Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][OH:30])=[CH:27][CH:28]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CO)cc2)cc1
Reaction time: 1 h
Yield: 101.9 %

Procedure:
Compound 9 (5.0 g, 11.9 mmol) was suspended in anhydrous ethanol (60 mL) at room temperature and sodium borohydride (0.23 g, 6.1 mmol) was added with efficient stirring. Reaction was complete in 1 h, solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was extracted with water (50 mL), brine (25 mL), dried on anhydrous magnesium sulfate, filtered and solvent was evaporated to yield the title compound 12 as white solid (5.1 g, 100%): mp 93-95° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.41 (t, J=2.4 Hz, 1H), 6.29 (d, J=2.0 Hz, 2H), 5.18 (t, J=6.4 Hz, 1H), 4.49 (d, J=4.8 Hz, 2H), 3.73 (s, 3H), 3.57 (s, 6H); MS (EI) m/z 315[M]+. Anal. (C25H24O6) C, H.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:14][C:15]([CH3:26])([CH3:25])[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].C(N(CC)C(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(#N)C.C(OCC)(=O)C.O>[CH3:14][C:15]([CH3:26])([CH3:25])[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[C:2]([F:1])([F:13])[F:12]
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)C#Cc1ccccc1N
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)C#Cc1ccccc1NC(=O)c1ccccc1C(F)(F)F
Yield: 38.4 %

Procedure:
190 mg (1.0 mmol) of 2-trifluoromethylbenzoic acid, 178 mg (0.83 mmol) of 2-(3,3-dimethyl-but-1-ynyl)phenylamine, 215 mg (1.67 mmol) of N,N-diisopropylethylamine and 583 mg (1.25 mmol) of PyBrOP in 8 ml of acetonitrile were stirred at room temperature for 4 days. 10 ml of ethyl acetate/water 1:1 were added to the mixture and the organic phase was separated off and washed with 10 ml of saturated ammonium chloride solution and subsequently with 10 ml of water. Separation, concentration and drying of the organic phase gave 950 mg of crude product. Column-chromatographic purification on silica gel 60 (petroleum ether/ethyl acetate 10:1→ethyl acetate) gave 110 mg of N-[2-(3,3-dimethylbut-1-ynyl)phenyl]-2-trifluoromethylbenzamide [logP (pH 2.3)=4.55].
Reaction SMILES: [O:1]=[C:2](C)[C:3]([NH:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])=O.[CH3:18]C1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:9]([C@@H:7]1[NH:8][C:2](=[O:1])[C:3](=[CH2:18])[NH:5][C:6]1=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)C(=O)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C1NC(=O)[C@H](Cc2ccccc2)NC1=O
Yield: 1789.5 %

Procedure:
Using a Dean-Stark trap whose trap part was filled with molecular sieves 3A, a solution of N-2-oxo-propanoyl-L-phenylalanine amide from Example 1a (100 mg, 0.427 mmol) in toluene (20 mL) was refluxed in the presence of p-TsOH.H2O (4.37 mg, 0.023 mmol, 0.05 eq) for 18 h. After removal of the solvent, the residue was triturated in ether to obtain 89 mg (96%) of the title compound as a white solid: mp 175-177° C. (decomp); 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.41 (s, 1H), 7.24-7.11 (m, 5H), 4.90 (s, 1H), 4.50 (s, 1H), 4.40-4.37 (m, 1H), 3.15 (dd, J=3.8, 13.5 Hz, 1H), 2.91 (dd, J=5.0, 13.5 Hz, 1H); HRMS (EI): m/z 216.0891(M+) (calcd for C12H12N2O2: 216.0899). Enantiomeric excess was determined to be >99% using chiral HPLC with a CHIRALCEL OD column.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.N1CCCCC1.[O:25]1[CH:29]=[C:28]([C:30]([OH:34])([C:32]#[CH:33])[CH3:31])[N:27]=[CH:26]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.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:33]#[C:32][C:30]([C:28]4[N:27]=[CH:26][O:25][CH:29]=4)([OH:34])[CH3:31])[CH:10]=3)[C:6]([CH3:18])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#CC(C)(O)c1cocn1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(I)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3cocn3)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a vial was added 4-(6-iodo-3-methylindazol-1-yl)pyrimidin-2-amine (150 mg, 0.43 mmol), piperidine (1.5 mL), tetrakis(triphenylphosphine)palladium (49.36 mg, 0.04 mmol), copper(I) iodide (8.14 mg, 0.04 mmol) and 2-(1,3-oxazol-4-yl)but-3-yn-2-ol (87.87 mg, 0.64 mmol). The mixture was stirred at RT for 20 mins. Reaction mixture was concentrated in vacuo. DCM (5 mL) added and mixture was concentrated in vacuo. This was repeated twice. The crude material was purified by column chromatography (Biotage, 98:2 to 88:12 DCM: methanol gradient). Further purification by flash column chromatography gave the title compound: 1H (500 MHz, DMSO) delta 1.81 (3H, s), 2.58 (3H, s), 6.26 (1H, s), 6.99 (2H, s), 7.04 (1H, d, J=5.5 Hz), 7.39 (1H, dd, J=8.2, 1.1 Hz), 7.85 (1H, d, J=8.1 Hz), 8.13 (1H, s), 8.26 (1H, d, J=5.5 Hz), 8.36 (1H, s), 8.87 (1H, s); LC-MS: m/z=+361.05 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(N)=O)ncn2-c2cccc(Cl)c2C1=O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1Cc2c(C#N)ncn2-c2cccc(Cl)c2C1=O

