Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:16]O>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cncc(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cncc(Cl)c1

Procedure:
5-Chloronicotinic acid (200 mg, 1.269 mmol) was refluxed overnight in the presence of concentrated sulfuric acid (8.20 mg, 0.063 mmol) in methanol (8 mL) at 70° C. The reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and the compound was purified by column chromatography affording the title compound (120 mg). 1H NMR (400 MHz, CDCl3): δ 9.07 (d, 1H, J=1.6 Hz), 8.72 (d, 1H, J=2.0 Hz), 8.26 (m, 1H), 3.95 (s, 1H).
Reaction SMILES: Cl.N1(C(=O)CC2C=CC(N3C=NN=N3)=CC=2)CCNCC1.[N:22]1([C:28]([O:30]C(C)(C)C)=O)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[C:35]([C:37]1[C:42]([F:43])=[CH:41][C:40]([CH2:44]C(O)=O)=[C:39]([F:48])[CH:38]=1)#[N:36]>>[F:43][C:42]1[CH:41]=[C:40]([CH2:44][C:28](=[O:30])[N:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)[C:39]([F:48])=[CH:38][C:37]=1[C:35]#[N:36]
Reactant: N#Cc1cc(F)c(CC(=O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Product: N#Cc1cc(F)c(CC(=O)N2CCNCC2)cc1F

Procedure:
2,5-difluoro-4-[2-oxo-2-(piperazin-1-yl)ethyl]benzonitrile was prepared in an analogous fashion as described above in the synthesis of 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride starting from tert-butyl piperazine-1-carboxylate and (4-cyano-2,5-difluorophenyl)acetic acid. LC/MS: [(M+1)]+=266.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].Cl[CH2:17][C:18]1[C:19]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:20]([O:24][CH3:25])[CH:21]=[CH:22][CH:23]=1.O.C(O)(=O)C>C(O)C>[C:1]([NH:4][C:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: COc1cccc(CCl)c1OCc1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1cccc(OC)c1OCc1ccccc1)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Yield: 66.4 %

Procedure:
A quantity of 136.20 g (0.42 mole) of 21 wt. % sodium ethoxide-in-ethanol is added to a stirred solution of 90.14 g (0.415 mole) of diethyl acetamidomalonate (Aldrich) in 800 mL of absolute ethanol. A solution of the benzyl chloride derivative of Example 38 in 500 mL of absolute ethanol is added and the mixture is heated at reflux for 2 hours. The cooled mixture is poured into 4 L of ice and water containing 20.0 g of glacial acetic acid. The supernatant is decanted from the separated gum. The gum is dissolved in 2 L of ether, the solution dried (magnesium sulfate), and concentrated to ca 300 mL volume. Petroleum ether (100 mL) is added to precipitate 107.1 g (66.4% yield) of pure crystalline product; mp 94°-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Br:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[CH2:27][C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11]
Reactant: BrCc1cccc(Br)c1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cccc(C2(Cc3cccc(Br)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (40 mg, 0.15 mmol) (from Example 6b supra), 1-bromo-3-bromomethyl-benzene (43 mg, 0.17 mmol) (Aldrich), potassium iodide (29 mg, 0.17 mmol) and potassium carbonate (43 mg, 0.31 mmol) in acetone (2 mL) was heated at 60° C. for 16 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-3-(3-bromo-benzyl)-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a white solid. (Yield 28 mg, 43%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.[CH3:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1[NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1B1OC(C)(C)C(C)(C)O1.Br[C:37]1[N:42]=[C:41]([CH2:43][NH:44][C:45]2[C:50]([CH:51]([CH2:54][CH3:55])[CH2:52][CH3:53])=[CH:49][CH:48]=[CH:47][C:46]=2[CH:56]([CH2:59][CH3:60])[CH2:57][CH3:58])[CH:40]=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.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.CO>[CH2:57]([CH:56]([C:46]1[CH:47]=[CH:48][CH:49]=[C:50]([CH:51]([CH2:54][CH3:55])[CH2:52][CH3:53])[C:45]=1[NH:44][CH2:43][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][C:13]=2[CH2:12][NH:11][C:10]2[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=2[CH3:8])[N:42]=1)[CH2:59][CH3:60])[CH3:58]
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: CCC(CC)c1cccc(C(CC)CC)c1NCc1cccc(Br)n1
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: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CCC(CC)c1cccc(C(CC)CC)c1NCc1cccc(-c2c(CNc3ccccc3C)ccc3ccccc23)n1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of 2.50 g (6.7 mmol) of Na2CO3×10H2O, 69 ml of water and 22 ml of methanol was purged with argon for 30 min. The obtained solution was added to a mixture of 2.50 g (6.7 mmol) of 2-methyl-N-{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}aniline, 2.70 g (6.7 mmol) of N-[(6-bromopyridin-2-yl)methyl]-2,6-bis(1-ethylpropyl)aniline, and 0.39 g (0.34 mmol) of Pd(PPh3)4 in 90 ml of toluene. This mixture was stirred for 12 h at 70° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×50 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was re-crystallized from 5 ml of diethyl ether. Yield 2.20 g (58%) of white crystalline powder. Anal. calc. for C39H45FN3: C, 84.31; H, 8.31; N, 7.37. Found: C, 84.28; H, 8.26; N, 7.19. 1H NMR (CDCl3): δ 7.90 (d, J=8.5 Hz, 1H), 7.88 (m, 1H), 7.83 (m, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.60 (m, 1H), 7.35-7.49 (m, 4H), 6.96-7.07 (m, 5H), 6.61 (m, 1H), 6.53 (m, 1H), 4.17-4.32 (m, 4H), 3.92 (br.m, 1H), 3.85 (br.s, 1H), 2.88 (m, 2H), 2.08 (s, 3H), 1.62 (m, 4H), 1.49 (m, 4H), 0.73 (t, J=7.1 Hz, 6H), 0.71 (t, J=7.1 Hz, 6H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([C:37]([OH:39])=O)[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl.[NH2:41][C@H:42]([CH2:60][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=1)[C:43]([NH:45][C@@H:46]([C:54]1[O:58][N:57]=[C:56]([CH3:59])[N:55]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44].C(N(CC)CC)C>CN(C)C=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([C:37](=[O:39])[NH:41][C@@H:42]([C:43](=[O:44])[NH:45][C@@H:46]([C:54]2[O:58][N:57]=[C:56]([CH3:59])[N:55]=2)[CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:60][C:61]2[CH:70]=[CH:69][C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH:62]=2)[CH2:32]1)=[O:30])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Yield: 87 %

