Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCCCCCCCN1.[C:23]1([CH2:33][NH:34][C:35]2[N:43]=[C:42]([C:44]#[N:45])[N:41]=[C:40]3[C:36]=2[N:37]=[CH:38][NH:39]3)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[C:46]([O:54][C@H:55]1[C@@H:59]([O:60][C:61](=[O:68])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C@@H:58](OC(=O)C)[O:57][C@@H:56]1[C:73]([NH:75][CH2:76][CH3:77])=[O:74])(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(O[C@H]1[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C)O[C@@H]1C(NCC)=O)(=O)C1C=CC=CC=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C.C(OCC)(=O)C>[C:61]([O:60][C@@H:59]1[C@H:55]([O:54][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:56]([C:73]([NH:75][CH2:76][CH3:77])=[O:74])[O:57][C@H:58]1[N:39]1[CH:38]=[N:37][C:36]2[C:40]1=[N:41][C:42]([C:44]#[N:45])=[N:43][C:35]=2[NH:34][CH2:33][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: N#Cc1nc(NCc2cccc3ccccc23)c2nc[nH]c2n1
Reactant: CCNC(=O)[C@H]1O[C@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: CCNC(=O)[C@H]1O[C@@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Diazabicycloundecane (0.18 ml, 1.2 mmol) was added to a solution of (6-[(1-naphthylmethyl)amino]-9H-purine-2-carbonitrile (200 mg, 0.67 mmol) (Preparation 10) and (2S,3S,4R,5R)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate and (2S,3S,4R,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (309 mg, 0.70 mmol) (Preparation 18) in acetonitrile (5 ml). Trimethylsilyl trifluoromethanesulfonate (0.24 ml, 1.33 mmol) was added and the reaction mixture heated under reflux for 30 minutes. The reaction mixture was then allowed to cool to room temperature, diluted with ethyl acetate (20 ml) and washed twice with water (20 ml). The ethyl acetate layer was then washed with 10% w/w aqueous citric acid and saturated aqueous sodium chloride solution (20 ml). The organic phase was dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane increasing in polarity to dichloromethane:methanol (98:2 by volume). The solvent was removed under reduced pressure to give the title compound (235 mg) as a foam.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH3:46][C:47]1[CH:48]=[C:49]([CH:94]=[CH:95][CH:96]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([CH:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[CH3:46][C:47]1[CH:48]=[C:49]([CH:94]=[CH:95][CH:96]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([CH:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:81])[CH3:82])=[O:78])[CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)cn2)c1
Yield: 85.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (164 mg, 0.233 mmol) was hydrolyzed by lithium hydroxide (98 mg, 2.33 mmol) in THF/methanol/water (16/4/4 ml) to yield crude 109 mg (86% yield) of the titled compound after column purification using 1.5% methanol in DCM as eluent. MS: m/z=548.4 (M+1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[C:16]([OH:19])(=[O:18])[CH3:17]>O>[O:13]=[C:11](/[CH:10]=[CH:9]/[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=1)/[CH:12]=[CH:17]/[C:16]([OH:19])=[O:18]
Reactant: CC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)O
Solvent: O
Product: O=C(O)/C=C/C(=O)/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 12 g (56 mmol) of (E)-4-(4-trifluoromethylphenyl)but-3-en-2-one and 5.15 g (56 mmol) of glyoxlic acid monohydrate in 14 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from ether/hexane yielded (E,E)-4-oxo-6-(4-trifluoromethylphenyl)-2,5-hexadienoic acid of melting point 192°-195°.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH:12]([OH:15])([CH3:14])[CH3:13]>>[CH:12]([O:15][C:4]([C:3]1[C:2]([C:1]([OH:6])=[O:11])=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([CH3:14])[CH3:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)O
