:2]=[CH:1][N:5]=[CH:4]1)=[O:7]
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C(Nc1nc2ccccc2s1)n1ccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
To CDI (1.6 g, 10 mmol) in acetonitrile (30 mL) was slowly added 2-aminobenzothiazole (1.0 g, 6.6 mmol) and allowed to stir at rt for 48 hours. The reaction mixture was filtered, washed with acetonitrile, and dried to provide 1.44 g (88%) of the desired product N-(benzo[d]thiazol-2-yl)-1-imidazole-1-carboxamide (1M): LC/MS (APCI): m/z 245.1 (M+H).
Reaction SMILES: [Cl:1]Cl.[CH:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1>>[Cl:1][C:10]1[C:9]2[C:8](=[O:18])[C:7]3[C:16](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15](=[O:17])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: ClCl
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Yield: 99 %

Procedure:
1,400 g of a 93% pure 1-chloroanthraquinone, produced from anthraquinone-1-sulphonic acid by exchanging the sulpho group by chlorine according to Fischer (Ullmann's Encyklopaedie der technischen Chemie (Ullmann's Encyclopaedia of Industrial Chemistry), 4th Edition, Volume 7, Example 1, page 589 (1973)) and contaminated with 0.5% of anthraquinone, 2.0% of 1,6- and 1,7-dichloroanthraquinone, 2.5% of 1,5- and 1,8-dichloroanthraquinone and 2.0% of other compounds, are employed in the flask of the test installation (according to Example 1). At an absolute pressure at the top of 20 mm Hg and a reflux ratio R/T= 4/1, highly pure 1-chloroanthraquinone (>99% pure) is obtained:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][P:5]([C:17]([C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=1[CH3:27])=[O:18])[C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[CH3:16])=[O:7].OO.C([O:32]CC)C>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][P:5]([C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[CH3:16])=[O:7])([C:17]([C:19]1[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25])=[O:18])=[O:32]
Reactant: CCOCC
Reactant: Cc1cc(C)c(C(=O)P(CCCBr)C(=O)c2c(C)cc(C)cc2C)c(C)c1
Agent: OO
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(=O)P(=O)(CCCBr)C(=O)c2c(C)cc(C)cc2C)c(C)c1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
((3-bromopropyl)phosphinediyl)bis(mesitylmethanone) of example 4 (1.16 g, 2.59 mmol, 1 eq.) was dissolved in toluene (5 mL) and hydrogen peroxide (10%) (8.88 mL, 2.59 mmol, 1 eq.) was added. The reaction mixture was stirred at 40° C. for 12 hours. Afterwards diethylether (50 mL) were added and the solution was washed with twice sodium hydrogencarbonate (2%) solution, once with brine and finally dried with magnesium sulfate. After removing the solvent in vacuo at room temperature, the pure product was obtained as a yellow oil (Yield: 0.97 g, 2.10 mmol).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)=[C:12]([O:22][CH3:23])[CH:11]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>CN(C)C=O>[CH3:23][O:22][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[C:16]1[NH:20][C:19](=[O:21])[O:18][N:17]=1)[O:9][CH2:8][C:7]1[S:6][C:5]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)=[N:4][C:3]=1[CH2:2][O:1][S:42]([CH3:41])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)ccc1-c1noc(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COS(C)(=O)=O)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 400 mg of 3-{4-[4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one in 8 mL of dimethylformamide was added 0.42 mL of triethylamine followed by dropwise addition of 0.1 mL of methanesulfonyl chloride. The resulting mixture was stirred at room temperature for 45 minutes then concentrated under reduced pressure to give 830 mg of crude methanesulfonic acid 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester which was used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]3[N:16](COCC[Si](C)(C)C)[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH2:26][C:27]5[S:28][CH:29]=[CH:30][CH:31]=5)[CH:20]=4)[C:13]3=[CH:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]3[NH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH2:26][C:27]5[S:28][CH:29]=[CH:30][CH:31]=5)[CH:20]=4)[C:13]3=[CH:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3cccs3)c2)c2cnc(NCCN3CCOCC3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(NCc2cccs2)cc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)c1
Reaction time: 3 h

