Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[C:22]1([C:28]#[C:29][C:30]2[CH:31]=[N:32][CH:33]=[C:34]([CH:38]=2)[C:35](O)=[O:36])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[CH3:40][NH:41][O:42][CH3:43]>O1CCCC1>[CH3:43][O:42][N:41]([CH3:40])[C:35](=[O:36])[C:34]1[CH:38]=[C:30]([C:29]#[C:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:31]=[N:32][CH:33]=1
Reactant: CNOC
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Add 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (3.86 g, 20.2 mmol) and diisopropylethylamine (7.0 mL, 40.3 mmol) to a suspension of 5-phenylethynylnicotinic acid (3.0 g, 13.4 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.97 g, 20.2 mmol) in tetrahydrofuran (100 mL) and stir at room temperature overnight. Concentrate the reaction mixture, dissolve the residue in ethyl acetate and wash sequentially with an aqueous solution of phosphate buffer (pH=7) and a saturated aqueous solution of sodium chloride. Dry the organic layer over magnesium sulfate, filter and concentrate. Purify the residue by silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes, to give the title compound as a pale yellow solid (2.4 g, 67%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[N:24]=[CH:23][N:22]=[C:21]2OC1C(F)=C(F)C(F)=C(F)C=1F.[Cl:49][C:50]1[CH:58]=[C:57]([C:59]#[C:60][CH2:61][O:62][CH3:63])[C:53]2[O:54][CH2:55][O:56][C:52]=2[C:51]=1[NH2:64].[Cl-].[NH4+]>CN(C)C=O>[Cl:49][C:50]1[CH:58]=[C:57]([C:59]#[C:60][CH2:61][O:62][CH3:63])[C:53]2[O:54][CH2:55][O:56][C:52]=2[C:51]=1[NH:64][C:21]1[C:20]2[C:25](=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[C:18]([O:17][CH3:16])[CH:19]=2)[N:24]=[CH:23][N:22]=1
Reactant: COc1cc2c(Oc3c(F)c(F)c(F)c(F)c3F)ncnc2cc1OCCN1CCOCC1
Reactant: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Temperature: 25 °C
Yield: 7.4 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.63 ml) in tetrahydrofuran (1.0M, 1.63 mmol) was added dropwise to an ice-cold solution of 6-methoxy-7-(2-morpholin-4-ylethoxy)-4-(pentafluorophenoxy)quinazoline (0.35 g, 0.74 mmol) and 5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (0.213 g, 0.89 mmol) in dimethylformamide (4 ml). The mixture was allowed to warm to room temperature over 3 hours. A saturated solution of ammonium chloride was added and the mixture was partitioned between water and dichloromethane. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. Flash chromatography on silica eluting with a mixture of 2-11% methanol in dichloromethane gave the product as a solid (0.029 g, 8%). NMR Spectrum: (CDCl3) 2.63 (m, 4H), 2.92 (t, 2H), 3.48 (s, 3H), 3.72 (m, 4H), 4.00 (s, 3H), 4.32 (t, 2H), 4.37 (s, 2H), 6.07 (s, 2H), 7.02 (s(broad), 1H), 7.07 (s, 1H), 7.12 (s, 1H), 7.25 (s, 1H), 8.62 (s, 1H). Mass Spectrum: M+H+ 525 and 527.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-])=O)=[CH:6][CH:5]=2>C(O)C.[Pd]>[CH3:1][C:2]1[N:3]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2n1CCN1CCCC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc2cc(N)ccc2n1CCN1CCCC1
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A solution of compound 26 (0.44 g, 1.609 mmol) in dry ethanol (5 mL) was treated with Pd—C (˜0.05 g) and flushed with hydrogen gas. The reaction was stirred under hydrogen atm. for overnight. The reaction was filtered through celite bed, washed with methanol (3×10 mL) and dried to obtain crude compound 27 (0.39 g, quantitative) as a syrup. 1H NMR (DMSO-d6) δ 1.60-1.70 (m, 4H), 2.32 (s, 3H), 2.40-2.48 (m, 4H), 2.60 (t, 2H, J=7.2 Hz), 4.06 (t, 2H, J=7.2 Hz), 4.37 (s, 2H), 5.88 (s, 1H), 6.42 (dd, 1H, J=2.1, 8.7 Hz), 6.56 (d, 1H, J=1.8 Hz), 7.00 (d, 1H, J=8.4 Hz); ESI-MS (m/z, %) 244 (MH+, 100).
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12](=[O:17])([O:14][CH2:15][CH3:16])N.C([Sn](=O)CCCC)CCC>C(O)C>[CH2:15]([O:14][C:12](=[O:17])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:16]
Reactant: CCOC(N)=O
Reactant: Nc1ccccc1
Agent: CCCC[Sn](=O)CCCC
Agent: NC(N)=O
Solvent: CCO
Product: CCOC(=O)Nc1ccccc1
Temperature: 170 °C

