Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[N:17]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]2)c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(-c2nn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]2)c1
Yield: 63 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-3-(1-(3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.400 g), KOH (0.200 g), water (2 mL) and THF (5.0 mL) to afford 0.200 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O>C(OC(=O)C)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13](/[CH:14]=[CH:1]/[C:2]2[N:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[N:7]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(O)nc(C)n1
Reactant: O=Cc1cccc(Cl)c1
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(O)nc(/C=C/c2cccc(Cl)c2)n1
Temperature: 145 °C
Yield: 77.8 %

Procedure:
1.24 g (10 mmol) of 2,4-dimethyl-6-hydroxypyrimidine in acetic anhydride (2.8 ml) were treated at RT with 1.41 g (10 mmol) of 3-chlorobenzaldehyde and the mixture was heated for 5 hours at 145° C. until completion of the reaction according to TLC analysis. The reaction mixture was cooled to RT, the crystalline solid which had formed was filtered off by suction and washed with diethyl ether to give 1.92 g (78%) of the desired (E)-2-[2-(3-chloro-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol as off-white crystals. EI mass spectrum, m/e: 246.1 (M calculated for C13H11ClN2O: 246).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:12]2[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(=[O:38])[N:28]([CH2:29][C:30](Cl)=[O:31])[C:27](=[O:33])[C:26]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:25]12.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCCl>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:12]2[N:11]([C:30](=[O:31])[CH2:29][N:28]2[C:27](=[O:33])[C:26]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:25]3[C:24]2=[O:38])[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: O=C1[C@H]2CCCC[C@H]2Nc2ccccc2N1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCCC[C@H]21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a solution of (4aR*,11aS*)-10-benzyl-1,2,3,4,4a,5,10,11a-octahydro-11H-dibenzo[b,e][1,4]-diazepin-11-one (200 mg, 0.65 mmol) in 1,2-dichloroethane (2 mL) was added phthalimidoacetyl chloride (175 mg, 0.78 mmol), and the mixture was stirred for 15 minutes at room temperature. To this solution was added pyridine (0.08 mL), and the mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was separated, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, which was dried over magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was crystallized from ethanol to give 138 mg (yield 43%) of the titled compound, m.p. 241°-242.5° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4](=[O:30])[CH2:3]1.Br[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:34]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:8]1[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4](=[O:30])[CH:3]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:34]=2)[C:2]1=[O:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: O=C(CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(CC2C(=O)N(CC(=O)OCc3ccccc3)c3ccccc3N(c3ccccc3)C2=O)c2ccccc21

Procedure:
To a stirring solution of benzyl (2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl)acetate (3.45 g, 8.62 mM) in 25 mL DMF at 0° C. was added 1.1 equiv. of 0.5 M solution of KN(TMS)2 in toluene. The resulting solution was stirred 10–30 min, then a solution of tert-butyl 3-(bromomethyl)-1H-indazole-1-carboxylate (2.95 g, 9.48 mM) in 15 mL DMF was added. The resulting solution was stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture was then poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer was separated, dried (MgSO4), and the solvents removed in vacuo. The resultant material was purified by silica gel flash column chromatography using methylene chloride/EtOAc 9/1 providing 4.4 g of white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1.C(=O)(O)[O-:13].[Na+]>C(#N)C.O>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([B:9]([OH:11])[OH:10])=[CH:7][CH:8]=1)=[O:13]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CS(=O)c1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of [4-(methylthio)phenyl]boronic acid (1.008 g) in acetonitrile (60 ml) and water (6 ml) was cooled with a dry ice-acetone bath until it just began to freeze. A solution of ceric ammonium nitrate (6.72 g) in water (10 ml) was added with swirling. The resulting solution was left to warm to room temperature. The mixture was then basified to pH5 by addition of 8% aqueous sodium bicarbonate (16 ml) and evaporated to dryness by re-evaporation with absolute ethanol. The dried residue was purified by SPC (Merck 7729) using ethyl acetate-ethanol (9:1 followed by 4:1 and 7:3) as eluent, to give a colourless solid. The solid was further purified by FCC eluting with dichloromethane:ethanol (9:1) to give the title compound (1.00 g) as a colourless gum.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=2)[NH:13][C:12]=1[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl>N1C=CC=CC=1>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]=[C:40]=[O:42])[CH:18]=2)[NH:13][C:12]=1[C:21]1[CH:22]=[C:23]([CH3:28])[CH:24]=[C:25]([CH3:27])[CH:26]=1)[CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N=C=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reaction time: 0.83 h
Yield: 253.2 %

