Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[F:12][C@@H:13]1[C@@H:18]([OH:19])[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1.CC([O-])(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:19][C@H:18]1[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:14][C@@H:13]1[F:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@@H](F)C1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])cc2Cl)[C@@H](F)C1
Temperature: 0 °C
Yield: 63 %

Procedure:
A mixture of 2-chloro-1-fluoro-4-nitrobenzene (2.0 g, 1.1 eq, 11.5 mmol) and tert-butyl (3S,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (2.3 g, 1.0 eq, 10.5 mmol) was taken in annhydrous THF (50 mL) and stirred at 0° C. KOtBu (2.1 g, 1.8 eq, 18.9 mmol) was added to the above solution at 0° C. and the heterogeneous mixture was warmed to room temperature. Then the reaction mixture was refluxed overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. EtOAc (100 mL) was added to the crude mixture and pardoned with aqueous saturated NaHCO3 (50 mL) solution. The layers were separated and the organic layer was washed with aqueous saturated NaHCO3 (50 mL) solution and brine (1×50 mL). The organic layers were dried over Na2SO4 and concentrated to leave cude solid. Purification of the crude mixture by column chromatography on silica gel (ISCO System) using EtOAc/hexane (gradient system from 0:1 to 2:8) as eluent gave the desired product in 63% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C@H:10]([O:14][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]/[CH:29]=[CH:28]\[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCC/C=C\CCCCCCCCCCOS(C)(=O)=O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Product: CCCCCCCC/C=C\CCCCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCCCC/C=C\CCCCCCCC

Procedure:
Compound VI-15 (251 mg, 62.7%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 103 mg, 0.534 mmol) and (Z)-icos-11-enyl methanesulfonate (Nu-Chek Prep, Inc; 500 mg, 1.34 mmol).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH2:10])[N:7]=[CH:6]1)#[N:2].[H][H]>N.C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH2:10])[N:7]=[CH:6]1
Reactant: [H][H]
Reactant: N#CCCn1cnc(N)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCCCn1cnc(N)c1
Yield: 73.7 %

Procedure:
1-(2-Cyanoethyl)-4-aminoimidazole (1 g, 6 mmol) was suspended in 3% ammonia/ethanol (50 ml), and Raney nickel was added to the solution. The mixture was stirred at 80° C. for 5 hours in a hydrogen atmosphere. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (chloroform:methanol:aqueous ammonia=5:1:0.5) to obtain 620 mg of the title compound (oil).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 3.6 %

Procedure:
To a solution of N-t-butoxycarbonylpiperazine (7 g, 1 mol. equiv.) in dichloromethane (140 ml) at 0° C. under nitrogen was added triethylamine (6.29 ml, 1.2 mol. equiv.). The reaction mixture was vigorously stirred and acetyl chloride (3.21 ml, 1.2 mol. equiv.) was added, dropwise. The mixture was stirred for twenty four hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution (30 ml), and the organic layer dried using magnesium sulphate. The organic solvent was removed under reduced pressure and the residue purified by flash column chromatography on silica gel eluting with methanol:ethyl acetate (1:19, by volume) to give the title compound (8.19 g). TLC Rf=0.33 (silica, methanol:ethyl acetate, 1:19, by volume). LRMS m/z=229(m+1)+. Found: C, 57.83; H, 8.83; N, 12.27. C11H20N2O3 requires C, 57.87; H, 8.92; N, 12.14%.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[Cl:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1F>ClCCl.CO>[Cl:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1[NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2]
Reactant: CCN(CC)CCN
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1Cl

