Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C@H:30]([CH:33]([CH3:35])[CH3:34])[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]5[O:32][CH2:31][C@@H:30]([CH:33]([CH3:35])[CH3:34])[N:2]=5)[CH:4]=4)=[CH:28][C:13]=3[C:14]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Reactant: CC(C)[C@@H](N)CO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=N[C@H](C(C)C)CO4)c3)cc12
Yield: 26.4 %

Procedure:
Zinc chloride (8 mg, 0.054 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and (R)-2-amino-3-methylbutan-1-ol (111 mg, 1.08 mmol) in PhCl (3 mL) at rt. It was subjected for two interations to microwave irradiation for 1 hr at 200° C. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (13 mg, 25%). 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (1H, s), 7.93-7.99 (2H, m), 7.89-7.93 (2H, m), 7.86 (1H, d, J=7.63 Hz), 7.63-7.69 (2H, m), 7.56 (1H, t, J=7.78 Hz), 7.26 (2H, t, J=8.55 Hz), 4.52 (1H, t, J=9.31 Hz), 4.30 (1H, t, J=8.09 Hz), 4.14-4.22 (1H, m), 2.98 (3H, s), 1.87-1.97 (1H, m), 1.04 (3H, d, J=7.02 Hz), 0.97 (3H, d, J=6.71 Hz). LC-MS retention time 1.64 min; m/z (MH+): 457. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=10.13 min, purity=95%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=10.58 min, purity=94%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=[O:17])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: Clc1ccnc2cc(Br)ccc12
Agent: Cl
Product: O=C(O)c1ccccc1Nc1ccnc2cc(Br)ccc12

Procedure:
7-Bromo-4-chloro-quinoline and 2-amino benzoic acid are refluxed in dilute hydrochloric acid for 1 hour to give 2-(7-bromo-4-quinolylamino) benzoic acid.
Reaction SMILES: [Br-].[NH2:2][C:3]1[C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([C:29]([F:32])([F:31])[F:30])[C:6]([C:33]#[N:34])=[CH:5][CH:4]=1.[F:35][C:36]([F:42])([F:41])[CH2:37][C:38](O)=O.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.CCN(C(C)C)C(C)C>C1COCC1>[F:35][C:36]([F:42])([F:41])[CH2:37][C:38]1[NH:2][C:3]2[C:8]([CH:9]=1)=[C:7]([C:29]([F:30])([F:31])[F:32])[C:6]([C:33]#[N:34])=[CH:5][CH:4]=2
Reactant: O=C(O)CC(F)(F)F
Reactant: N#Cc1ccc(N)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]c(CC(F)(F)F)cc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.3 %

Procedure:
A mixture of {[6-amino-3-cyano-2-(trifluoromethyl)phenyl]methyl}(triphenyl)phosphonium bromide (0.50 g, 0.92 mmol), 3,3,3-trifluoropropanoic acid (0.175 g, 1.40 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (2.60 g, 4.10 mmol, 50% in EtOAc) and DIEA (0.65 mL, 3.70 mmol) in THF (25 mL) was stirred at ambient temperature for 6 h. The mixture was concentrated and then diluted with anhydrous DMF (15 mL) and stirred at 100° C. for 18 h. The reaction was poured into water (100 mL) and extracted with Et2O (2×60 mL). The combined organic portions were washed with sat'd NaHCO3 (50 mL) and brine (50 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 30% EtOAc in hexanes) to afford 2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.189 g, 70%) as a pale yellow solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)sc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)sc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 55.5 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.30 g), tetraethyl methylenediphosphonate (0.19 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.03 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.21 g, yield 55%) from a fraction eluted with ethyl acetate-hexane (9:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 110-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([CH2:14][C:15]([CH3:28])([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=2)[CH2:16][NH2:17])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][C:15]([CH3:28])([C:18]1[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=1)[CH2:14][CH:11]1[CH2:13][CH2:12]1)=[O:6]
Reactant: CC(CN)(CC1CC1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: CC(CNC(=O)c1ccccc1Cl)(CC1CC1)c1cnc(C(F)(F)F)nc1

Procedure:
From 2-chlorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:11]=[C:10]([OH:12])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Yield: 32.2 %

