Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[O:10])=[CH:4][CH:3]=2)=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Br)nc2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A mixture of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate (1.75 g, 4.55 mmol), [4-(methylsulfonyl)phenyl]boronic acid (911 mg, 4.55 mmol), 2M Na2CO3 (5 mL) and Pd(PPh3)2Cl2 (400 mg, 0.57 mmol) in DME (10 mL) was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, and the organic phase was separated and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 5% MeOH/CH2Cl2 to give 1.41 g (68%) of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}amino)carbonyl]-1-piperidinecarboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.74 (bs, 1H), 8.57-8.46 (m, 1H), 8.16 (d, 2H, J=8.5 Hz), 8.03 (d, 2H, J=8.4 Hz), 7.81 (d, 1H, J=8.7 Hz), 4.28-4.11 (m, 2H), 3.07 (s, 3H), 2.85-2.74 (m, 2H), 2.55-2.44 (m, 1H), 2.00-1.80 (m, 2H), 1.82-1.69 (m, 2H), 1.45 (s, 9H); LRMS (ESI), m/z 460 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].[OH-].[Na+]>ClCCl>[C:31]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([N:12]([CH2:22][P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)(=[O:33])[CH3:32]
Reactant: CCOP(=O)(CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOP(=O)(CN(c1ccc2c(c1)CCN2C(C)=O)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.45 g diethyl {[(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-methyl}-phosphonate are dissolved in 20 ml dichloromethane, combined with 2 ml acetic anhydride and stirred for 2 hours at ambient temperature. The mixture is diluted with dichloromethane, cooled to 0° C. and 20 ml of 4 N sodium hydroxide solution are added thereto. After stirring for 30 minutes the phases are separated and the organic phase is washed with saturated sodium chloride solution. Then it is dried on magnesium sulphate, the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol 95:5 to 75:25).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:31]=[C:32]([CH:38]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:40]=1)[C:33]([N:35]([CH3:37])[CH3:36])=[O:34].BrC1C=C(C=C(O)C=1)C(N(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(COC)OC>[NH2:1][C:2]1[C:3]([C:39]2[CH:38]=[C:32]([CH:31]=[C:30]([OH:29])[CH:40]=2)[C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CN(C)C(=O)c1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: CN(C)C(=O)c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(C(=O)N(C)C)c3)n(-c3ccccc3)c(=O)c12
Yield: 44 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70.5 mg, 0.16 mmol) was treated with 3-hydroxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (113 mg, 0.39 mmol, prepared from 3-bromo-5-hydroxy-N,N-dimethylbenzamide, as described at WO 2009077385 A1 20090625, and bis(pinacolate)diboron according to the method describe at Preparation 119b), sodium carbonate (40.55 mg, 0.38 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (39.2 mg, 0.05 mmol) in water (1.7 ml) and dimethoxyethane (6.5 ml) according to the method described in Example 3 to give 40.7 mg (44% yield) of the title compound. Purity 90%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=[O:19].CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1>[C:24]([C:17]1[O:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1)(=[O:26])[CH3:25]
Reactant: O=C(O)c1ccco1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)c1ccc(C(=O)O)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a solution of diisopropylamine (27.5 mL, 0.20 mol) in 200 mL of THF at 0° C. was added n-butyllithium (78.5 mL, 0.196 mol; 2.5M in hexanes). The solution was stirred 30 min and was cooled to -78° C. A solution of furoic acid (10.0 g, 0.089 mol) in 100 mL of THF was added and the solution stirred 30 min. To this mixture was added N-methoxy- N-methyl-acetamide (13.8 g, 0.134 mol) in 50 mL of THF. The reaction mixture was warmed to room temperature and stirred 1 h. The mixture was quenched with saturated ammonium chloride solution and the aqueous layer was washed with ether (3×50 mL) to remove impurities. The aqueous layer was acidified with 2M HCl and extracted with ethyl acetate (3×100 mL). The combined organic extract was washed with brine, dried over MgSO4, filtered and evaporated to yield 11.1 g (81%) of 2-acetyl-fur-5-yl carboxylic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][OH:10])[N:6]=[CH:5]1.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[Si:11]([O:10][CH2:9][C:7]1[N:6]=[CH:5][N:4]([CH2:3][O:2][CH3:1])[CH:8]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COCn1cnc(CO)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCn1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reaction time: 24 h

