Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>CS(C)=O.O>[CH:23]1([NH:28][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCCC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (250 mg, 0.79 mmol) in DMSO (3 mL) was added cyclopentylamine (402.6 mg, 4.73 mmol), and the resulting solution was stirred overnight at 100° C. The resulting mixture was diluted with water (15 mL) and extracted with dichloromethane (3×10 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2%-5% ethyl acetate in petroleum ether) to afford methyl 3-(cyclopentylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (240 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([I:31])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[Se](=O)=[O:33]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:33])[C:5]2[C:9]([I:31])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 53.1 %

Procedure:
6-Chloro-3-iodo-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (20 g, 37.3 mmol) was dissolved in dioxane (400 mL) and selenium dioxide (12.43 g, 112 mmol) was added. The reaction mixture was stirred at 100° C. for 6 hrs. Selenium dioxide (4.14 g, 37.3 mmol) was added and the reaction mixture continued stirring at 100° C. overnight. The reaction was filtered over celite, rinsed with DCM, and concentrated in vacuo. The residue was dissolved in DCM (1.0 L) and filtered over celite. The material was concentrated in vacuo while loading on silica gel. Purification by flash chromatography (0-5% DCM/EtOAc) gave 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (10.88 g, 19.79 mmol, 53.0%). 1H NMR (ppm, 500 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.39-7.35 (m, 10H), 7.17-7.11 (m, 5H), 6.29 (s, 1H).
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=1.[C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH3:18].[Li]>>[C:21]([O:20][C:17](=[O:19])[CH2:18][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from 3-pyridin-3-yl-benzoic acid methyl ester [CAS-No. 79601-27-7] (1.00 g, 4.69 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as an orange oil (673 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].[CH:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1>CN(C=O)C>[OH:1][CH2:2][CH2:3][C:4]([O:6][CH2:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCO
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CCO)OCc1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 46.5 %

Procedure:
3-Hydroxypropanoic acid solution (12 g, 40 mmol, 30% in H2O solution, TCI, TOKYOKASEI) and KOH (2.24 g, 40 mmol, Shantou Xilong chemical factory) was stirred at rt for 30 min, the mixture was concentrated in vacuo to give a white solid. The solid was suspended in 50 mL of DMF was added BnBr (4.75 mL, 40 mmol, Aldrich) via a syringe at rt. After stirring at 80° C. for 5 h, the reaction mixture concentrated in vacuo. The residue was purified by a silica gel column chromatography (10:1 (v/v) petroleum ether/EtOAc) to give the title compound as colorless oil (3.35 g, 46%).
Reaction SMILES: CS(Cl)(=O)=O.[O:6]([CH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]O)[Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li+].[Cl-:34].CC1C=C(C)N=C(C)C=1>CN(C=O)C.O>[O:6]([CH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][Cl:34])[Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [Cl-]
Reactant: CC(C)(C)[Si](OCc1cccc(CO)c1)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCc1cccc(CCl)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
Methanesulfonyl chloride (3.96 g, 34.6 mmol) was added dropwise to a stirred solution of 23 (11.8 g, 31.4 mmol), LiCl (1.33 g, 31.4 mmol), and s-collidine (4.19 g, 34.6 mmol) in anhydrous DMF (120 mL) at 0° C. under argon. The reaction mixture was allowed to warm to room temperature over 2 h, and was then poured into water and extracted twice with diethyl ether. The organic layers were combined and washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 11.8 g (95%) of 24 as a clear, dark yellow liquid. The chloride was used without purification in the next reaction. 1H NMR (300 MHz, CDCl3) δ7.72-7.76 (m, 4H, ArH), 7.31-7.48 (m, 10H, ArH), 4.82 (s, 2H, CH2OSi), 4.62 (s, 2H, CH2C1), and 1.15 (s, 9H, SiC(CH3)3); 13C NMR (75 MHz, CDCl3) δ141.71, 137.35, 135.58, 135.51, 133.39, 129.74, 129.60, 128.64, 127.74, 127.08, 126.20, 126.06, 65.24 (CH2OSi), 46.34 (CH2C1), 26.84 (SiC(CH3)3), and 19.32 (SiC(CH3)3); MS (DCI) m/e 395 (MH+).
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:34]1[CH2:38][C@@H:37]([CH3:39])[C:36](=[O:40])[O:35]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[Cl:31])[CH2:19][C:18]1([CH3:33])[CH3:32])([CH3:11])([CH3:10])[CH3:9].[CH3:42][C:43]([CH3:47])([CH3:46])[CH2:44][NH2:45]>O>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[Cl:31])[CH2:19][C:18]1([CH3:32])[CH3:33])[C@@H:34]([OH:35])[CH2:38][C@H:37]([C:36](=[O:40])[NH:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH3:42])[CH3:39])([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)CN
Reactant: C[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3cc(F)ccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Agent: Oc1ccccn1
Solvent: O
Product: C[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2cc(F)ccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
20 mg of 2-hydroxypyridine (0.21 mmol) was added to a solution of 210 mg of {(S)-2-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (97b) (0.42 mmol) in (2,2-dimethylpropyl)amine (0.74 ml) (6.30 mmol), and the mixture was stirred at 80° C. for two hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride/acetone=5/2-2/1) to obtain 228 mg of the title compound (yield: 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C:8](=O)[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[N:13]=1)([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=1[N+:31]([O-])=O>>[C:1]([O:5][C:6]([C:7]1[C:23]2[C:24](=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=2)[NH:31][C:8]=1[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[N:13]=1)([CH3:11])[CH3:10])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1cccc(C(C)(C)C(=O)CC(=O)OC(C)(C)C)n1
Product: COc1cccc(C(C)(C)c2[nH]c3cc(C#N)ccc3c2C(=O)OC(C)(C)C)n1