Product: CC(C)OC(=O)c1ccccc1C(=O)O

Procedure:
To a suitable reaction vessel there is charged phthalic anhydride and a 2.0X molar excess of isopropyl alcohol. The charge is heated to reflux temperature for about one hour. At the end of this time period an aliquot of the reaction mixture shows an absence of anhydride by infra-red analysis. The solvent is removed under vacuum and the residue recrystallized from toluene to obtain 1,2-benzene dicarboxylic acid mono-isopropyl ester (M.P. 73°-77° C.).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].N1C=CC=CC=1.[NH2:11][C:12]1[C:17]([NH2:18])=[C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:22][CH:21]=2)[CH:15]=[CH:14][N:13]=1.C1(C)C=CC=CC=1>C1COCC1>[O:2]=[C:1]1[NH:11][C:12]2=[N:13][CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:24][CH:25]=3)=[C:17]2[NH:18]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Method E2 (with phosgene and pyridine). tert-Butyl 4-(2,3-diaminopyridin-4-yl-oxy)phenyl-carbamate (1 g, 3.16 mmol) was dissolved in dry THF (32 mL, 10 mL/mmol). The solution was cooled in an ice bath under nitrogen. Pyridine (0.59 mL, 7.27 mmol) was added and followed by dropwise addition a phosgene solution 1.93 M in toluene (2 mL, 3.79 mmol) under vigourous stirring. The ice bath was removed and the mixture was stirred at room temperature overnight, then at 60° C. during 2 hours. The solvent was evaporated under reduced pressure and the solid residue was washed with water and dried to afford the title compound (952 mg, 88%) as a brown solid. 1H-NMR (δ, ppm, DMSO-d6): 1.48 (9H, s, t-Bu), 6.29 (d, 1H, HPy,5, J=6.0 Hz), 7.09 (d, 2H, Harom,Ph,3+5, J=9.0 Hz), 7.51 (d, 2H, Harom,Ph,2+6, J=9.0 Hz), 7.73 (d, 1H, HPy,6, J=6.0 Hz), 9.43 (bs, 1H, NHBoc), 11.16 (bs, 1H, NHPy3) 11.34 (bs, 1H, NHPy2).; LC-MS (m/z): 343 (M+H, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:18]2[CH:23]=[C:22]([OH:24])[C:21]([Cl:25])=[CH:20][C:19]=2[F:26])[C:6](=[O:17])[CH:7]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[N:9]=1)[CH3:2].[CH2:27](Br)[C:28]#[CH:29].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4]1[N:5]([C:18]2[CH:23]=[C:22]([O:24][CH2:29][C:28]#[CH:27])[C:21]([Cl:25])=[CH:20][C:19]=2[F:26])[C:6](=[O:17])[CH:7]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:12])([F:13])[F:14])[N:9]=1)[CH3:2]
Reactant: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(OCC)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5 -hydroxyphenyl) -4-pentafluoroethyl-6(1H)-pyrimidinone and propargyl bromide with sodium carbonate in acetone there is obtained 2-ethoxy-1-[4-chloro-2-fluoro-5 -(2-propynyloxy)-phenyl]-4-pentafluoroethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.35 ppm (d,1H), 6.98 ppm (d,1H), 6.65 ppm (s,1H), 4.77 ppm (m,2H), 4.48 ppm (m,2H), 2.57 ppm (t,1H), 1.29 ppm (t,3H);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([I:9])=[CH:4][N:3]=1.C=O.[CH3:12][C:13](O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C([O-])(O)=O.[Na+].C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:12][CH3:13])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CCNc1cc(Cl)ncc1I
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A mixture of 2-chloro-5-iodopyridin-4-amine (262 mg, 1.03 mmol), excess paraformaldehyde (618 mg, 21 mmol) and AcOH (10.3 mL) was stirred at 40° C. for 15 minutes, followed by addition of excess sodium triacetoxyborohydride (4.8 g, 23 mmol). After stirring for 2.5 hours, further paraformaldehyde (236 mg, 7.86 mmol) and sodium triacetoxyborohydride (1.83 g, 8.63 mmol) were added. After 18 hours, the mixture was diluted with water and basified with NaHCO3. The mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were dried and evaporated onto silica. Gradient chromatography, eluting with 5-10% EtOH: CH2Cl2 over 17 column volume, gave 2-chloro-N-ethyl-5-iodopyridin-4-amine (291 mg, 1.03 mmol, 100% yield). LC-MS (LCT, 3.5 minutes) Rt=2.56 minutes; m/z (ESI) 282 (M+H). The material was reacted with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following General Procedure i to give 2-chloro-N-ethyl-5-(1-methyl-1H-pyrazol-4-yl)pyridin-4-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([Cl:21])[N:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([Cl:21])[N:14]=1)=[O:9]