Procedure:
Following the procedure of example 23 60.1 g of urea, 93.1 g of aniline, 8.9 g of ethyl carbamate and 0.5 g of dibutyl-tin-oxide are heated to 170° C. Subsequently 84 g of ethanol are added dropwise at such a rate that the reaction temperature can be maintained between 170° and 175° C. After a total reaction time of 10 hours the reaction is stopped by cooling to room temperature. 161 g (98% of the theoretical yield) of N-phenyl-carbamic acid ethyl ester are found by HPLC analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([OH:18])=[C:10]([C:15](=[O:17])[CH3:16])[CH:11]=[C:12]([OH:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:10]2[CH:11]=[C:12]([O:14][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)[CH:13]=[CH:16][C:15]=2[OH:17])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc(O)cc(-c2cccc(Br)c2)c1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(Cc1cccc(Br)c1)c1cc(OC2CCCCO2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a mixture of 3-(3-bromophenyl)-1-(2,5-dihydroxyphenyl)ethanone (4.79 g, 16.2 mmol) and pyridinium p-toluene sulfonate (815 mg, 3.24 mmol) in DCM (100 mL), 3,4-dihydro-2H-pyran (2.2 mL, 24.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and diluted with DCM (100 mL). The solution was washed (100 mL sat'd aqueous NaHCO3), dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified on a silica gel column to give 2-(3-bromophenyl)-1-(2-hydroxy-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone (5.28 g, 83%) as a yellow solid. 1H NMR (DMSO-d6): δ 11.23 (s, 1H), 7.56 (d, 1H), 7.51 (m, 1H), 7.46 (dt, 1H), 7.32-7.24 (m, 3H), 6.92 (d, 1H), 5.42 (t, 1H), 4.46 (s, 2H), 3.80 (m, 1H), 3.55 (m, 1H), 1.96-1.68 (m, 3H), 1.68-1.48 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].C([NH:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[CH2:37][S:36][C:35]1=[O:40])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.NCCN1C(=O)/C(=C/C2C=CC=CC=2)/SC1=O>>[NH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])/[C:37](=[CH:6]/[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3][CH2:1][CH3:2])/[S:36][C:35]1=[O:40]
Reactant: O=C1CSC(=O)N1CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccccc1C=O
Agent: NCCN1C(=O)S/C(=C\c2ccccc2)C1=O
Solvent: C1CCNCC1
Product: CCOc1ccccc1/C=C1\SC(=O)N(CCN)C1=O

Procedure:
The title compound 30c was prepared from 2-ethoxybenzaldehyde (87 μL, 0.62 mmol) and compound 29 (250 mg, 0.62 mmol) and piperidine (7.0 μL, 0.062 mmol) in a manner similar to that described for 30a in 35.4% (64 mg) yield as a white solid.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[OH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCCCCCCOCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
16 g (100 mmol) of nonane-1,9-diol was dissolved in 150 ml of dimethylformamide and instilled in a suspension of 2.88 g (1.20 mmol) of sodium hydride in 100 ml of DMF. It is stirred for 2 hours at 50° C. It is cooled in an ice bath to 0° C. and 17.1 g (100 mmol) of benzyl bromide is instilled within 3 hours. Then, it is stirred for 5 hours at 60° C. The solution is cooled to room temperature, 1 l of water is added and it is extracted 3 times with 150 ml of ether. The combined organic phases are dried on magnesium sulfate and concentrated by evaporation in a vacuum. The remaining oil is chromatographed on silica gel (mobile solvent: hexane/acetone=15:1).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH:6]=[CH:5]2.[H][H]>CO.[Pd]>[OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)C=CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
Following the procedure described in Preparation 58, 120 mg of 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy)benzyl]thiazolidine -2,4-dione (prepared as described in Example 32) were dissolved in 4 ml of methanol and, in the presence of 40 mg of 10% w/w palladium-on-carbon, it was reduced under 3-5 atmospheres (about 3-5 bars) pressure of hydrogen, to give the title compound. The melting point and nuclear magnetic resonance spectrum of this compound accorded with those of the compound obtained in Example 27(b).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH3:37][CH:38](O)[CH3:39]>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH:38]([CH3:39])[CH3:37])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCC(OC(C)C)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (151.3 mg, 0.368 mmol) in 2-propanol (10.0 mL) was added sulfuric acid (0.45 mL) at 0° C. The reaction mixture was stirred at 100° C. for 16 hrs. The mixture was poured into aqueous saturated sodium hydrogen carbonate and concentrated. The residue was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (84.7 mg, 0.187 mmol, 51%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([C:26]3[CH2:27][CH2:28][O:29][C:30]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=5)=[CH:33][C:31]=4[CH:32]=3)=[O:25])[CH2:19][CH2:18]2)[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:44]>C(O)C>[ClH:44].[ClH:44].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([NH:23][C:24]([C:26]3[CH2:27][CH2:28][O:29][C:30]4[CH:36]=[CH:35][C:34]([C:37]5[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=5)=[CH:33][C:31]=4[CH:32]=3)=[O:25])[CH2:21][CH2:22]2)[CH3:15])[CH2:12][CH2:13]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N[C@H]2CC[C@H](CN(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC2)CCO3)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N[C@H]2CC[C@H](CN(C)C4CCNCC4)CC2)CCO3)cc1
Reaction time: 48 h