Procedure:
Prepared analogously to Example 4.25.a. from N1,N1-diethylethane-1,2-diamine and 3-chloro-4-fluoronitrobenzene. Yield: 9.2 g (99.1% of theory); C12H18ClN3O2 (M=271.74); calc.: molecular ion peak (M+H)+: 272/274; found: molecular ion peak (M+H)+: 272/274; Rf value: 0.72 (Alox, dichloromethane/methanol (49:1)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:39])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:39])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)=[CH:20][C:21]=1[C:22]([F:24])([F:25])[F:23])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc3c2CC(=O)N3)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc3c2CC(=O)N3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-({5-[(2-oxo-2,3-dihydro-1H-indol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.10 g, 0.17 mmol) in DCM (5 mL) was added TFA (1.5 mL). The mixture was stirred at room temperature 1 h and evaporated. Isolate 0.14 g of crude product which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([O:12][CH3:13])[CH:3]=1.N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>O1CCCC1>[F:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH:6][S:21]([CH3:20])(=[O:23])=[O:22])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(F)c([N+](=O)[O-])cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-fluoro-2-methoxy-5-nitroaniline (0.16 g) and pyridine (0.21 mL) in tetrahydrofuran (3 mL) was added methanesulfonyl chloride (0.074 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours, and then stirred at 50° C. overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/3) to give 5-fluoro-2-methanesulfonylamino-4-nitroanisole (0.1 g). This material was dissolved in N,N-dimethylformamide (3 mL). To the solution were added potassium carbonate (68 mg) and 2,3-difluoro-6-methoxybenzyl bromide (99 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=½) to give 5-fluoro-2-[N-(2,3-difluoro-6-methoxybenzyl)-N-methanesulfonylamino]-4-nitroanisole (0.14 g). This material was dissolved in tetrahydrofuran (2 mL). To the solution was added 10% palladium-carbon powder (13 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=½) to give the title compound (80 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26].O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:26]([C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1)[CH:25]=[CH2:24]
Reactant: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.15 g, 0.37 mmol) in 5 ml of anhydrous DMF was added allyl tributyltin (0.26 ml, 0.86 mmol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.007 g, 0.0056 mmol) was then added and the reaction mixture was heated at 120° C. for 1 h under the nitrogen atmosphere. Then reaction mixture was cooled to room temperature added water (25 mL) and extracted the compound with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (100-200 M) using ethyl acetate/Hexane (60:40) as the eluent to provide the title compound (0.10 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[C:6]([F:8])[CH:7]=1.[CH:11](O)=O>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]2[NH:9][CH:11]=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Br)cc(F)c1N
Reactant: O=CO
Product: Fc1cc(Br)cc2nc[nH]c12
Yield: 92 %

Procedure:
A solution of 5-bromo-2,3-diaminofluorobenzene (Apollo, 3 g; 14.63 mmol) in formic acid (75 mL) was heated at reflux overnight after which the reaction mixture was concentrated under vacuum to give a brown oil. It was extracted with EtOAc from a saturated aqueous solution of NaHCO3, dried over MgSO4 and evaporated under vacuum to give the title compound as a light pink solid (2.91 g, 92%). 1H NMR (DMSO-d6): δ 8.30 (s, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.27 (dd, J=10.3, 1.5 Hz, 2H), 3.32 (bs, 2H). HPLC (Method A), Rt: 2.09 min (purity: 97.4%). LC/MS (Method B): 216.9 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].OC1C=CC([N:19]2[C:23](=[O:24])[N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21](=[O:31])[NH:20]2)=CC=1>>[OH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[N:19]1[C:23](=[O:24])[N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21](=[O:31])[NH:20]1
Reactant: O=c1[nH]n(-c2ccc(O)cc2)c(=O)n1-c1ccccc1
Reactant: Oc1ccc2ccccc2c1
Product: O=c1[nH]n(-c2c(O)ccc3ccccc23)c(=O)n1-c1ccccc1