Reactant: COc1cc(Cl)nc(N)n1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: COc1cc(Cl)nc(NC(=O)c2cc(Cl)ccc2O)n1
Yield: 2.2 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-6-chloro-4-methoxypyrimidine as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@:10]1([CH2:26][O:27]C(=O)C1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25])C1C=CC=CC=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CO.C1CCCCC=1.CO.ClCCl.[OH-].[OH-].[Pd+2]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:26][OH:27])[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@]2(COC(=O)c3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.1 %

Procedure:
A mixture of compound 19 (0.95 g, 2.01 mmol) and Pd(OH)2/C (20%, 1 g) was suspended in methanol/cyclohexene (1:1, 20 mL) and refluxed overnight. The reaction mixture was cooled to rt, filtered through Celite™ column, and concentrated under reduced pressure. The residue was co-evaporated with anhydrous pyridine (2×20 mL), dissolved in anhydrous pyridine, and cooled in ice-bath. Benzoyl chloride (1.15 mL, 10 mmol) was added dropwise and the mixture was stirred at RT for 20 h. Reaction was then quenched by addition of ice-cold water (40 mL), and washed with dichloromethane (2×50 mL). The organic layers were combined, concentrated under reduced pressure, re-dissolved in pyridine/methanol (1:2, 30 mL), and 2 M aqueous NaOH (5 mL) was added. After 15 min, the mixture was neutralised with acetic acid (5 mL) and solvents were removed to give an oily residue. The latter was suspended in 5% methanol/dichloromethane, applied to a silica gel column and eluted by 5 to 15% of methanol/dichloromethane as a solvent. The fractions containing compound 20 were concentrated to yield 0.54 g (70%) of glass-like solid material with the same chromatographic mobility as authentic compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[C:16]#[CH:17])[CH3:13].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[C:16]#[C:17][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:13]
Reactant: C#CC(OCC)OCC
Reactant: Brc1ccc2ncccc2c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(C#Cc1ccc2ncccc2c1)OCC
Temperature: 90 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
A mixture of 6-bromoquinoline (8, 2.63 g, 12.6 mmol), propargylaldehyde diethyl acetal (3.73 mL, 25.2 mmol, 2.0 equiv), triethylamine (TEA, 12.7 mL, 90.8 mmol, 7.2 equiv), copper(I) iodide (CuI, 24.0 mg, 0.126 mmol, 0.01 equiv), and triphenylphosphine (PPh3, 0.39716 g, 1.5142 mmol, 0.12 equiv) in N,N-dimethylformamide (DMF, 15.6 mL, 202 mmol) was degassed with nitrogen bubbling for 5 min. Palladium acetate (Pd(OAc)2, 0.08499 g, 0.3786 mmol, 0.03 equiv) was added and the mixture was degassed with nitrogen bubbling for 5 min. The reaction mixture was heated to 90° C. under nitrogen with stirring. After 3 h and 10 min, HPLC indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (EtOAc, 100 mL) and washed with water (H2O, 2×100 mL). The aqueous layer was extracted with ethyl acetate (EtOAc, 20 mL). The combined organic extracts were then concentrated under the reduced pressure to give the crude product as a black oil. The crude product was purified by flash column chromatography (SiO2, 0-40% EtOAc in hexane gradient elution) to afford 6-(3,3-diethoxyprop-1-ynyl)quinoline (22, 3.2 g, 3.22 g theoretical, 99% yield) as a colorless oil. For 22: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.92 (dd, 1H, J=4.35 Hz, 1.86 Hz), 8.36 (d, 1H, J=8.40 Hz, 1.66 Hz), 8.20 (d, 1H, J=1.78 Hz), 7.99 (d, 1H, J=8.71 Hz), 7.76 (dd, 1H, J=8.71 Hz, 1.87 Hz), 7.57 (dd, 1H, J=8.09 Hz, 4.05 Hz), 5.58 (s, 1H), 3.75-3.55 (m, 4H), 1.17 (t, 6H), J=7.16 Hz); C16H17NO2 (MW 255.31), LCMS (EI) m/e 256.0 (M++H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][O-:4].[F:7][C:8]([F:12])([F:11])[CH2:9][O-:10].C([Al+2:15])C.[F:16][C:17]([F:21])([F:20])[CH2:18][OH:19].[Al]>C(Cl)Cl>[F:1][C:2]([F:6])([F:5])[CH2:3][O-:4].[F:7][C:8]([F:12])([F:11])[CH2:9][O-:10].[F:16][C:17]([F:21])([F:20])[CH2:18][O-:19].[Al+3:15]
Reactant: CC[Al+2]
Reactant: OCC(F)(F)F
Agent: [Al]
Agent: [O-]CC(F)(F)F
Solvent: ClCCl
Product: [Al+3]
Temperature: 40 °C
Reaction time: 1 h

Procedure:
In a flask, under a nitrogen blanket, were placed 7.43 g (0.29 mole) of the product of Example 2 and 50 ml methylene chloride. Then, 3.07 g (0.031 mole) of 2,2,2-trifluoroethanol was added in a way so as to maintain the temperature at about 40° C. After the addition was complete, the flask was placed in an oil bath at 60° C. and most of the methylene chloride was evaporated. The product was allowed to stand at the same temperature for one hour and the remainder of the solvent stripped off under vacuum. There was obtained 9.09 g (95% of theoretical yield) of a white crystalline solid. Analysis for aluminum showed 8.36% Al. The theoretical value was 8.33%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[N+:31]([O-:33])=[O:32])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>O.C(O)C>[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26](/[CH:27]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])=[CH:25][C:24]=1[N+:31]([O-:33])=[O:32])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)/C=C/c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
2-hydroxy-5-methyl-3-nitroacetophenone (200 mg, 1.02 mmol), 4-benzyloxy-3-nitrobenzaldehyde (300 mg, 1.16 mmol) and 3 equivalents of sodium hydroxide (120 mg) were introduced into 80% aqueous ethanol solution and the resulting mixture was stirred for 3 hours at room temperature. The reaction solution was acidified by 2N hydrochloric acid solution and diluted with water. The resulting solid was filtered, washed with large amount of water and methanol, and then dried to give 430 mg (Yield 97%) of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH3:12])([OH:11])[CH3:10].C([Li])CCC.C([O:21][B:22](OC(C)C)OC(C)C)(C)C.Cl>C1COCC1.CCOC(C)=O.O>[CH3:10][C:9]1([CH3:12])[O:11][B:22]([OH:21])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8]1
Reactant: CC(C)(O)Cc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)Cc2ccccc2B(O)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
To a solution of 1-(2-bromophenyl)-2-methylpropan-2-ol (3.48 g, 15 mmol) in THF (100 mL) cooled to −78° C. was added n-butyllithium (15.2 mL, 2.5M in hexanes) in a dropwise fashion. The reaction was permitted to stir for 10 minutes, prior to the addition of triisopropylborate (10.5 mL, 45 mmol). The reaction was permitted to stir for 16 hours, gradually warming to room temperature. Aqueous hydrochloric acid (10 mL, 6M) was added, and the mixture stirred for 1 hour. The reaction was diluted with EtOAc (250 mL) and water (50 mL). The organic portion was washed with brine, dried over sodium sulfate, and evaporated. The resultant crude material was purified by silica gel chromatography to yield 3,3-Dimethyl-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol as a white semisolid product. 1H NMR (400 MHz, acetone) δ ppm 1.13 (s, 6H) 2.76 (s, 2H) 6.99-7.04 (m, 1H) 7.05-7.14 (m, 1H) 7.21-7.27 (m, 1H) 7.58-7.64 (m, 1H). Amount obtained: 830 mg, 31% yield.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:16]([OH:18])=O)=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:16]([C:9]2[O:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][C:10]=2[C:12]([F:13])([F:14])[F:15])=[O:18])=[CH:28][CH:29]=1