Procedure:
According to the method that is used for the preparation of Compound PR5-1, the title compound was synthesized from 4-(6-methoxy-pyridin-2-yl)-4-methyl-3-oxo-pentanoic acid tert-butyl ester and 4-chloro-3-nitrobenzonitrile
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:27].C(Cl)(Cl)Cl.CO.CC(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([F:27])=[O:18])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)F
Reaction time: 0.67 h
Yield: 118.5 %

Procedure:
To a stirred solution of N-benzyloxycarbonyl-L-valine (0.50 g, 2.00 mmol) and pyridine (0.16 ml, 2.00 mmol) in anhydrous DCM (5 ml) kept under a N2 atmosphere was added cyanuric fluoride (0.90 ml, 10.00 mmol) at −15 to −10° C. A white precipitate formed. The reaction was followed by TLC CHCl3/MeOH/AcOH (9:1:0.1) on a small amount of reaction mixture quenched in MeOH. After 1 hr 40 min, crushed ice was added along with DCM (10 ml). The organic layer was separated and the aqueous layer extracted with DCM (5 ml). The combined DCM layers were washed with ice-cold water (10 ml), dried (MgSO4) and concentrated under reduced pressure to afford a colourless oil (0.60 g, 119%) which was used in subsequent reactions without further purification: Rf=0.78 CHCl3/MeOH/AcOH (9:1:0.1); νmax(polyethylene card) 3320 (N—H), 1843 (acid fluoride), 1738 (urethane, C═O), 1538 (amide II); δH (200 MHz, CDCl3) 1.01 (3H, d, J 7.0, CH(CAH3CBH3)), 1.05 (3H, d, J 7.0, CH(CAH3CBH3)), 2.26 (1H, m, CH(CH3)2), 4.49 (1H, m, NHCH), 5.14 (3H, m, OCH2Ph & NH (masked)), 7.37 (5H, s, Ar—H); MS ES (+ve) found m/z 233.8 (C6H5CH2CONHCH(CH(CH3)2)CO—, 41%), 251.8 (N-Cbz-Val, 58), 268.9 (N-Cbz-ValNH4+, 64), 273.8 (N-Cbz-ValNa+, 33), 289.9 (N-Cbz-ValK+, 22), 341.9 (100), 502.1 (N-Cbz-Val dimer, 53), 507.1 (M+ dimer, 55).
Reaction SMILES: BrBr.[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([C:14]([F:17])([F:16])[F:15])=[C:8]([NH:10][C:11]([NH2:13])=[S:12])[CH:9]=1>C(Cl)Cl>[NH2:13][C:11]1[S:12][C:9]2[C:4]([CH3:3])=[CH:5][CH:6]=[C:7]([C:14]([F:17])([F:15])[F:16])[C:8]=2[N:10]=1
Reactant: Cc1ccc(C(F)(F)F)c(NC(N)=S)c1
Agent: BrBr
Solvent: ClCCl
Product: Cc1ccc(C(F)(F)F)c2nc(N)sc12
Temperature: 25 °C