Procedure:
The compound (8.81 g) obtained in (2) was dissolved in dichloromethane (100 mL), followed by addition of tert-butyldiphenylsilyl chloride (hereinafter, also referred to as TBDPSCl) (24.3 mL), DIEA (21.6 mL) and DMAP (0.760 g) under stirring, and the stirring was continued for 1 day. The reaction solution was concentrated, and the resulting residue was purified by flash chromatography (ethyl acetate/hexane=50%→100%) using silica gel column (product name: Hi-Flash Column 4 L, manufactured by Yamazen Corporation) to afford the title compound (16.9 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[N:16]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[C:22]([CH3:29])[N:23]=[CH:24]2)=[C:17]=[O:18].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[CH3:29][C:22]1[N:23]=[CH:24][C:25]2[C:20]([CH:21]=1)=[C:19]([NH:16][C:17]([NH:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:15][CH:14]=1)=[O:18])[CH:28]=[CH:27][CH:26]=2
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: CC1CCN(c2ccc(CN)cc2)CC1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCC(C)CC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(4-methyl-1-piperidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.66 (s, 1H), 8.74 (s, 1H), 8.59 (d, 1H, J=8.7 Hz), 8.01 (d, 1H, J=8.7 Hz), 7.82 (m, 2H), 7.65 (m, 2H), 7.48 (m, 2H), 4.40 (d, 2H, J=6 Hz), 3.54 (m, 4H), 2.78 (s, 3H), 1.90-1.50 (m, 5H), 0.98 (d, 3H, J=6 Hz); MS (ESI) 389 (M+H)+; Anal. Calcd for C24H28N4O.2.6HCl: C, 59.64; H, 6.38; N, 11.59. Found: C, 59.31; H, 6.39; N, 11.19.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]([C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=O)=[CH:27][CH:26]=1)=[O:20].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:10]([N:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:32](=[O:34])[CH2:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:22]2[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=2[C:19]([O:18][CH3:17])=[O:20])=[CH:30][CH:29]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCNCCc1ccccc1
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCN(CCc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
N-(2-Phenylethyl)heptan-1-amine (0.080 g, 0.366 mmol) was dissolved in DMF (5 ml), (4-{[2-(methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (0.100 g, 0.333 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-Benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.118 g, 0.366 mmol) and N-ethyl-N,N-diisopropylamine (0.090 g, 0.699 mmol) were added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of water (2×20 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.146 g of methyl 2-[(4-{2-[heptyl(2-phenylethyl)amino]-2-oxoethyl}phenoxy)methyl]-benzoate (yield 87.4%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][C@@H:15]1[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:19]=[CH:20][CH:21]=2)[CH2:16]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:31][N:28]1[CH2:29][CH2:30][N:25]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH2:16][C@H:15]([NH:14][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:24][CH2:23]3)[CH2:26][CH2:27]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)CCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)CCCCc2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Phenylvaleric acid (1.0 g, 5.6 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (93 mg, 0.47 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine (93 μL, 0.68 mmol) in methylene chloride (15 mL) . After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (66%) of the title compound as viscous oil: [α]21D +7.4° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 405 (11, M+).
Reaction SMILES: O=O.C[N:4]([CH3:21])[CH:5]=[CH:6][C:7]([C:9]1[CH:10]=[C:11]([N:15]([CH2:19][CH3:20])[C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1)=O.N[C:23]1[C:27]([C:28]#[N:29])=C[NH:25][N:24]=1>O>[CH3:20][CH2:19][N:15]([C:16]([CH3:17])=[O:18])[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[N:25]3[N:24]=[CH:23][C:27]([C:28]#[N:29])=[C:21]3[N:4]=[CH:5][CH:6]=2)[CH:10]=1
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Agent: O=O
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Yield: 91 %

Procedure:
WO O2/100828 A2 discloses a further improvement in the '538 process by reacting the same intermediates, N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide and 3-amino-4-cyanopyrazole, in a liquid medium of water and a water-miscible organic compound under acidic conditions. Although the reaction is claimed to proceed through an imine intermediate that was prone to precipitate from water, the imine intermediate remained dissolved in the reaction media. It is stated in the '828 patent that the process proceeds rapidly at ambient temperature to produce zaleplon with a 91-97% yield having a purity ranging from 98.7 to 99.5% according the HPLC analysis. The method minimized the formation of a regioisomer by-product, N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide which is favored under excess acid conditions.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:17]#[N:18])[CH:14]=3)[C:9]2=[O:19])[CH2:6][CH2:5][C:4](=[O:20])[NH:3]1.[ClH:21]>CN1CCCC1=O.[Pd]>[ClH:21].[NH2:18][CH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:19])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:20])[NH:3][C:2]1=[O:1])[CH2:16]2
Reactant: N#Cc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: [Pd]
Agent: Cl
Solvent: CN1CCCC1=O
Product: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O