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.42 g, 2.18 mmol) and 1-hydroxybenzotriazole monohydrate (0.33 g, 2.18 mmol) were added to a solution of (R)-N-tertbutoxycarbonyl-3-piperidine carboxylic acid (0.50 g, 2.18 mmol) in N,N-dimethylformamide (7 ml). After 30 min at 20° C. a mixture of (2R)-2-amino-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]-3-(2-naphthyl)propionamide hydrochloride (0.68 g, 1.56 mmol) and triethylamine (0.16 g, 1.56 mmol) in N,N-dimethylformamide (8 ml) was added. After 18 h at 20° C. the reaction mixture was poured on ice water (90 ml) and extracted several times with ethyl acetate (total 90 ml). The organic phases were collected and washed with aqueous citric acid (10%, 15 ml), a saturated solution of sodium hydrogencarbonate (3×15 ml) and water (3×15 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and purified by flash chromatography on silica gel (90 g) using ethyl acetate and heptane (3:2) as eluent to give 0.83 g of (3R)-3-{(1R)-1-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl]-2-(2-naphthyl)ethylcarbamoyl}piperidine-1-carboxylic acid tertbutyl ester.
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.O1CCOCC1.[ClH:31]>>[ClH:31].[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1)#[N:8]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C#N)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(CN)cc1
Reaction time: 3 h

Procedure:
4-cyanobenzylamine hydrochloride (EX-59A) was prepared from 10 g (0.030 moles) of 4-{N,N-bis-(tert-butoxycarbonyl)aminomethyl}benzonitrile, prepared following Synthetic Communication, 28(23), 4419–4429 (1998), by stirring it in 4N HCl Dioxane (75 ml). After 3 h, the solution was concentrated in vacuo and triturated with ether. The solid was collected by filtration and vacuum dried to yield 5 g (98%) of EX-59A as a white solid: 1H NMR (DMSO) d 8.68 (br s, 2H), 7.84 (m, 2H), 7.67 (m, 2H), 4.06 (s, 2H); HRMS (EI) calcd for C8H8N2 133.0766, found 133.0807
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[O:1]1[CH:5]=[CH:4][CH:3]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:2]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccoc1
Product: O=C(OCc1ccccc1)C1C=COC1

Procedure:
Synthesis takes place first of all by Birch reduction of 3-furancarboxylic acid followed by esterification with benzyl bromide to form benzyl 2,3-dihydrofuran-3-carboxylate (in accordance with G. Lowe, St. Swain; J. Chem. Soc. Perkin Trans I (1985), 391) ##STR31##
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:14])[C@@H:6]([OH:13])[CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:2]=[CH2:3].IC.[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:4][C:5](=[O:14])[C@@H:6]([OH:13])[CH2:7][N:8]([CH3:17])[S:9]([CH3:12])(=[O:10])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@@H](O)CNS(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCOC(=O)[C@@H](O)CN(C)S(C)(=O)=O
Yield: 86.6 %