Procedure:
A mixture of 50.0 g (0.297 mol) of methyl 3,5-dihydroxybenzoate, 99.2 g (0.297 mol) of 1-bromooctadecane and 41 g (0.297 mol) of potassium carbonate in 100 ml of acetone and 50 ml of DMF was stirred at reflux under argon for 24 hours. The solvents were removed at reduced pressure and the residue was heated with methylene chloride and filtered hot. The filtrate was concentrated at reduced pressure to a solid which was recrystallized from methylene chloride-methanol to give the 3,5-dialkylated product. The filtrate was concentrated to dryness and the residue was recrystallized from methylene chloride-methanol to give more of the dialkylated product. The filtrate was concentrated to dryness and recrystallized from ether-hexane to give 40.2 g (32% yield, mp 95°-97°) of 3-hydroxy-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:21]=[CH:22][C:2]([NH:1][C:32]([NH:31][C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[F:23])=[O:33])=[CH:3][CH:4]=1)#[N:18]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)c2cc1C#N
Yield: 70 %

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-methoxyquinoline (180 mg) was added to 5.5 ml of toluene, and the mixture was heated to reflux. After then adding 2,4-difluorophenyl isocyanate (0.12 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene=1/1 to obtain 195 mg of the title compound as light brown crystals (70% yield).
Reaction SMILES: [CH:1]([N:3]([CH2:16][C:17](=O)[CH3:18])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])=O.C([O-])(=O)C.[NH4+:24].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:15][O:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[N:3]1[CH:16]=[C:17]([CH3:18])[N:24]=[CH:1]1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(N(C=O)CC(C)=O)c(OC)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A mixture of methyl 4-[formyl(2-oxopropyl)amino]-3-methoxybenzoate (32.6 g) and ammonium acetate (47.5 g) in acetic acid (65.6 mL) was stirred at 140° C. for 1 hr. After completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added under ice-cooling, and the organic layer was separated. To the aqueous layer was added ethyl acetate, and the organic layer was separated. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate/hexane) to give the title compound (16.0 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:9])[C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=1[O:18][CH3:19]
Reactant: COc1cc(C)c(F)cc1C(=O)c1ccc(Cl)nc1N
Reactant: CC(=O)N1CCC(N)CC1
Product: COc1cc(C)c(F)cc1C(=O)c1ccc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 43) and 1-(4-amino-piperidin-1-yl)-ethanone (prepared as described in D. Manefti et al, Biorg. Med. Chem. Lett., 13 (2003), 2303-2306) using the procedure described in Step B. Example 6. HRMS, observed: 401.1084, Calcd for (M+H)+: 401.1084.
Reaction SMILES: [C:1]([NH2:6])(=O)[CH:2]([CH3:4])[CH3:3].C1(N)CC1.[CH:11]1([C:14]2[N:18](C)[C:17]([CH:20]=[O:21])=[CH:16]N=2)[CH2:13]C1>>[CH:14]1([N:18]2[C:17]([CH:20]=[O:21])=[CH:16][N:6]=[C:1]2[CH:2]([CH3:4])[CH3:3])[CH2:11][CH2:13]1
Reactant: CC(C)C(N)=O
Reactant: Cn1c(C=O)cnc1C1CC1
Agent: NC1CC1
Product: CC(C)c1ncc(C=O)n1C1CC1

Procedure:
3-Cyclopropyl-2-isopropyl-3H-imidazole-4-carbaldehyde was prepared from isobutyramide and cyclopropylamine in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].[CH3:16][C:17]1[S:18][C:19]([CH:22]=O)=[CH:20][N:21]=1>>[CH3:16][C:17]1[S:18][C:19]([CH:22]=[C:10]2[CH2:9][CH2:8][C:7]3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]=3[C:11]2=[O:15])=[CH:20][N:21]=1
Reactant: Cc1ncc(C=O)s1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Product: COC(=O)c1ccc2c(c1)CCC(=Cc1cnc(C)s1)C2=O
Yield: 60 %

Procedure:
The title compound was prepared from 5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396 mg, 1.9 mmol) and 2-methyl-1,3-thiazole-5-carbaldehyde (220 mg, 2.0 mmol) according to Method A3 in 60% yield. ES-MS m/z 314 (M+H)
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8](=O)[CH2:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O=P(Cl)(Cl)[Cl:15]>>[CH2:1]([C:5]1[NH:9][C:8]([Cl:15])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=NCC(=O)N1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1ncc(Cl)[nH]1
Temperature: 100 °C