Procedure:
To a stirred solution of (2-morpholin-4-yl-ethyl)-[3-{3-[(thiophen-2-ylmethyl)-amino]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-amine (170 mg, 0.3 mmol) in dichloromethane (10 mL) was added TFA (10 mL) at room temperature. The resulting mixture was stirred for another three hours at this temperature. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc (10 mL). The organic phase was washed with saturated aqueous NaHCO3 (3 mL), brine (5 mL) and dried over anhydrous Na2SO4, filtered and concentrated. It was purified by prep-HPLC to give (2-morpholin-4-yl-ethyl)-(3-{3-[(thiophen-2-ylmethyl)-amino]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-amine as yellow solid. (Yield 20 mg, 11.7%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH2:13](O)[CH3:14]>S(=O)(=O)(O)O.C(OCC)(=O)C>[OH:1][C:2]1[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cnc(C(=O)O)c(O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc(OC)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
3-hydroxy-5-methoxypicolinic acid (200 mg, 1.18 mmol) was dissolved in ethanol (10 mL). To the mixture was added one drop of sulfuric acid. The mixture was refluxed with stirring for 3 days. After cooling to room temperature, the mixture was concentrated in vacuo to afford an oil. The residual oil was dissolved in ethyl acetate and washed with aq. sodium bicarbonate and brine. The extract was dried over sodium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:3 to 1:1) to afford 178 mg (76%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([CH3:8])=[O:7])[CH3:2].OS(O)(=O)=O.[CH2:15](OC(OCC)OCC)[CH3:16]>C(O)C>[CH2:1]([O:3][C:4](=[O:9])[CH:5]=[C:6]([O:7][CH2:15][CH3:16])[CH3:8])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)C=C(C)OCC
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To a solution of ethylacetoacetate (2.7 kg, 20.74 mol) in ethanol (4 L) was added conc. H2SO4 (4 ml) at 25° C. under a nitrogen atmosphere. The mixture was heated to 50° C. before adding triethylorthoformate (3073.6 g, 20.74 mol) drop wise. The mixture was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure to give the title compound (2.8 kg, 85%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 4.9 (s, 1H), 4.1 (m, 2H), 3.7 (m, 2H), 2.2 (s, 3H), 1.2 (m, 3H), 1.1 (m, 3H).
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][N:9]=1)(=O)C>>[OH:6][CH2:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][N:9]=1
Reactant: COc1ccnc(COC(C)=O)c1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccnc(CO)c1OC
Reaction time: 2 h
Yield: 93.6 %

Procedure:
After adding 15 ml of 2N sodium hydroxide solution, 4.8 g of 2-acetoxymethyl-3,4-dimethoxypyridine are stirred vigorously at 80° C., whereupon a homogeneous solution forms from the initial two-phase mixture. After 2 hours, the solution is allowed to cool and is extracted five times with 30 ml of methylene chloride each time, the combined organic phases are washed twice with 5 ml of 0.3N sodium hydroxide solution each time, dried over potassium carbonate, filtered and concentrated and the distillation residue is stirred with petroleum ether. 3.6 g (96% of theory) of 2-hydroxymethyl-3,4-dimethoxy-pyridine are obtained as a colorless solid of m.p. 87°-89° C.
Reaction SMILES: [C:1]([O:24][CH3:25])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[O:26]1[CH2:31][CH2:30][N:29]([CH2:32]CO)[CH2:28][CH2:27]1>C[O-].[Na+].C1(C)C=CC=CC=1>[C:1]([O:24][CH2:25][CH2:32][N:29]1[CH2:30][CH2:31][O:26][CH2:27][CH2:28]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)OC
Reactant: OCCN1CCOCC1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCCN1CCOCC1
Yield: 90.9 %

Procedure:
A mixture of 35.5 g of methyl behenate (18), 19.7 g of 2-morpholinoethanol (17), 270 mg of sodium methoxide and 150 g of toluene was heated under reflux for 6 hours while distilling off the methanol resulting from the reaction. The reaction solution was cooled. By standard aqueous work-up and distilling off toluene, 41.3 g of (2-morpholinoethyl) behenate (Quencher 2) was obtained (yield 91%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([C:23]#[N:24])[O:21][CH:22]=1>>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([C:23]#[N:24])[O:21][CH:22]=3)=[CH:8][C:7]1=2
Reactant: N#Cc1cc(Br)co1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3coc(C#N)c3)cc21

Procedure:
Prepared from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 4-bromo-2-furancarbonitrile according to Procedure B. Off-white solid: mp 255-256° C. 1H-NMR (DMSO-d6) δ10.32 (s, 1H, D2O exchangeable), 8.57 (s, 1H), 8.15 (s, 1H), 7.61 (s, 1H), 7.55 (dd, 1H, J=8.3, 1.5 Hz), 6.92 (d, 1H, J=8.2 Hz), 1.65 (s, 6H); MS (ESI) m/z 269(M+H, 72%). Anal. Calc. For C15H12N2O3: C, 67.16; H, 4.51; N, 10.44. Found: C, 67.14; H, 4.59; N, 10.07.