Procedure:
Compound 35 was prepared from 2-naphthol in the same manner of compound 27, and was obtained as white solids (89%). 1H NMR (300 MHz, DMSO-d6): δ 10.94 (br s, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.58-7.50 (m, 5H), 7.44-7.35 (m, 2H), 7.27 (dd, J=2.4, 9.0 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ 154.39, 152.93, 152.16, 133.29, 132.99, 132.18, 129.59, 128.77, 128.58, 128.45, 128.29, 126.88, 124.19, 121.90, 119.38, 114.74. HRMS: calcd for C18H13N3O3 (MH+) 320.103. found 320.1032.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Product: O=C(CNC(=O)c1ccccc1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and benzoic acid.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:15]([OH:17])=O)[C@H:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])=[O:6])[CH:2]=[CH2:3].[NH2:18][C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:22][C:23]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:15]([NH:18][C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:22][C:23]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]1)=[O:17])[C@H:9]([C:11]([F:12])([F:13])[F:14])[CH3:10])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@H](C(=O)O)[C@@H](C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=CCOC(=O)N[C@H](C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2)ccc1Cl)[C@@H](C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
398.5 mg (1.56 mmol) of (3R)—N-[(allyloxy)carbonyl]-4,4,4-trifluorovaline (diastereomer mixture) and 400 mg (1.42 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate were dissolved in a mixture of 4.7 ml of DMF and 1.6 ml of pyridine, and 647.8 mg (1.70 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight. A further 400 mg (1.42 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate and 647.8 mg (1.70 mmol) of HATU were added, and the reaction mixture was stirred at 50° C. for another 4 h. After dilution with ethyl acetate, the mixture was washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water). This gave 453 mg of the target product (55.9% of theory, diastereomer ratio >8:1).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]([CH:31]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[CH2:29]([O:28][C:26](=[O:27])[CH:31]=[C:16]1[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15]1)[CH3:30]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a stirring solution of DMSO (5.3 mL, 75 mmol) in methylene chloride (100 mL) at −78° C. under argon was added oxalyl chloride (4.6 mL, 53 mmol) dropwise. After stirring for 30 min., a solution of 1-benzhydryl-azetidin-3-ol hydrochloride (12) (10 g, 36 mmol) in methylene chloride (10 mL) was added dropwise. The reaction mixture was stirred for 1 hr at −78° C. before triethylamine (18 mL, 128 mmol) was added. The ice bath was removed and the reaction quenched with saturated ammonium chloride (75 mL) at 0° C., then extracted with ethyl acetate (3×150 mL). The combined ethyl acetate layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was stirred in ethyl acetate and hexane, filtered to give 1-benzhydrylazetidin-3-one (9 g, 33 mmol, 92%). To a stirring solution of the resulting 1-benzhydryl-azetidin-3-one (8.3 g, 30 mmol) in methylene chloride (120 mL) was added triethylamine (6.4 mL, 45 mmol), and carbethoxymethylene triphenylphosphorane (15.9 g, 45 mmol). This reaction mixture was stirred under argon at room temperature for 2 hrs., then quenched with acetone (1 mL), and concentrated in vacuo. The residue was stirred in 20% ethyl acetate in hexane (20 mL) as triphenyl phosphine oxide precipitated. The mixture was then filtered and concentrated. The crude product was chromatographed on silica gel, eluting with 50:40:10 methylene chloride:hexane:ether to give 9.3 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(Cl)Cl.C(O)C>[ClH:28].[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)(=[NH:34])[NH2:2]
Reactant: [NH4+]
Reactant: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(OCc2cccc(C(=N)N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.9 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl) methoxy]-5-methylphenyl ester (207 mg, 0.5 mmol), as prepared in the preceding step, in methylene chloride (10 mL) was added 37% HCl in ethanol (10 mL) at 0° C. The mixture was allowed to stand at 0° C. for 3 days. The solvent was evaporated in vacuo and the residue was co-evaporated with methylene chloride several times. The residue was dissolved in ethanol (10 mL) and ammonium carbonate (192 mg, 2.0 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. Methylene chloride (150 mL) was added to the mixture. The methylene chloride solution was washed with 10% K2CO3 (2×50 mL) and dried over K2CO3. The solvent was removed in vacuo, HCl in methanol (30 mL) was added, and the solvent again removed in vacuo. The residue was purified by flash chromatography (10% methanol in methylene chloride) to give the title compound as a white solid (112 mg, 48%). 1H-NMR (300 MHz, DMSO-d6) δ 2.23 (s, 3 H), 5.11 (s, 2 H), 6.54 (s, 1 H), 6.56 (s, 1 H), 6.88 (s, 1 H), 7.58 (t, 1 H, J=6.5 Hz), 7.61 (t, 1 H, J=12.2 Hz), 7.66 (d, 1 H, J=3.9 Hz), 7.73-7.95 (m, 5 H), and 9.40 (br s, 4 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H19N2O4SCl: 431.1 (M+H), 453.1 (M+Na). Found: 0 431.0, 452.9.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].O.[NH2:11][NH2:12]>C(O)C>[CH2:2]([C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[NH:12][N:11]=1)[CH3:1]
Reactant: NN
Reactant: CCC(=O)CC(=O)CC
Solvent: CCO
Solvent: O
Product: CCc1cc(CC)[nH]n1
Temperature: 25 °C
Yield: 99728.3 %