Procedure:
19.0 g 7-Chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide were suspended under stirring and argon atmosphere in 95 ml 1,4-dioxane and 6.58 ml phosphorous oxychloride were added in one portion. The reaction mixture was heated to reflux for one hour giving a yellow solution, which was concentrated at 50° C. under reduced pressure. The residue was digested in 100 ml deionized water for two hours at r.t. The precipitate (7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile) was filtered off, washed three times with 30 ml deionized water and dried under vacuum at 80° C. for 18 hours. Crude product: 17.3 g as a light yellow powder. m.p. 238.5-239.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1.[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:28][CH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1CBr
Temperature: 0 °C
Yield: 32.8 %

Procedure:
A mixture of ethyl 2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (5 g), N-bromosuccinimide (5.9 g) and benzoyl peroxide (0.1 g) in carbon tetrachloride (200 ml) was refluxed for 5 hours. The reaction mixture was poured into ice water (100 ml). The separated organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel eluting with a mixture of n-hexane and chloroform (1:2 V/V). The fractions containing the desired compound were combined and evaporated in vacuo to give ethyl 2-bromomethyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (2 g).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C@@H:25]1[CH2:29][S:28][CH2:27][N:26]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].[H][H]>O1CCCC1.P([O-])([O-])([O-])=O.[OH-].[OH-].[Pd+2]>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C@@H:25]1[CH2:29][S:28][CH2:27][NH:26]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C([C@@H]3CSCN3C(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C([C@@H]3CSCN3)C[C@H]12
Yield: 6.3 %

Procedure:
A solution of 4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(4R)-3-(4-nitrobenzyloxycarbonyl)thiazolidin-4-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.00 g) in a mixture of tetrahydrofuran (30 ml) and phosphate buffer (pH 6.5) (30 ml) was hydrogenated under atmospheric pressure of hydrogen over palladium hydroxide on carbon (20%, 0.6 g) for 3 hours at ambient temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give an aqueous solution. The solution was washed with ethyl acetate, subjected to a column chromatography on silica gel (75 g), and eluted with a mixture of acetonitrile and 75:25, V/V). The fractions containing the object compound were collected and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(4R)-thiazolidin-4-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.06 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[F:30])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=C2N=NN(O)C2=CC=1.O.C(Cl)Cl.[F:64][C:65]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:66]O>>[F:64][C:65]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:66][O:34][C:33](=[O:35])[C@H:32]([OH:36])[CH2:31][N:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:37])=[CH:9][CH:10]=1)[NH:16][C:17]([C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH:20]=1)=[O:18]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.8 %

Procedure:
A mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (30.0 mg, 57 μmol), EDC HCl (65.4 mg, 341 μmol), and HOBt hydrate (52.2 mg, 341 μmol) in DCM (0.5 mL, 8 mmol) was stirred at room temperature for 10 minutes. 2,2,3,3,3-Pentafluoro-1-propanol (45.3 μL, 455 μmol) was added and the resulting mixture was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in AcOH (2 mL), filtered, and purified by reverse phase prep HPLC to yield the title compound (4.8 mg, purity 90.2%) as a TFA salt. MS m/z [M+H]+ calc'd for C29H21ClF7N3O5, 660.11. found 660.3.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH2:26]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C#N)cc1