Procedure:
A solution of bromine in dichloromethane (3.4 mL, 1.0M in DCM, 1.0 eq) was added dropwise to a solution of (5-methyl-2-trifluoromethylphenyl)-thiourea (800 mg, 3.4 mmol, 1.0 eq) in dry DCM (100 mL) below 30° C. The reaction mixture was heated at reflux for 3 h and cooled to room temp. A precipitate was collected by filtration, then suspended in water (20 mL), and the pH was adjusted to 11 with NH4OH. The mixture was then extracted with ethyl acetate (3×20 mL), and the combined organic layers were washed with water (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The brown residue was purified by column chromatography on silica gel (eluted by 1% methanol in DCM) to afford 2-amino-7-methyl-4-trifluoromethyl-1,3-benzothiozole as white solid. 1H-NMR (CDCl3, 300 MHz): δ=7.53 (d, J=8.4, 1H), 7.15 (d, J=8.4, 1H), 5.76 (brs, 2H), 2.59 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH2:34](I)[CH3:35]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:34][CH3:35])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCI
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1(c2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3,4-difluorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (200 mg) in DMF (4 mL) was added sodium hydride (60%, 28.4 mg) at room temperature, and the mixture was stirred at 60° C. for 30 min under a nitrogen atmosphere. Ethyl iodide (45.2 μL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was 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) to give the title compound (37.1 mg).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23](B(O)O)=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:7]3[C:6](=[CH:11][C:10]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][C:24]=4[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:9][CH:8]=3)[C:5]([CH3:16])([CH3:17])[C:4]=2[CH:3]=1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: COc1ccc(B(O)O)c(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3c(c2)C(C)(C)c2cc(Br)ccc2-3)c(-c2ccccc2)c1
Temperature: 110 °C
Yield: 75 %

Procedure:
A mixture of 3.52 g (10 mmol) of 2,7-dibromo-9,9-dimethyl-9H-fluorene, 2.75 g (12 mmol) of 5-methoxybiphenyl-2-ylboronic acid, 0.12 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium, 15 ml of 2M Na2CO3, 20 ml of EtOH and 60 ml toluene was degassed and placed under nitrogen, and then heated at 110° C. for 8 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica(hexane-dichloromethane) afforded a white solid (3.4 g, 7.5 mmol, 75%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.ON1C2C=CC=CC=2N=N1.[CH3:24][C:25]1[O:26][C:27]([CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[NH:40][CH:41]2[CH2:46][CH2:45][N:44]([C@@H:47]3[CH2:52][CH2:51][NH:50][C@@H:49]([CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[CH2:48]3)[CH2:43][CH2:42]2)=[CH:28][N:29]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([N:50]1[CH2:51][CH2:52][C@@H:47]([N:44]2[CH2:43][CH2:42][CH:41]([NH:40][C:32]3[N:31]([CH2:30][C:27]4[O:26][C:25]([CH3:24])=[N:29][CH:28]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=3)[CH2:46][CH2:45]2)[CH2:48][C@@H:49]1[CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:13]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: Cc1ncc(Cn2c(NC3CCN([C@@H]4CCN[C@@H](Cc5ccccc5)C4)CC3)nc3ccccc32)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc(Cn2c(NC3CCN([C@@H]4CCN(C(=O)c5oc6ccccc6c5C)[C@@H](Cc5ccccc5)C4)CC3)nc3ccccc32)o1
Yield: 45.2 %