Procedure:
A mixture of 2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (9.2 g, 34 mmol), 10% Pd—C (1.7 g) and concentrated HCl (5.3 g) in N-methylpyrrolidone (300 mL) was hydrogenated at 58 psi overnight. The crude reaction mixture was filtered through Celite, and the catalyst washed with water. The combined filtrate was concentrated in vacuo, and the product, 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride, was isolated by fractional crystallization of the residue from isopropanol-water (1.9 g, 18%); 1H NMR (DMSO-d6) δ 1.85-2.20 (m, 1H), 2.35-2.45 (m, 1H), 2.58-2.80 (m, 1H), 2.87-2.99 (m, 1H), 4.16 (s, 2H), 4.35 (d, J=17.5 Hz, 1H), 4.49 (d, J=17.5 Hz, 1H), 5.13 (dd, J=13.2 Hz, J=4.8 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.72 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 8.43 (br, 3H), 11.01 (s, 1H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:20]=2)=[CH:12][CH:11]=1.C(O)(=O)C>ClCCl>[Br:8][C:18]1[O:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:20][C:19]=1[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2nc(-c3ncccn3)co2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc(-c2nc(-c3ncccn3)c(Br)o2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NBS (2.03 g, 11.4 mmol) and 2-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrimidine (1.4) (2.5 g, 10.36 mmol) in a solvent mixture of 1:1 acetic acid and dichloromethane were stirred at room temperature for 3 hr. Then the solvents were removed in vacuo, and the resulting residue was dissolved in EtOAc. The solution was washed with aqueous Na2S2O3 and brine, and dried over MgSO4. The drying agent was filtered off and the filtrate was concentrated to give the title compound. LC-MS m/z 321.96 [M+1]+.
Reaction SMILES: O1CCCC1.[C:6]1([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([NH2:19])[CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31]>O.C(Cl)Cl>[CH3:27][O:28][CH2:29][C:30]([NH:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:13]([CH2:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:14]1)=[O:31]
Reactant: COCC(=O)Cl
Reactant: N[C@@H]1CCCN(Cc2ccccc2)C1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COCC(=O)N[C@@H]1CCCN(Cc2ccccc2)C1
Yield: 96.8 %

Procedure:
To a 50 ml anhydrous tetrahydrofuran solution of 5.00 g (26.3 mmol) of (R)-1-phenylmethyl-3-aminopiperidine (Referential example 7) in a 300 ml three-necked flask was added a 50 ml anhydrous tetrahydrofuran solution of 3.20 g (1.2 eg.) of triethylamine, and, to this reaction mixture was added dropwise a 50 ml anhydrous tetrahydrofuran solution of 2.85 g (1.0 eg.) of methoxyacetyl chloride under stirring and cooling with ice. After reacted for 5 hours at room temperature, methylene chloride and small amount of water were added to extract (20 ml×6). The organic layers were combined and dried over anhydrous sodium sulfate. Then, solvent was distilled off under reduced pressure and the residue thus obtained was purified by column chromatography (alumina, ethyl acetate:n-hexane=1:1) to obtain 6.67 g (yield 97 %) of title compound as a pale yellow oil.
Reaction SMILES: C(OC(=O)[C:7]([N:29]=C(C1C=CC=CC=1)C1C=CC=CC=1)([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][CH2:11][B:12]1[O:16]C(C)(C)C(C)(C)[O:13]1)(C)(C)C>Cl.O>[NH2:29][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:16])[OH:13])[C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(N=C(c1ccccc1)c1ccccc1)C(=O)c1ccccc1
Agent: Cl
Solvent: O
Product: NC(CCCCB(O)O)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
A solution of 2-(benzhydrylidene-amino)-2-benzoyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-hexanoic acid tert-butyl ester (186 mg, 0.32 mmol) in 6 N HCl (6 mL) was stirred at 65° C. for 1 day. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×5 mL). The aqueous layer was frozen in liquid nitrogen and lyophilized to give 2-amino-6-borono-1-phenyl-hexan-1-one (76.5 mg, 88%). 1H NMR (D2O, 300 MHz) δ 8.04-7.60 (m, 2H), 7.77 (tt, J=7.6, 1.2 Hz, 1H), 7.61 (d, J=7.6 Hz, 2H), 5.18 (dd, J=7.5, 4.7 Hz, 1H), 2.15-1.82 (m, 2H), 1.5-1.2 (m, 4H), 0.69 (t, J=7.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH:10]C(OC(C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:18][C:19]1[C:24]([C:25]([N:27]=[C:28]=[O:29])=O)=[C:23]([F:30])[C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([F:30])[C:24]=1[C:25]1[NH:27][C:28](=[O:29])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)c(Cl)c3)c(=O)[nH]2)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 7.1 %