Procedure:
(S)-2-Hydroxy-3-((methylsulphonyl)amino)propanoic acid 2-propenyl ester (0.9 g, 4.04 mmol), iodomethane (9 ml) and potassium carbonate (0.64 g) in acetone (50 ml) were heated at reflux for 20 h. The solvent was evaporated and the residue dissolved in water/ethyl acetate. The organic layer was separated, dried (MgSO4) and the solvent evaporated to give the sub-title ester (0.83 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[C:17](=O)([O-])O.[Na+]>CO>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:17])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: O=C(O)CCc1cccc(I)c1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)CCc1cccc(I)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of the mixture of 3-(3-iodophenyl)propionic acid (12.0 g) in methanol (200 ml) was added thionyl chloride (11.0 g, 92.5 mmol), and the mixture was stirred for 30 minutes at 40° C. To the mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was extracted with toluene:ethyl acetate (1:1). The organic layer was washed with water and an aqueous saturated sodium chloride solution, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was separated and purified with silica gel chromatography (hexane:ethyl acetate=5:1→4:1) to give the subject compound (9.66 g, 61%:total of 3 steps).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To mixture of methyl-3-amino-5-phenylthiophene-2-carboxylate (100 mg, 0.428 mmol) in anhydrous pyridine (4.3 ml) was added p-chlorobenzoyl chloride (71 μl, 0.556 mmol). The mixture was stirred for 3 hours at room temperature and concentrated. Purification chromatography (silica gel, hexane to hexane:ethyl acetate; 95:5) gave 145 mg (91% yield) of 3-(4-Chloro-benzoylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester. 1H NMR (CDC3, 400 MHz) 8.54 (s, 1H), 7.99-7.96 (m, 2H), 7.73-7.71 (m, 2H); 7.52-7.50 (m, 2H), 7.46-7.39 (m, 3H), 3.95 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][N:24]2C2CCCCO2)=[C:20]([CH2:33][NH:34][CH2:35][CH2:36][N:37](C)[C:38](=O)OC(C)(C)C)[CH:19]=1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([N:34]([CH2:33][C:20]4[CH:19]=[C:18]([F:17])[CH:26]=[C:25]5[C:21]=4[CH:22]=[N:23][NH:24]5)[CH2:35][CH2:36][NH:37][CH3:38])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: CN(CCNCc1cc(F)cc2c1cnn2C1CCCCO1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CNCCN(Cc1cc(F)cc2[nH]ncc12)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 115 °C
Reaction time: 16 h
Yield: 12.7 %

Procedure:
A vial was charged with 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (100 mg, 0.42 mmol), tert-butyl (2-(((6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methyl)amino)ethyl)(methyl)carbamate (207 mg, 0.51 mmol), DIPEA (0.22 mL, 1.27 mmol) and n-BuOH (0.9 mL), sealed and heated at 115° C. for 4 d. The reaction mixture was then cooled to RT and 4N HCl/dioxane (1.06 mL, 4.24 mmol) was added. The reaction mixture was stirred at RT for 16 h then concentrated nvacuo. The crude mixture was purified by preparative HPLC to afford 22.4 mg (13%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((6-fluoro-1H-indazol-4-yl)methyl)-N2-(2-(methylamino)ethyl)pyrimidine-2,4-diamine (II-47).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.C(N(CC)CC)C.[CH3:32][O:33][C:34](=[O:37])[CH2:35]Br>C1COCC1.CCOC(C)=O>[CH3:32][O:33][C:34](=[O:37])[CH2:35][N:12]([CH2:11][C:7]1[N:6]([CH2:5][C:4]2[CH:21]=[C:22]([Cl:24])[CH:23]=[C:2]([Cl:1])[CH:3]=2)[CH:10]=[CH:9][N:8]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1
Reactant: COC(=O)CBr
Reactant: Fc1cccc(CNCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)CN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.8 %

Procedure:
To a solution of [1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amine (200 mg, 0.55 mmol) and triethylamine (0.18 mL, 1.37 mmol) in THF (2 mL) was added methylbromoacetate (78 uL, 0.82 mmol). The reaction was stirred at ambient temperature for 18 h before diluting with EtOAc (50 mL). The solution was washed with water (20 mL) and brine then dried over Na2SO4. The solvent was removed in vacuo and the residue purified by column chromatography (silica gel, 5% MeOH in CH2Cl2). The purified product was treated with excess 2N HCl in Et2O solution to afford the hydrochloride salt of the desired product 7e (74 mg, 26%): ESI MS m/z 436 [C21H20Cl2FN3O+H]+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.[C:22]12([CH2:32][N:33]=[C:34]=[O:35])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>O1CCCC1.[Cl-].[Na+].O>[C:22]12([CH2:32][NH:33][C:34](=[O:35])[C:15]3[C:14]([Br:13])=[CH:19][N:18]=[C:17]([O:20][CH3:21])[CH:16]=3)[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2
Reactant: O=C=NCC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Br)cn1
Temperature: 0 °C