Procedure:
Into a solution of trans-N-[4-[N-(1-tert-butoxycarbonylpiperidin-4-yl)-N-methylaminomethyl]cyclohexyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.41 g) in ethanol (30 ml) was added at room temperature concentrated hydrochloric acid (5 ml), and the resulting mixture was stirred for 2 days. After the reaction mixture was concentrated under reduced pressure, the resulting crystals were purified by recrystallization (ethanol/diethyl ether) to obtain trans-N-[4-[N-(piperidin-4-yl)-N-methylaminomethyl]cyclohexyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide dihydrochloride (compound 66) (381 mg) as colorless crystals.
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[CH2:24][C:25]2[O:33][C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[O:17])=[CH:6][CH:5]=1>ClCCl>[Cl:1][C:26]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:32]2[O:33][C:25]=1[CH2:24][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[C:16]([C:11]1[N:12]=[C:13]([CH3:15])[S:14][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1)=[O:17]
Reactant: ClCl
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2cc3ncccc3o2)c(-c2ccc(F)cc2)s1
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCCCC2Cc2oc3cccnc3c2Cl)c(-c2ccc(F)cc2)s1
Temperature: -12 °C
Reaction time: 0.5 h

Procedure:
A solution of chlorine (28 mg) in dichloromethane (3 ml) was added to a cooled (−12° C.) solution (RS)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-(2-furo[3,2-b]-pyridin-2-ylmethyl-piperidin-1-yl)methanone, E79 (170 mg) in dichloromethane (4 ml). After stirring at −12° C. for 0.5 h the reaction mixture was stirred at room temperature for 16 h then the solution was washed with saturated aqueous NaHCO3, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-100% ethyl acetate-hexane then 0-10% methanol-ethyl acetate) afforded the title compound (24 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>C(#N)C>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:11]=1
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: Clc1ncccn1
Solvent: CC#N
Product: NC(=NCC(F)(F)F)Nc1nc(CCCCNc2ncccn2)cs1
Yield: 51 %