Procedure:
A sample of p-aminobenzonitrile is treated at 135° for 15 hours with equimolar quantities of 1-bromohexadecane and anhydrous potassium carbonate in hexamethylphosphoramide. Upon cooling the mixture is diluted with water and extracted with ether. Evaporation of the ether extracts and recrystallization of the residue yields p-(hexadecylamino)benzonitrile.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:13]=[CH:14][C:3]=12.C([OH:23])C>Cl>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:12]1[C:4]2[NH:5][C:6]3[C:11]([C:2](=[O:23])[C:3]=2[CH:14]=[N:13]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCO
Reactant: Clc1c2ccccc2nc2c1cnn2-c1ccccn1
Agent: Cl
Product: O=c1c2ccccc2[nH]c2c1cnn2-c1ccccn1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 4-chloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (14 g, 0.050 mol) in ethanol (600 mL), 6N hydrochloric acid (30 mL) was added and the mixture was heated under reflux for 12 hours. The reaction solution was allowed to cool to room temperature, and concentrated and evaporated under reduced pressure. The residue was made basic by addition of an aqueous sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=96:4) to give the title compound (10.8 g, 82% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:8][S:7][CH:6]=1)=[O:4].[Br:22]N1C(=O)CCC1=O>CCOCC>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:8]([Br:22])[S:7][CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cscc1NS(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COC(=O)c1csc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of the product of Example 2 in 5.0 mL of AcOH--CHCl3 (1:1) at room temperature was added 0.299 g (1.682 mmol) of N-bromosuccinimide. The reaction was stirred for 18 h and then diluted with ether, washed with water and saturated sodium bicarbonate solution, dried over MgSO4, filtered and concentrated in vacuo. The tan solid residue was washed with ether-hexanes (1:1) to provide 0.504 g (81%) of the desired product as a tan solid. Electrospray Mass Spec: 406.1 (M+H)+
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[C@@H:11]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:29]([O:15][C@H:12]1[CH2:13][CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[CH2:10][C@@H:11]1[C:16]1[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1nccc1[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nccc1[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1OC(=O)c1ccccc1
Yield: 90.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 107a by using the (1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (1.07 g, 3.45 mmol) prepared in Example 161a, triethylamine (2.88 mL, 20.7 mmol), benzoyl chloride (2.00 mL, 17.2 mmol) and dichloromethane (10 mL), to yield the title compound (1.30 g, 91%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][NH:6][N:7]=[C:8]([C:10]1[C:19]2[C:18]([C:20]([OH:22])=[O:21])=[CH:17][C:16](Cl)=[C:15]([C:24]([OH:26])=[O:25])[C:14]=2[C:13]([C:27](=[N:29][NH:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[OH:28])=[CH:12][C:11]=1Cl)[OH:9].[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][NH:6][N:7]=[C:8]([C:10]1[C:19]2[C:18]([C:20]([OH:22])=[O:21])=[CH:17][C:16]([NH:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[C:15]([C:24]([OH:26])=[O:25])[C:14]=2[C:13]([C:27](=[N:29][NH:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[OH:28])=[CH:12][C:11]=1[NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[OH:9]
Reactant: CN(C)CCCNN=C(O)c1cc(Cl)c(C(O)=NNCCCN(C)C)c2c(C(=O)O)cc(Cl)c(C(=O)O)c12
Reactant: NCCN1CCCCC1
Product: CN(C)CCCNN=C(O)c1cc(NCCN2CCCCC2)c(C(O)=NNCCCN(C)C)c2c(C(=O)O)cc(NCCN3CCCCC3)c(C(=O)O)c12

Procedure:
Compound 7 (45 mg, 0.089 mmol) was suspended in 1-(2-aminoethyl)piperidine (0.5 ml) in a microwave reaction vessel. The tube was flushed with nitrogen, sealed and treated at 150° C. for 10 min in the microwave. The amine was then evaporated off under high vacuum. The crude mixture was purified by HPLC to obtain 8 as a blue solid. Yield 8 (6.62 mg, 0.0096 mmol, 10.8%): 1H NMR (CDCl3) δ: 1.47(m, 4H), 1.64(m, 8H), 1.90(5q, 4H, J=7.3 Hz), 2.26(s, 12H), 2.43(t, 4H, J=7.3 Hz), 2.51(m, 8H), 2.73(t, 4H, J=6.5 Hz), 3.58(m, 4H), 4.22(t, 4H, J=7.5 Hz), 8.07(s, 2H), 9.50(t, 2H, J=4.9 Hz); 13C NMR (CDCl3) δ: 24.44(2×CH2), 26.06(4×CH2, 2×CH2), 38.66(2×CH2), 40.49(2×CH2), 45.34(4×CH2), 54.57(4×CH3), 57.29(2×CH2), 57.38(2×CH2), 101.97(2×C), 118.38(2×CH), 121.07(2×C), 125.62(2×C), 148.90(2×C), 163.05(2×C═O), 165.79(2×C═O); HRMS (ES+) calcd C38H56N8O4 [M+2H]2+ 345.2285. Found: 345.2293.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.CS[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:18][N:17]=1>>[CH3:13][C:4]1[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:16]2[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:18][N:17]=2)=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Reactant: Cc1cc(Br)cnc1CCCCN
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Reaction time: 6 h
Yield: 77 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine, (0.73 g), was fused with 2-methylthio-5-(4-chlorobenzyl)-4-pyrimidone (0.75 g) at 160°-170° C. and heating was continued for 6 hours. The mixture was cooled and recrystallised from chloroform/petroleum-ether (b.p. 60°-80° C.), to give 2-[4-(3-methyl-5-bromopyrid-2-yl)butylamino]-5-(4-chlorobenzyl)-4-pyrimidone (1.0 g) m.p. 149°-150° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:28])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]#[N:27])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[N-:29]=[N+:30]=[N-:31].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC.Cl>>[CH3:1][C:2]1[N:3]=[C:4]([CH3:28])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:31][N:30]=[N:29][N:27]=4)=[CH:16][CH:15]=3)[C:6]=2[N:7]=1
Reactant: Cc1nc(C)c2ccc(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2n1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Product: Cc1nc(C)c2ccc(=O)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2n1