Procedure:
To a solution of 3-{2-[benzyl-(4-pyridin-3-yl-butyl)amino]ethyl} -2-(3,5-dimethylphenyl)-1H-indol-5-ylamine (120 mg in 8 mL dry methylene chloride) at 0° C. was added 26.6 mg triphosgene followed by 0.050 mL pyridine and the mixture stirred at low temperature. After 50 minutes, the mixture was concentrated in vacuo to give the crude title compound (120 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][NH:10][C:11](=O)[CH2:12][CH3:13])=[CH:4][C:3]=1[O:16][CH3:17]>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][NH:10][CH2:11][CH2:12][CH3:13])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: CCC(=O)NCC(O)c1ccc(F)c(OC)c1
Agent: Cl
Product: CCCNCC(O)c1ccc(F)c(OC)c1
Yield: 81.4 %

Procedure:
Prepared following the same method as for example 3 starting with the amide from example 18 (585 mg, 2.42 mmol). After refluxing in 6M HCl (aq) the reaction mixture was cooled and extracted with diethyl ether (2×50 ml). The organic layers were discarded and the aqueous layer basified by the addition of potassium carbonate. The aqueous residue was then extracted with ethyl acetate (3×50 ml). The organic extracts were combined and dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (448 mg, 1.97 mmol, 81%), 1H NMR (CD3OD, 400 MHz) δ: 0.96 (t, 3H), 1.58 (m, 2H), 2.63 (m, 2H), 2.79 (d, 2H), 3.96 (s, 3H), 4.77 (t, 1H), 6.90 (m, 1H), 7.03 (t, 1H), 7.11 (d, 1H). LRMS: m/z 228 (M-H+).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.F[C:24]1[CH:29]=[CH:28][N:27]2[C:30]([C:33]([NH:35][C:36]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:37]=3[C:38]([CH3:53])=[N:39][N:40]4[CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=3)=[O:34])=[CH:31][N:32]=[C:26]2[CH:25]=1>C1COCC1.CN1C(=O)CCC1>[CH3:53][C:38]1[C:37]2[C:41](=[CH:42][CH:43]=[CH:44][C:36]=2[NH:35][C:33]([C:30]2[N:27]3[CH:28]=[CH:29][C:24]([O:7][CH2:8][CH2:9][N:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[CH:25][C:26]3=[N:32][CH:31]=2)=[O:34])[N:40]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=2)[N:39]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(F)ccn45)cccc32)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C(=O)OC(C)(C)C)CC6)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 0.4 M solution of potassium tert-butoxide (0.068 g, 0.606 mmol) in THF cooled in an ice-water bath was added tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate 0.278 g, 1.21 mmol). The reaction was stirred for 10 minutes before adding 7-fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 53; 0.100 g 0.241 mmol) in 2 mL of NMP. The reaction was warmed to ambient temperature and stirred for 1 hour, then heated to 60° C. and stirred for 12 hours. THF was removed by rotary evaporation and the mixture was heated to 120° C. for 5 hours. Another equivalent of potassium t-butoxide was added and the mixture was heated for another 3 hours. The reaction was quenched with water and extracted with EtOAc. The extracts were dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative thin layer chromatography and reverse phase chromatography gave the title compound. MS (APCI), positive scan, m/z=625.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][SH:9].[CH3:10][S:11]SC>[H-].[Na+]>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][S:9][S:11][CH3:10]
Reactant: Cc1ncsc1CCS
Reactant: CSSC
Agent: [H-]
Agent: [Na+]
Product: CSSCCc1scnc1C
Yield: 60.4 %