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.45 g.) and 2-chloropyrimidine (0.18 g.) was heated under reflux in acetonitrile (5 ml.) for 16 hours. The reaction mixture was then evaporated to dryness and the residue purified by medium pressure liquid chromatography on silica gel using chloroform/methanol/ammonia 1900:100:5 v/v/v as eluant. The appropriate fraction was evaporated to dryness and the residue recrystallised from acetonitrile to give 2-(4-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]butylamino)pyrimidine (0.29 g.), m.p. 173°-175°.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH2:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30]>>[OH:31][C@@H:28]([CH2:29][OH:30])[CH2:27][NH:26][C:22]([C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:25])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1)=[O:23]
Reactant: NC[C@@H](O)CO
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(C(=O)NC[C@@H](O)CO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and (R)-(+)-3-amino-1,2-propanediol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:2]1.Br[CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:21][CH2:22][OH:23])=[CH:2]1
Reactant: OCCBr
Reactant: c1ccc(CCCCCCNCc2ccoc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN(CCCCCCc1ccccc1)Cc1ccoc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 2.538 g (9.861 mmol) of N-(3-furylmethyl)-6-phenylhexylamine and 7.39 g (59.2 mmol) of 2-bromoethanol in 50 ml of N,N-dimethylformamide, 13.6 g (98.6 mmol) of potassium carbonate was added, followed by overnight stirring at 90° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2F)OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1=Cc2c(ccc(Cl)c2Oc2ccccc2)OC1C(F)(F)F
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To 162.3 g (0.5 mmole) of ethyl 6-chloro-5-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 75 mg (0.80 mmole) of phenol and 120 mg (0.87 mmole) of potassium carbonate in 1.5 mL DMF. The mixture was heated to 110° C. and allowed to stir overnight. After cooling, the mixture was diluted with water and extracted three times with diethyl ether. The combined organic fractions were washed with water, dried and concd to give a crude oil. Preparative reverse phase chromatography (C 18, 4.0 cm×25 cm column, gradient 50%-100% CH3CN) afforded 50 mg (25.1%) of a clear, colorless oil: 1H NMR (CDCl3/400 MHz) 1.28 (t, 3H, J=7.1 Hz), 4.26 (m, 2H), 5.70 (q, 1H, J=6.7 Hz), 6.82 (d, 2H, J=7.9 Hz), 6.87 (d, 1H, J=8.7 Hz), 7.06 (t, 1H, J=7.4 Hz), 7.31 (t, 2H, J=8.1 Hz), 7.38 (d, 1H, J=8.9 Hz), 7.79 (s, 1H); 19F NMR (CDCl3/400 MHz) −78.7 (d, 3F, 6.8 Hz); MS (ESI+) 399 (M+1, 100); MS (EI) 398 (M+, 50), 329 (100), 283 (79), 231 (32); HRMS (EI) m/z calcd for (C19H14O4ClF3) 398.0533, found 398.0538.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]2[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][C:6]=2[CH:13]=1.[Br:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]=[O:21]>C1C=CC=CC=1>[Br:15][CH2:16][CH2:17][N:18]([CH2:19][CH:20]=[O:21])[C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([Cl:14])[C:2]([Cl:1])=[CH:13][C:6]=2[N:7]=1)=[O:12]
Reactant: O=CCNCCBr
Reactant: O=C=Nc1nc2cc(Cl)c(Cl)cc2s1
Solvent: c1ccccc1
Product: O=CCN(CCBr)C(=O)Nc1nc2cc(Cl)c(Cl)cc2s1
Reaction time: 1 h

Procedure:
5,6-Dichlorobenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-β-bromoethylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-β-bromoethyl-3-(5,6-dichlorobenzothiazol-2-yl)ureido]-acetaldehyde as the residue.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].N[C@H:7]([C:9]([OH:11])=[O:10])[CH3:8]>>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:8][CH2:7][C:9](=[O:10])[OH:11]
Reactant: NCC(=O)O
Reactant: C[C@H](N)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Gly 127.8; Ala 150.4;
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.[CH2:10]([CH:17]1[CH:21]([CH2:22][CH2:23][CH3:24])[CH2:20][NH:19]C1=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:6][O:7][C:9]1[CH:17]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:21]([CH2:22][CH2:23][CH3:24])[CH2:20][N:19]=1
Reactant: C[O+](C)C
Reactant: CCCC1CNC(=O)C1Cc1ccccc1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCC1CN=C(OC)C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.2 %

Procedure:
Trimethyloxonium tetrafluoroborate (0.85 g, 5.7 mmol) was added to a solution of 3-benzyl-4-propyl-2-pyrrolidinone (0.83 g, 3.8 mmol) in methylene chloride (15 ml) and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture to render it weekly basic and then extraction was performed with ethyl acetate. After washing the organic layer with brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (0.67 g) as a light yellow oil. 1H-NMR (CDCl3) δ(ppm) 0.75 (3H, t, J=7.2 Hz), 1.02-1.28 (4H, m), 2.02-2.16 (1H, m), 2.55-2.66 (1H, m), 2.69 (1H, dd, J=13.2 Hz, 8.4 Hz), 2.99 (1H, dd, J=13.2 Hz, 4.8 Hz), 3.10 (1H, dd, J=13.2 Hz, 5.2 Hz), 3.58 (1H, dd, J=13.2 Hz, 8.8 Hz), 3.83 (3H, s), 7.05-7.40 (5H, m)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH-:25].[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:25])[C:8]=1[CH3:24]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Yield: 23.9 %

Procedure:
2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2% purity; 5.37 g (21.8 mmol)) was added little by little such that the internal temperature did not exceed −15° C. After the addition, a 10% sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using dichloromethane (14 ml) and acetonitrile (92 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (6.26 g) (HPLC purity 99.7%, yield 23.9%).