Procedure:
3-methyl-2-benzofurancarboxylic acid (0.100 g) and 1-hydroxy-1H-benzotriazole (0.070 g) were added to (±)-trans-1-[(2-methyl-5-oxazolyl)methyl]-N-[1-[2-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-1H-benzimidazol-2-amine (0.100 g) in CH2Cl2 (5 ml). The mixture was stirred under N2 atmosphere. A solution of triethylamine (0.5 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1:1) (0.080 g) in CH2Cl2 (10 ml) was added dropwise and the reaction mixture was stirred overnight at RT, under N2. Then, the compound was isolated and purified by column chromatography (eluent gradient: (0.5% ammoniumacetate in H2O)/CH3OH/CH3CN 70/15/15 upgrading over 0/50/50 to 0/0/100). The desired fractions were collected and the solvent was evaporated, yielding 0.060 g of (±)-trans-1-[(3-methyl-2-benzofuranyl)-carbonyl]-4-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-(phenylmethyl)piperidine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](O)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:8]=3[C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:21].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[Cl:21][C:4]1[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:8]=3[C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)c2c(n1)-c1cc(Cl)ccc1OCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Nc1nc(Cl)c2c(n1)-c1cc(Cl)ccc1OCC2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of Example 45C (0.56 g, 2.1 mmol) in CHCl3 (4.2 mL) was treated with POCl3 (0.97 mL, 10.5 mmol), cooled to 0° C., treated with triethylamine (0.59 mL, 4.2 mmol), stirred at ambient temperature for 4 hours, diluted with CHCl3 (5 mL), treated with a stream of HCl gas for 2 minutes, stirred at ambient temperature overnight and partitioned between cold 1 M NaOH (50 mL) and CH2Cl2 (50 mL). The layers were separated and the aqueous was extracted with CH2Cl2 (2×50 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed eluting with CH2Cl2 and then 9:1 CH2Cl2:EtOAc to provide the title compound. 1H NMR (DMSO-d6) δ 2.87 (t, J=5.76 Hz, 2H) 4.43 (t, J=5.93 Hz, 2H) 7.12 (s, 2H) 7.15 (d, J=8.81 Hz, 1H) 7.52 (dd, J=8.65, 2.88 Hz, 1H) 7.88 (d, J=2.71 Hz, 1H); MS (M+H)+ m/z 282.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH2:32][CH2:33][CH:34]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:39][C@H:40]1[C@H:49]([O:50]C(=O)C)[C@@H:48]([CH2:54][O:55]C(=O)C)[O:47][C@@H:42]([O:43][CH2:44][CH2:45][NH2:46])[C@@H:41]1[NH:59][C:60](=[O:62])[CH3:61])(=O)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O(C)[Na]>C(Cl)Cl.CO>[C:60]([NH:59][C@@H:41]1[C@@H:40]([OH:39])[C@H:49]([OH:50])[C@@H:48]([CH2:54][OH:55])[O:47][C@H:42]1[O:43][CH2:44][CH2:45][NH:46][CH2:34][CH2:33][CH2:32][C@@H:10]1[O:11][C@@H:12]([CH3:31])[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:62])[CH3:61]
Reactant: C[C@@H]1O[C@@H](CCC=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CC(=O)N[C@H]1[C@H](OCCN)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CO[Na]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N[C@H]1[C@H](OCCNCCC[C@@H]2O[C@@H](C)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)propanal (800 mg, 1.69 mmol) and 2-aminoethyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxy-β-D-glucopyranoside (987 mg, 2.53 mmol) in CH2Cl2 (15 mL) was added acetic acid (29 μL, 0.506 mmol) and sodium triacetoxyborohydride (893 mg, 4.21 mmol). After stirring at rt overnight, the reaction mixture was concentrated and the residue was taken up in EtOAc (70 mL), washed with sat'd NaHCO3 (2×100 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was taken up in CH3OH (8 mL), to which NaOCH3 (27 mg, 0.506 mmol) was added. After stirring at rt for 2 hr, the resulting mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (120 g), eluting with 5-100% AcCN in water to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 1.30 (d, J=6.6, 3H), 1.50 (m, 1H), 1.60 (m, 1H), 1.68 (m, 1H), 2.02 (s, 3H), 2.64 (m, 2H), 2.81 (m, 2H), 3.39 (m, 1H), 3.57 (m, 2H), 3.69 (m, 1H), 3.78-3.85 (m, 4H), 3.92 (m, 2H), 4.00 (m, 2H), 4.45 (d, J=7.7, 1H), 4.52 (d, J=11.9, 1H), 4.62 (d, J=11.8, 1H), 4.68 (d, J=12.1, 1H), 4.79 (d, J=12.0, 2H), 7.28-7.38 (m, 15H), 7.65 (s, 1H); [M+H/e]+=723.3925.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>C(Cl)Cl.CCOC(C)=O>[C:19]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)Cl
Reactant: CN(CCO)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OCCN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.3 %

Procedure:
To a solution of 2-[methyl(phenyl)amino]ethanol (500 mg, 3.3 mmol) in CH2Cl2 (17 mL) was added triethylamine (1.4 mL, 9.9 mmol) followed by propionyl chloride (0.4 mL, 5.0 mmol). After stirring at ambient temperature over 18 hours, the reaction mixture was diluted with EtOAc and washed several times with brine. The organic layer was dried (Na2SO4) and concentrated to afford the title compound (700 mg, quantitative yield). MS (ES+) m/z 208 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
22.4 g of 1-[2-(4-chlorophenyl)-ethyl]piperazine and 12.1 g of triethylamine are dissolved in 200 ml of dichloromethane, and a solution of 20.4 g of 4-methoxybenzoyl chloride in 30 ml of dichloromethane is added dropwise, while stirring, at 25°-30°. Stirring is continued overnight at room temperature and then the whole is washed in succession with 150 ml of 2N sodium hydroxide solution and with water, dried over sodium sulphate and concentrated to dryness by evaporation. The residue is crystallised from ethanol. 1-[2-(4-chlorophenyl)-ethyl]-4-(4-methoxybenzoyl)piperazine having a melting point of 105°-106° is obtained.