Reactant: O=C(O)c1oc(-c2ccccc2)nc1C(F)(F)F
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2oc(-c3ccccc3)nc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O3 (m/e) 420, obsd 421 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH3:17][NH2:18]>C1COCC1>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:18][CH3:17])=[CH:4][CH:5]=1)#[N:16]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C

Procedure:
62.1 g (228 mmol) 4-bromomethyl-2'-cyanobiphenyl (prepared according to D. J. Carini et al., J. Med. Chem. 1992, 34, 2525) were dissolved in 3 l THF. After addition of 1.5 l of a 40% aqueous solution of methylamine the mixture was stirred over night at room temperature, and the THF distilled off in vacuo. The remaining aqueous layer was extracted with ethyl acetate, the extract dried by stirring over night with 0.4 nm mole sieve, and evaporated in vacuo. The title compound was obtained as a viscous oil, which was pure enough according to its 1H-NMR spectrum for further conversions,
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[O:7][C:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[N:23]([CH3:24])[C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[N:20]=3)=[CH:13][CH:12]=2)[N:10]=1.[Li+].[OH-].ClCCl.C(O)C>O1CCCC1>[CH3:24][N:23]1[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]=[C:19]1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:6]([CH2:5][CH2:4][C:3]([OH:35])=[O:2])[O:7][C:8]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)CCc1nc(-c2ccc(OCc3nc4ccccc4n3C)cc2)c(-c2ccccc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(-c3nc(CCC(=O)O)oc3-c3ccccc3)cc2)nc2ccccc21

Procedure:
A solution of the ester (1 g, 2.14 mmole) of Step A, in tetrahydrofuran (13 mL) containing 1N-LiOH (6.42 mL) is stirred under nitrogen at room temperature for 1 hour (TLC, dichloromethane-ethanol 9:1 ). The solvent is evaporated, water added and the pH adjusted to 6.5 with 10% acetic acid. The fight yellow precipitate is collected, washed with water and dried in vacuo. It is redissolved in hot ethyl acetate (containing enough methanol to obtain a clear solution), concentrated to a smaller volume and cooled in an ice bath. The crystals are collected and dried (0.642 g, 66.2%, m.p. 222°-224° C.).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].C[O-].[Na+].Cl[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl(O)(=O)=O>CO.O.CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Reactant: CCOC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Agent: [O-][Cl+2]([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCOC(=O)COc1cc(C(=O)O)c(O)c2ccccc12
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
To 700 ml of dimethylformamide, 249 g (1.22 mol) of 1,4-dihydroxy-2-naphthoic acid was added, and the mixture was stirred under a nitrogen atmosphere. To the mixture, 490 ml (2.44 mols) of a 28% solution of sodium methoxide in methanol was added dropwise over 20 minutes. After 10 minutes, 150 g (1.22 mol) of ethyl chloroacetate was added dropwise over 30 minutes, and the mixture was stirred for 3 hours while keeping the temperature at 50° C. The reaction solution was poured into a mixture of 160 ml of concentrated chloric acid and 5 l of iced water, and the precipitated crystals were filtered off and dried to obtain 335 g (95% yield) of 1-hydroxy-4-ethoxycarbonylmethyloxy-2-naphthoic acid.