Procedure:
To a solution of tert-butyl 2-(3,4-dichlorophenyl)hydrazinecarboxylate (Intermediate-52, 0.060 g, 0.21 mmol) in DCM (10 mL) was added solution of 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.101 g, 0.32 mmol) in DCM and the reaction mixture was stirred for 20 h at room temperature, followed by addition of TFA (3 mL) and further stirred for 20 h at room temperature. The reaction mass was quenched in water, extracted with DCM and concentrated to afford crude product which was purified by column chromatography eluting with MeOH:DCM to afford 0.007 g of pure product. 1H NMR (300 MHz, CDCl3): δ 1.20 (s, 9H), 4.44 (d, J=5.4 Hz, 2H), 6.20 (m, 1H), 7.29 (m, 1H), 7.41-7.49 (m, 2H), 7.91 (d, J=8.1 Hz, 1H), 8.15 (s, 1H); MS (m/z): 471.26 (M+).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([OH:11])[CH2:7][CH2:8][CH2:9][OH:10]>>[P:1]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:11][P:1]([Cl:5])([Cl:3])=[O:2])([Cl:5])([Cl:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCCCCO
Product: O=P(Cl)(Cl)OCCCCOP(=O)(Cl)Cl
Reaction time: 2 h

Procedure:
A 500 ml four-necked flask with stirrer, thermometer, dropping funnel with pressure compensation and reflux condenser was charged with 300.0 g of phosphoryl chloride at 20° C. Then a vacuum of 200 mbar was applied and 45.0 g of 1,4-butanediol were added dropwise over the course of 45 minutes. Cooling in an ice-water bath kept the temperature at 20° C. A clear, colourless reaction mixture was formed. After the end of the metered addition, the pressure was lowered to about 100 mbar, and stirring was continued for 2 hours. A distillation bridge was then mounted on, and the excess of phosphoryl chloride was removed by distillation. This left 144.9 g (91%) of 1,4-butanediol bis(dichlorophosphate).
Reaction SMILES: CC1C=CC(CCO)=CC=1CCCCC.[O:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][C:19]=1[CH:27]=[CH:28][CH2:29][CH2:30][CH3:31])[CH3:17].CC1C=CC(CCO)=CC=1C=CCCC>>[CH3:17][O:16][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][C:19]=1[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCC=Cc1cc(CCO)ccc1OC
Agent: CCCC=Cc1cc(CCO)ccc1C
Agent: CCCCCc1cc(CCO)ccc1C
Product: CCCCCc1cc(CCO)ccc1OC

Procedure:
By working as described for preparation 1d), but using compound 2c) from the previous step instead of compound 1c), the title compound is obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(CCCCCBr)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCCCCc1ccc(OCc2ccccc2)cc1

Procedure:
5-Bromo-1-(4-benzyloxy-phenyl)-pentane (10.4) was prepared as in 10.1 using 9.4 (2.99 g, 12.3 mmol), K2CO3 (4.24 g, 30.75 mmol) and benzyl bromide (2.31 g, 13.53 mmol). The title compound (10.4) was isolated as a white semi-solid after purification by flash column chromatography (3.11 g, 76% yield).
Reaction SMILES: [N+:1](=[C:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])=[N-].[I:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)N>>[I:11][C:12]1[CH:13]=[C:14]([N:1]([C:3]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[OH:10])[C:3]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[OH:10])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(I)c1
Reactant: [N-]=[N+]=C1C(=O)CCCC1=O
Product: O=C1CCCC(O)=C1N(C1=C(O)CCCC1=O)c1cccc(I)c1

Procedure:
Following the procedure described in the Example 1, using 2-diazo-cyclohexane-1,3-dione and 3-iodoaniline as starting materials to yield the title compound as a white solid.