Procedure:
A solution of 3,5-heptanedione (10.0 g, 0.078 mmol) in ethanol (40 ml) was treated dropwise with hydrazine hydrate (4.2 ml, 0.086 mmol) at room temperature producing an exotherm that was cooled by use of an ice bath. After the addition was complete the reaction mixture was allowed to warm to room temperature. The solution was concentrated under reduced pressure. The oil was partitioned between dichloromethane and brine. The aqueous layer was extracted with dichloromethane (×2). The combined organic phases were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to afford the title compound (9.66 g) as a pale yellow oil that partly solidified on standing.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6]2.C([N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1)(=O)C>C(#N)C>[CH3:25][C:23]1[NH:22][C:21]([CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6]3)=[N:20][CH:24]=1
Reactant: CC(=O)n1cnc(C)c1
Reactant: COC(=O)c1ccc2cc(CBr)ccc2c1
Solvent: CC#N
Product: COC(=O)c1ccc2cc(Cc3ncc(C)[nH]3)ccc2c1
Yield: 69.8 %

Procedure:
2 g (7.16 mmol) of methyl 6-bromomethyl-2-naphthoate and 1.07 g (8.6 mmol) of 1-acetyl-4-methylimidazole are heated under reflux in absolute acetonitrile (8 hours). After the reaction solution has been evaporated, the residue is taken up in 2N HCl, and the solution is extracted with ethyl acetate. The ethyl acetate phases are discarded. After the aqueous phase has been neutralized with sodium carbonate, it is extracted with ethyl acetate, and the ethyl acetate phase is dried and evaporated in vacuo. 1.4 g (70%) of methyl 6-(5-methyl-1-imidazolylmethyl)-2-naphthoate are obtained by trituration of the residue with ether. Melting point 101°-102° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1.I[CH2:11][CH2:12][CH3:13]>C1COCC1>[CH2:11]([N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1)[CH2:12][CH3:13]
Reactant: CCCI
Reactant: O=Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1cnc(C=O)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a suspension of NaH (95%, 231 mg, 9.18 mmol) in THF (20 ml) was added 4-imidazole carboxaldehyde (588 mg, 6.12 mmol) under ice cooling. The mixture was refluxed for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature and 1-iodopropane (5 ml) was added to the mixture and then refluxed for another 2 hours. The mixture was cooled down to rt and quenched with water. The solution was extracted with EtOAc (2×50 ml), washed with brine, dried over Na2SO4, concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-10% MeOH in CH2Cl2) to give the title compound (487 mg, 58%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH:13](Br)[CH3:14].[N-:16]=[N+:17]=[N-:18].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[N:16]([CH:13]([C:3]1[N:4]=[C:5]2[S:11][CH:10]=[C:9]([CH3:12])[N:6]2[C:7](=[O:8])[C:2]=1[Br:1])[CH3:14])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1csc2nc(C(C)Br)c(Br)c(=O)n12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reaction time: 0.12 h
Yield: 97.5 %

Procedure:
To a suspension of 6-bromo-7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (6.85 g, 19.4 mmol) in N,N-dimethylformamide (30.1 mL) was added sodium azide (1.45 g, 22.4 mmol). The mixture slowly turned clear after 5-10 min. After 50 min, a solution of sodium bicarbonate (4.7 g, 56 mmol) in water (90 mL) was added dropwise with stirring. The mixture was stirred at room temperature for 1 h and the solid precipitates were filtered off. The solid was then washed with water (30 mL×3), and dried to give 7-(1-azidoethyl)-6-bromo-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one as an off-white solid (5.94 g, 97.2%). LCMS calculated for C9H9BrN5OS (M+H)+: m/z 313.96, 315.96. Found: 313.75, 315.75. 1H NMR (400 MHz, DMSO-d6) δ 7.15 (q, J=1.3 Hz, 1H), 4.83 (q, J=6.8 Hz, 1H), 2.67 (d, J=1.4 Hz, 3H), 1.48 (d, J=6.8 Hz, 3H).