Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14](Cl)=[O:15])[S:13][C:6]=12.[NH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]1>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([NH:24][CH:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)=[O:15])[S:13][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=C(Cl)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of 40 (shown in the scheme 7, 600 mg, 1.54 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (369 mg, 2.0 mmol) in DCM (15 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography, eluents EtOAc and EtOAc/MeOH (10:1), to afford the title compound 289 (160 mg, 20%) as an off-white solid. MS (m/z): 503.3 (M+H) (found).
Reaction SMILES: [Si]([O:8][CH:9]([CH:11]1[CH:14]([S:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[NH:13][C:12]1=[O:24])[CH3:10])(C(C)(C)C)(C)C>O1CCCC1.CO>[OH:8][CH:9]([CH:11]1[CH:14]([S:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[NH:13][C:12]1=[O:24])[CH3:10]
Reactant: COc1ccc(SC2NC(=O)C2C(C)O[Si](C)(C)C(C)(C)C)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(SC2NC(=O)C2C(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
600 mg (1.68 mmol) of rac -(αS*,3S*,4R*)-3-[1-(t-butyldimethylsilyloxy)ethyl]-4-[(p-methoxyphenyl)thio]-2-azetidinone are dissolved in 35 ml of tetrahydrofuran/methanol/12 percent hydrochloric acid (4:2:1), whereupon the solution is stirred at room temperature for 4 hours and worked-up as described in Example 2. There is obtained rac-(αS*,3S*,4R*) -3-(1-hydroxyethyl)-4-[(p-methoxyphenyl)thio]-2-azetidinone as a colourless oil; IR: 1765 cm-1.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.Cl>O1CCCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:1]([O:5][CH2:6][CH3:7])=[O:8])=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Diethyl carbonate (130 g, 1.1 mol) was dissolved in a suspension of NaH (60% in oil, 50.2 g, 1.3 mol) in anhydrous tetrahydrofuran (1.5 L), and then 1-(4-fluorophenyl)ethanone (150 g, 1.09 mol) was added dropwise at 70° C. The resulting mixture was stirred at 70° C. for 3 hours. After the reaction mixture was cooled to room temperature and poured into HCl (1 N). The mixture was extracted with EtOAc, the organic phase was dried with anhydrous NaSO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with petroleum ether/EtOAc=50/1) to provide ethyl 3-(4-fluorophenyl)-3-oxopropanoate (217 g, yield: 95%). 1H-NMR (CDCl3, 400 MHz) δ 7.92˜7.97 (m, 2H), 7.07˜7.13 (m, 2H), 4.14˜4.20 (m, 2H), 3.93 (s, 2H), 1.22 (d, J=7.2 Hz, 3H). MS (M+H)+: 211.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][OH:20])[CH:13]=1)[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CC#N.O=[Mn]=O>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=[O:20])[CH:13]=1)[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CO)c1)C1CC1
Agent: O=[Mn]=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C=O)c1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.5 %

Procedure:
MnO2 (815 mg, 8.44 mmol) was added to a sol. of (4-chloro-3-hydroxymethyl-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (526 mg, 1.69 mmol) in CH3CN (34 mL). The mixture was stirred at rt for 3 h, and was filtered over celite, and washed with CH3CN and CH2Cl2. Evaporation of the solvents under reduced pressure yielded the crude title compound (563 mg, quantitative yield) that was used further without purification. LC-MS: tR=1.05 min; ES+: 310.04.
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[S:21]C(C2(C)CCCCC2)=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[K+].O>CO.O1CCCC1>[SH:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[NH:10][C:8]([C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9]
Reactant: CC1(C(=O)Nc2c(SC(=O)C3(C)CCCCC3)ccc3ccccc23)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C(=O)Nc2c(S)ccc3ccccc23)CCCCC1
Reaction time: 1 h

Procedure:
The crude product obtained in step A) is dissolved in a mixture of methanol and tetra-hydrofuran (1:1). Then 3.5 mol equivalents of potassium hydroxide are added at room temperature and the mixture is stirred for 1 hour. Then water is added and the mixture is washed with n-hexane. The aqueous layer is then acidified by addition of KHSO4 and extracted with chloroform. The combined extracts are washed with water and brine, dried (Na2SO4) and concentrated to obtain the desired title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:29][CH2:30][N:31]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:19])=[CH:8][C:9]=2[N+:16]([O-:18])=[O:17])=[O:13])[CH2:32][CH2:33]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1[N+](=O)[O-]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3[N+](=O)[O-])CC2)c(C)c1
Yield: 16.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-nitrobenzoic acid (967 mg) described in Preparation Example 24 and 1-(2,4-dimethylphenyl)piperazine (639 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (250 mg) was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][O:11][CH2:12][O:13][CH3:14].[Li+].[Cl-].C([Sn](CCCC)(CCCC)/[C:22](/[CH2:29][CH3:30])=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])CCC>CS(C)=O.Cl[Cu].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>[CH2:27]([O:26][C:24](=[O:25])[CH:23]=[C:22]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][O:11][CH2:12][O:13][CH3:14])[CH2:29][CH3:30])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/C(=O)OCC)CC
Reactant: COCOCc1c(I)ccnc1OC
Agent: Cl[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CS(C)=O
Product: CCOC(=O)C=C(CC)c1ccnc(OC)c1COCOC
Reaction time: 24 h
Yield: 82.1 %