Procedure:
A mixture of 8.26 g (0.052 mol) of 2-(4-methyl-5-thiazolyl)-ethyl-mercaptan and 33.07 g (0.208 mol) of dimethyldisulphide is treated with 50 mg of sodium hydride (50% dispersion in oil) and the mixture is heated to reflux for 4 hours. The mixture is then left to cool, filtered over 10 g of aluminium oxide (activity I, neutral), which is back-washed with ether, and concentrated in a vacuum. The resulting crude product (9.5 g) is distilled through a Hempel column under a high vacuum, there being obtained 6.45 g of [2-(4-methyl-5-thiazolyl)ethyl]-methyl-disulphide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9](=[O:19])[CH:8]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:7]2.[CH:28](=O)[CH3:29].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:12]([N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH2:28][CH3:29])[CH2:7][CH:8]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:9]1=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)NC1Cc2cccc(N)c2N(Cc2ccccc2)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNc1cccc2c1N(Cc1ccccc1)C(=O)C(NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 8-amino-1-benzyl-1,2,3,4-tetrahydro-2-oxoquinolin-3-ylcarbamate (1.0 g) was dissolved in methanol (10 mL), and acetaldehyde (599 mg), acetic acid (10 mg), and sodium cyanoborohydride (171 mg) were sequentially added to the solution under cooling on ice. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated under reduced pressure. The thus-recovered residue was dissolved in ethyl acetate, and the solution was sequentially washed with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, and solvent was evaporated under reduced pressure. The recovered residue was purified through silica gel column chromatography (ethyl acetate: n-hexane=1:3), whereby the title compound (600 mg) was yielded.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.C(N(CC)CC)C.[CH2:35]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)[CH3:36]>C1COCC1>[CH2:35]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([N:25]2[CH2:24][CH2:23][CH:22]([O:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]4[N:12]([C:3]5[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=5[F:1])[N:13]=[CH:14][C:15]=34)[CH2:27][CH2:26]2)=[O:43])=[CH:40][CH:39]=1)[CH3:36]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Reactant: CCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccc(C(=O)N2CCC(Oc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 mL round-bottomed flask fitted with N2 inlet was placed 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.117 mmol) and triethylamine (65 μl) and THF (0.8 mL). The reaction flask was immersed in an ice-bath. 4-Ethoxy-benzoyl chloride (24 mg, 0.129 mmol) was added to the solution and the mixture was stirred 2 h under N2 at 0° C. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was then concentrated under vacuum and purified by column chromatography using EtOAc as eluent to give Compound A184. 1H NMR (CDCl3, 400 MHz) δ 1.43 (t, 3H), 1.96 (m, 2H), 2.17 (m, 2H), 3.13 (s, 3H), 3.55 (m, 2H), 4.06 (m, 2H), 4.12 (m, 2H), 5.71 (m, 1H), 6.92 (d, 2H), 7.43 (d, 2H), 7.92 (m, 3H), 8.33 (s, 1H), 8.62 (s, 1H). Exact mass calculated for C26H26FN5O5S 539.16, found 540.2 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:30][C:31](=[O:33])[CH3:32])[CH3:29])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1>C(#N)C>[CH:3]1([N:2]([CH3:1])[C:9]2[N:14]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:30][C:31](=[O:33])[CH3:32])[CH3:29])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCC1
Reactant: CC(=O)NC(C)Cc1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Solvent: CC#N
Product: CC(=O)NC(C)Cc1ccc(C2CCN(c3ccnc(N(C)C4CCCC4)n3)CC2)cc1
Temperature: 150 °C