Procedure:
n-Butyllithium (2.51 ml of a 2.5M solution in hexanes) was added to diisopropylamine (0.88 ml) in dry tetrahydrofuran,(15 ml) at 65° C. To this solution was added a solution of 5-bromo-2-methoxypyridine (0.82 ml) in dry tetrahydrofuran (10 ml) dropwise over 30 minutes at −65° C. A solution of 1-adamantylmethylisocyanate (1 g) in dry tetrahydrofuran (10 ml) was then added in small portions over 30 minutes at −65° C. The reaction mixture was allowed to warm to 0° C., diluted with saturated brine (20 ml) and extracted into ethyl acetate (3×20 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with dichloromethane:acetone (19:1 to 2.5:1) to afford the sub-titled compound (1.1 g) as a colourless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[BH4-].[Na+].C([O-])(O)=O.[Na+].[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: CC(C)C(=O)Cl
Reactant: N#Cc1nccc(Cl)c1COC1CCCCO1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(=O)NCc1nccc(Cl)c1COC1CCCCO1

Procedure:
4-Chloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine-2-carbonitrile (30 mg. 0.12 mmol) was dissolved in a mixture of MeOH (0.75 mL) and THF (1 mL). CoCl2 hexahydrate (56 mg. 0.24 mmol) and NaBH4 (45 mg. 1.19 mmol dissolved in 1 mL MeOH) were added. After stirring for 8 min at RT sat. NaHCO3 solution (1 mL) and isobutyryl chloride (125 μL. 1.19 mmol) were added. The solvents were removed in vacuo and the residue was partioned between sat. NH4Cl solution (10 mL) and DCM (10 mL) and extracted with DCM (3×10 ml). The combined organic layers were washed with brine and dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EtOAc 2:1→1:2) to give the title compound. MS (m/z): 326.8 [M+H+]
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH3:9].N#N.[CH3:12][CH2:13][OH:14].[Li][CH:16](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[CH2:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:12][C@H:13]([OH:14])[CH3:16])[CH3:9]
Reactant: CCc1ccccc1Br
Reactant: [Li]C(C)CC
Reactant: CCO
Agent: FB(F)F
Agent: N#N
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCc1ccccc1C[C@@H](C)O
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A solution of 1-bromo-2-ethylbenzene (3.70 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −78° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −78° C. The mixture was stirred for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1:9, Rf=0.55 in EtOAc/hexane 3:7) to give (2R)-1-(2-ethylphenyl)propan-2-ol (877 mg, 26%) as pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.19 (m, 4H), 4.02 (m, 1H), 2.80 (m, 2H), 2.68 (q, J=7.53 Hz, 2H), 1.51 (s, 1H), 1.28 (d, J=6.21 Hz, 3H), 1.22 (t, J=7.53 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.CN(C=O)C.C(Cl)(=O)C([Cl:32])=O>ClCCl>[ClH:32].[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([Cl:32])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)Cl
Product: Cl
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Under an argon gas flow, to a suspension of 32.5 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid in 807 ml of dichloromethane were added 190 μl of DMF and 17.2 ml of oxalyl chloride under ice-cooling, followed by stirring at room temperature for 80 minutes. The reaction mixture was concentrated under reduced pressure to obtain 38.0 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carbonyl chloride hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](Cl)=[N:10][OH:11].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([OH:29])[C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:14]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C.CCOCC>[Cl:28][C:24]1[CH:23]=[C:22]([C:21]2[O:11][N:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:20]=2[CH:19]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[OH:29])[CH:27]=[CH:26][CH:25]=1
Reactant: ON=C(Cl)c1ccc(Cl)cc1Cl
Reactant: OC(C#Cc1cccc(Cl)c1)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: OC(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1cccc(Cl)c1
Temperature: 55 °C
Reaction time: 20 h
Yield: 16.7 %

Procedure:
A mixture of 53 mg (0.24 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 50 mg (0.21 mmol) of 1-(3-pyridyl)-3-(3-chlorophenyl)-2-propyn-1-ol, and 26 mg (0.31 mmol) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. on a rotary table shaker equipped with a heated sand bath. After 20 hrs, an additional 20 mg of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride and 10 mg of sodium bicarbonate was added, and the reaction mixture was stirred and heated for another 16 hrs. The mixture was then diluted with ether, and the solution was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 15 mg (0.035 mmol) of 5-(3-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. 1H NMR (CDCl3): δ 5.92 (br s, 1), 7.04 (d of d, 1), 7.12 (d, 1), 7.72 (m, 1), 8.86 (br s, 1), and 8.29 ppm (br s, 2). MS m/z: 430.9 (M+H).