Procedure:
Using the same procedure as described in Step 3 of Example 8, heat a mixture of 2,4-dimethyl-8-[[2'-cyano[1,1-biphenyl]-4-yl]methyl]-7H-pyrido[2,3-d]pyrimidin-7-one, NaN3, and tri-n-butyltin chloride in xylenes under reflux for 48 h. Cool the mixture and add 1N HCl (2 mL). Add CHCl3 and water, and dry (MgSO4) and concentrate the organic phase. Recrystallization from EtOAc gives the product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[CH2:22]([O:29][CH2:30][C:31](Cl)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([O:29][CH2:30][C:31]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)COCc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc2cccc(NC(=O)COCc3ccccc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 80 °C
Yield: 46 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.42 g, 1.4 mmol) in tetrahydrofuran (10 mL), was added benzyloxyacetyl chloride (0.75 mL, 4.8 mmol) and heated at 80° C. for three hours. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-benzyloxy-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamide as a white solid (280 mg, 47% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.46 min (99.2%); mp, 272-274° C.; 1HNMR (DMSO-d6) δ 2.17-2.22 (m, 1H, CHH), 2.65-2.93 (m, 6H, CHCH2, CH3), 4.13-4.30 (dd, J=15, 36 Hz, 2H, CH2), 4.64 (s, 2H, CH2), 5.33 (dd, J=5, 11 Hz, 1H, CH), 7.25-8.68 (m, 8H, Ar), 11.10 (s, 1H, NH), 12.48 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.62, 23.38, 30.83, 56.93, 70.17, 72.80, 107.95, 115.38, 120.97, 127.47, 127.53, 128.13, 135.52, 137.33, 138.95, 147.90, 154.90, 162.73, 168.94, 169.28, 172.51, 172.62. LCMS MH=435; Anal Calcd For C23H22N4O5+0.6H2O: C, 62.04; H, 5.25; N, 12.58. Found: C, 61.82; H, 4.90; N, 12.49.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])(=O)=O>>[N:1]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[N+:2]=[N-:3]
Reactant: COCCOCCOCCOS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COCCOCCOCCN=[N+]=[N-]
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Sodium azide (5.37 g, 83 mmol) and 2-(2-(2-methoxyethoxy)ethoxy)ethyl methanesulfonate (20 g, 83 mmol) were added without solvent, the temperature was raised to 60° C. and the mixture stirred for 48 hours. The salts were filtered and ethyl acetate added to precipitate the dissolved salts and filtered again, producing 1-azido-2-(2-(2-methoxyethoxy)ethoxy)ethane.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([N:12]=[CH:13][N:14]([CH3:16])[CH3:15])(=[O:11])=[O:10].O>C(C(C)=O)C>[CH3:15][N:14]([CH:13]=[N:12][S:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][I:1])(=[O:11])=[O:10])[CH3:16]
Reactant: CN(C)C=NS(=O)(=O)CCCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CN(C)C=NS(=O)(=O)CCCCCI
Yield: 93.3 %

Procedure:
2.98 g of sodium iodide were added to a solution of 2.09 g of the product of Step B in 31.5 ml of methyl ethyl ketone (M.E.K.), and the mixture was refluxed for 4 hours. After cooling, water was added and extraction was carried out with ethyl acetate. The extracts were washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 2.69 g of the expected product.