Procedure:
181 μL (1.61 mmol) N-Methyl-cyclopentylamine are added to 120 mg (0.32 mmol) N-(2-{4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-1-methyl-ethyl)-acetamide (XIV.2) in 3 mL acetonitrile. The mixture is heated at 150° C. for 30 min under microwave irradiation. After that time, the solvent is evaporated and the residue is purified using reversed phase HPLC (eluent A: water+0.1% TFA, eluent B: acetonitrile+0.1% TFA) to yield the desired product.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[OH:21])[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][C:20]=1[OH:21]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Oc1ccc(-c2nc(-c3cccnc3)no2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-fluoro-4-hydroxybenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.09 (t, J=8.7 Hz, 1H), 7.63 (ddd, J=7.9, 5.2, 0.8 Hz, 1H), 7.86-7.93 (m, 2H), 8.53 (dt, J=7.9, 2.0 Hz, 1H), 8.72 (dd, J=4.8, 1.6 Hz, 1H), 9.27 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 258 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([O:25][C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:24][B:14]1[C:13]2[CH:12]=[C:11]([O:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[CH:10]=[C:9]([OH:8])[C:17]=2[CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCc3ccccc3)c21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of ethyl 2-(4-(benzyloxy)-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]-oxaborol-3-yl)acetate (1.61 g, 3.8 mmol) and 10% Pd/C (0.24 g) in EtOH (10 mL) was stirred at room temperature under H2 atmosphere overnight. The reaction mixture was filtrated through a pad of Celite and the filtrate was concentrated in vacuo to give the title compound (0.71 g, yield: 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=1)[C:15](O)=[O:16].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[O:16])[CH:18]=[CH:19][N:20]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccnc(Cl)c1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
174 mg (1.27 mmol) 5-fluoro-2,3-dihydro-1H-indole were added to 198 mg (1.26 mmol) 2-chloroisonicotinic acid, 351 μL (2.50 mmol) triethylamine and 434 mg (1.35 mmol) TBTU in 3 mL DMF. The reaction mixture was stirred overnight at RT. Purification was carried out by preparative HPLC. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].C(N(CC)CC)C>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15](=[O:26])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCCCO
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCO)Oc1ccc(Oc2ccccc2)cc1
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of the carbonate prepared in Example 1 (10.0 g, 28.4 mmol) in 75 mL of methylene chloride was added under nitrogen dropwise to a solution of 6-amino-1-hexanol (3.34 g, 28.4 mmol) and triethylamine (19.8 mL, 142 mmol) in 100 mL of methylene chloride at ice-bath temperature. The reaction was stirred at ice bath temperature for approximately eight hours and at room temperature overnight. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 8.1 g of a solid. Recrystallization of the solid from diisopropyl ether gave 6.55 g (70%) of the title compound as a white crystalline solid, mp 72°-75° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH2:7]([NH2:10])[C:8]#[CH:9]>C1COCC1>[CH2:7]([N:10]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6])[C:8]#[CH:9]
Reactant: C#CCN
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: C#CCN1CCNC1=O
Temperature: 25 °C
Yield: 81.3 %

Procedure:
Chloroetyl isocyanate (12.2 g, 0.11 mol) was added at 0° C. to a stirred solution of propargylamine (6.6 g, 0.12 mol) in THF (200 mL). The solution was allowed to warm to room temperature and sodium hydride (5.5 g of 50% in oil, washed with ether to remove the oil) was added. The reaction was quenched with acetic acid (6.0 mL), the THF was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The ethyl acetate was evaporated and the residual solid was crystallized from ethyl acetate:Skellysolve B to give 11.1 g of 1-(2-propynyl)-2-imidazolidinone, m.p. 110°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.CN.[C:21]([BH3-])#[N:22].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>C(O)(=O)C.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:22][CH3:21])[CH:12]=2)[CH:3]=1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 58.4 %

Procedure:
4-Chloro-2-(3-formyl-phenoxy)-benzonitrile (0.52 g, 2.02 mmol), methylamine (2M in methanol, 1.0 ml, 2.0 mmol) and sodium cyanoborohydride (0.14 g, 2.2 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (30 ml) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% aqueous sodium carbonate and extracted with ethyl acetate. The ethyl acetate layer was separated and washed with water, brine and dried over MgSO4. After filtration, fumaric acid (0.23 g, 2.0 mmol) was added to the filtrate and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 4-chloro-2-(3-methylaminomethyl-phenoxy)-benzonitrile fumarate (454 mg, 58%) as a white solid.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][CH2:14][O:15][CH3:16])[N:3]=1.C([OH:19])C>[OH-].[Na+]>[CH3:16][O:15][CH2:14][O:13][CH2:12][C:4]1[NH:3][C:2](=[O:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1
Reactant: CCO
Reactant: COCOCc1nc(N)c2nccnc2n1
Agent: [Na+]
Agent: [OH-]
Product: COCOCc1nc2nccnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in section d of Example 2, starting with 5.3 g (0.024 mole) of 4-amino-2-(methoxymethoxymethyl)pteridine in 250 ml of 5% aqueous sodium hydroxide. Heating time: 2 hours at 80° C. Yld: 2.2 g (41%), m.p. 161°-163° C. (ethanol).