Procedure:
2-n-Butyl-3,5-dihydroimidazol-4-one (14.02 g, 0.1 mol) was added in portions for 15 minutes to POCl3 (50 ml) at 95° C. The solution was heated for 2 hours at 100° C., cooled and poured on 400 g of ice. The mixture was adjusted to pH 7 with 255 ml of 30 percent sodium hydroxide solution and extracted three times with 500 ml of ethyl acetate each. The combined organic phases were dried with MgSO4, filtered and concentrated by evaporation on a Rotavapor. After purification of the residue by column chromatography the title compound (5.52 g, 34.7 percent) was obtained in a high yield (>98 percent, according to GC and 1H-NMR). The product had a melting point of 85° to 87° C. Other data regarding the product was:
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)([OH:3])=[O:2].S(Cl)([Cl:20])(=O)=O>C(O)(=O)C>[Cl:20][C:14]1[C:5]([CH2:4][C:1]([OH:3])=[O:2])=[CH:6][C:7]([O:15][CH3:16])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(CC(=O)O)cc1OC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(CC(=O)O)cc1OC

Procedure:
To 300 mg of methyl 4-carboxymethyl-2-methoxy-benzoate from preparation 1 placed in 6 mL of acetic acid, are added 110 μL of sulfuryl chloride (1 equivalent). The whole is refluxed for 6 hours. After evaporation of the solvent, the reaction crude product is purified on silica gel (petroleum ether/ethyl acetate: 80/20 then 60/40) leading to 165 mg of the desired compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=1[O:6][CH2:7][CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11]1.[N:47]1([C:52](N2C=CN=C2)=[O:53])[CH:51]=[CH:50][N:49]=[CH:48]1>C(#N)C.COC(C)(C)C>[N:47]1([C:52]([O:1][CH2:2][CH2:3][C:4]2[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=2[O:6][CH2:7][CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:20][CH:21]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:11]2)=[O:53])[CH:51]=[CH:50][N:49]=[CH:48]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCO)cc1
Solvent: COC(C)(C)C
Solvent: CC#N
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOC(=O)n2ccnc2)cc1
Temperature: 25 °C

Procedure:
A solution of 0.100 g of tert-butyl 3-{2-[2-(2-hydroxyethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 26c) and 0.049 g of diimidazol-1-ylmethanone in 4 ml of acetonitrile is stirred at reflux over 5 hours. The reaction mixture is cooled at room temperature, diluted with tert-butyl methyl ether, washed with 1N HCl and 0.5N NaOH, dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a yellow oil from the residue. Rf=0.41 (2:1 EtOAc-heptane); Rt=5.61.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][N:19]([CH3:26])[C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:27][N:28](C)C=O>>[CH3:26][N:19]([CH2:18][C:8]1[N:6]2[CH:7]=[C:2]([C:27]#[N:28])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: Cc1ccc(-c2nc3ccc(I)cn3c2CN(C)C(=O)CC(C)C)cc1
Reactant: CN(C)C=O
Product: Cc1ccc(-c2nc3ccc(C#N)cn3c2CN(C)C(=O)CC(C)C)cc1
Yield: 96 %

Procedure:
3.7 g (0.041 mole) of cuprous cyanide and 19 g (0.041 mole) of N-{[6-iodo-2-(4-methylphenyl)imidazo-[1,2-a]pyrid-3-yl]methyl}-N,3-dimethylbutanamide, prepared according to the process described in European Patent Application No. 0,172,096, are introduced into 100 ml of dimethylformamide. The mixture is heated under reflux for 4 hours and the solvent then evaporated off under reduced pressure. The residue is taken up with water and dichloromethane and the mixture treated with ammonia solution. The organic phase is washed with water and dried, and the solvent evaporated off. The residue is purified by column chromatography and taken up with pentane. 14.4 g (96%) of white solid are obtained.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:7]=[C:8]([C:23]2[S:27][C:26]([C:28]3([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][CH:24]=2)[CH:9]=[C:10]([NH:12][C:13]2[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=2)[CH:11]=1.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[OH:34][C:28]1([C:26]2[S:27][C:23]([C:8]3[CH:9]=[C:10]([NH:12][C:13]4[N:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][N:14]=4)[CH:11]=[C:6]([CH3:5])[CH:7]=3)=[CH:24][N:25]=2)[CH2:29][CH2:30][N:31]([C:1](=[O:3])[CH3:2])[CH2:32][CH2:33]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Reactant: CC(=O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1

Procedure:
To a mixture of acetic acid (9 μL, 0.15 mmol) and Si-carbonyl diimidazole (266 mg, 0.287 mmol) was added a solution of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) and hydroxybenzotriazole (26 mg, 0.17 mmol) dissolved in N,N-dimethylformamide, and the resultant suspension was shaken in a Bohdan block overnight at room temperature. The reaction mixture was filtered and concentrated in vacuo, and the resultant residue was dissolved in DMSO and purified via HPLC (30-64% CH3CN:H2O) to provide 1-{4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone. MS ESI: [M+H]+ m/z 478.1. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 7.95 (s, 2H), 7.44 (s, 1H), 7.26 (d, J=5.1 Hz, 1H), 7.14 (s, 1H), 6.30 (s, 1H), 4.25-3.99 (m, 1H), 3.73 (m, 1H), 3.41-3.34 (m, 1H), 3.07-2.97 (m, 1H), 2.47 (s, 3H), 2.32 (s, 3H), 2.25-2.14 (m, 1H), 1.93 (m, 2H), 1.75 (m, 1H). rhSYK activity=+++
Reaction SMILES: CS(O[C@H:6]([CH3:28])[CH2:7][O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.Cl.[F:30][C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C@@H:6]([CH3:28])[CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:32]1
Reactant: F[C@@H]1CCNC1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CC[C@@H](F)C1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A mixture of (R)-1-(trityloxy)propan-2-yl methanesulfonate (1.25 g, 3.15 mmol), (R)-3-fluoropyrrolidine hydrochloride (480 mg, 3.52 mmol), and K2CO3 (1.31 g, 9.48 mmol) in acetonitrile (40 mL) was heated at reflux for 4 days. The reaction was cooled to room temperature, concentrated under reduced pressure, and diluted with DCM (100 mL). The solution was washed (50 mL sat'd NaHCO3), dried (Naz SO4), and concentrated under reduced pressure. The crude material was purified on a silica gel column to yield (R)-3-fluoro-1-((S)-1-(trityloxy)propan-2-yl)pyrrolidine (725 mg) as a pale brown oil. 1H NMR (CDCl3): δ 7.60-7.20 (m, 15H), 5.40-4.95 (m, 1H), 3.30 (m, 1H), 3.05-2.50 (m, 5H), 2.29 (m, 1H), 2.06-1.70 (m, 2H), 1.07 (d, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[CH2:3][NH:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)[C:6]=1[CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:1][C@@H:2]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[CH2:3][NH:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)[C:6]=1[CH2:20][CH2:21][NH2:22]
Reactant: CC(C)(C)OC(=O)NCCc1c(-c2ccc3cnccc3c2)noc1NC[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1c(-c2ccc3cnccc3c2)noc1NC[C@@H](N)Cc1c[nH]c2ccccc12
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
To a 25 mL of round-bottom flask was added tert-butyl 2-(5-((S)-2-amino-3-(1H-indol-3-yl)propylamino)-3-(isoquinolin-6-yl)isoxazol-4-yl)ethylcarbamate (11 mg, 21 μmol). 2 mL of 50% TFA/DCM was added to the reaction mixture dropwise. After 10 minutes, LC-MS showed that the BOC group had been removed. The reaction mixture was concentrated under reduced pressure and purified by preparative LC to give N-((S)-2-amino-3-(1H-indol-3-yl)propyl)-4-(2-aminoethyl)-3-(isoquinolin-6-yl)isoxazol-5-amine (7 mg, 79% yield). MS m/z: 427 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 9.79 (s, 1H), 8.56-8.66 (m, 2H), 8.52 (s, 1H), 8.45 (s, 1H), 8.18 (d, J=8.22 Hz, 1H), 7.60 (d, J=7.83 Hz, 1H), 7.39 (d, J=8.02 Hz, 1H), 7.26 (s, 1H), 7.14 (t, J=7.53 Hz, 1H), 7.06 (t, J=7.43 Hz, 1H), 3.75-3.79 (m, 2H), 3.62-3.71 (m, 1H), 3.20 (td, J=14.48, 7.04 Hz, 2H), 2.99 (s, 2H), 2.88 (d, J=6.46 Hz, 2H).