Procedure:
Following the procedure in Example 3, the reaction was carried out with 3b (1.0 g, 3.23 mmol), LiCl, predried under vacuum at 120° C. for a period of 24 h (0.82 g, 19.4 mmol), CuCl (1.60 g, 16.2 mmol), Pd(PPh3)4 (0.19 g, 0.16 mmol) and ethyl (E)-3-(tributylstannyl)-2-pentenoate (1.62 g, 3.88 mmol) in dry DMSO (35 mL). The crude product was subjected to flash chromatography (hexanes/ethyl acetate 95:5) to afford 4b as a yellow oil (0.82 g, 82%). IR (CH2Cl2, NaCl,cm−1) 2982, 1713, 1640, 1593, 1560, 1453, 1392, 1266, 1186, 1040, 743; 1H NMR (300 MHz, CDCl3) δ0.99 (t, J=7.6 Hz, 3H), 1.30 (t, J=7.1 Hz, 3H), 2.99 (q, J=7.6 Hz, 2H), 3.43 (s, 3H), 4.01 (s, 3H), 4.21 (q, J=7 Hz, 2H), 4.49 (s, 2H), 4.73 (s, 2H), 5.81 (s, 1H), 6.69 (d, J=5 Hz, 1H), 8.11 (d, J=5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ12.46, 14.43, 26.58, 54.05, 55.58, 60.26, 62.05, 96.96, 116.27, 116.85, 120.00, 146.36, 153.34, 159.37, 163.42, 165.90; HRMS (EI) m/z calcd for C16H23NO5 (M+) 309.1576, found 309.1587; LRMS (EI) m/z 309(M+, 32), 277(42), 236(100), 190(84), 174(73), 160(22), 77(10).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[N:6](CC3C=CC(OC)=CC=3)[C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(OCC)(=O)C>C1(OC)C=CC=CC=1>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3ccc(OC)cc3)c3cc(Cl)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(C2=NC(Cc3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)cc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
(Z)-7-Chloro-3-(2-chlorobenzyl)-5-(4-methoxyphenyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (128 mg, 0.235 mmol) was dissolved in anisole (1 mL) under nitrogen and AlCl3 (125 mg, 0.939 mmol) was added in one portion. The resulting orange solution was heated to 85° C. for 2 h. After the mixture was cooled to room temperature, ice and ethyl acetate were added and the mixture was stirred for 30 min. The layers were partitioned and the organic layer was washed with water then brine. The combined aqueous layers were back-extracted with ethyl acetate and the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel, eluting with 5%, then 30% ethyl acetate in hexanes to give (Z)-7-chloro-3-(2-chlorobenzyl)-5-(4-methoxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one as a white solid (99 mg, 99%). 1H NMR (300 MHz, CDCl3) δ 3.60-3.77 (m, 2H), 3.84 (s, 3H), 3.84-3.86 (m, 1H), 6.88 (dd, J=7, 2 Hz, 2H), 7.08 (d, J=9 Hz, 1H), 7.15-7.33 (m, 3H), 7.38 (dd, J=7, 2 Hz, 2H), 7.45 (dd, J=9, 2 Hz, 1H), 7.60 (dd, J=8, 2 Hz, 1H), 8.59 (s, 1H); ESI m/z 425.1.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:8]=1[NH2:14])[CH3:2].CO[C:17](=N)[C:18]([Cl:21])([Cl:20])[Cl:19]>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:8]2[N:14]=[C:17]([C:18]([Cl:21])([Cl:20])[Cl:19])[NH:13][C:9]=2[CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: CCOCCOc1cccc(N)c1N
Product: CCOCCOc1cccc2[nH]c(C(Cl)(Cl)Cl)nc12

Procedure:
4-(2-Ethoxy-ethoxy)-2-trichloromethyl-1H-benzoimidazole was prepared by a procedure according to example 108 (iii) starting from 345 mg (1.76 mmol) 3-(2-Ethoxy-ethoxy)-benzene-1,2-diamine and 0.30 mL (2.46 mmol) 2,2,2-trichloro-acetimidic acid methyl ester.
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[NH:3][CH2:2]1.[H-].[Na+].Cl[C:11]([CH3:15])([CH3:14])[C:12]#[CH:13]>CN(C)C=O>[CH3:14][C:11]([N:3]1[CH2:2][CH2:1][CH2:7][S:4]1(=[O:6])=[O:5])([C:12]#[CH:13])[CH3:15]
Reactant: O=S1(=O)CCCN1
Reactant: C#CC(C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(C)N1CCCS1(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a stirred solution of 1,3-propanesultam (2.000 g, 16.5 mmol) in anhydrous N,N-dimethylformamide (30 mL) at 0° C. was added 60% sodium hydride in mineral oil (1.981 g, 49.5 mmol) and the mixture was stirred at 0° C. for 1 hr. 3-Chloro-3-methyl-1-butyne (2.300 g, 22.4 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hr and then slowly warmed to room temperature and stirred for 16 hrs. The reaction was carefully quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), and concentrated in vacuo. The residue was purified by silica gel chromatography (0-70% ethyl acetate/hexanes) to afford the desired product as a yellow oil (1.35 g, 44%). 1H NMR (300 MHz, CDCl3) δ 3.52 (t, 2H, J=6.6 Hz), 3.23 (t, 2H, J=7.5 Hz), 2.46 (s, 1H), 2.42-2.28 (m, 2H), 1.74 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1([C:29]2[O:30][C:31]([C:37]([F:40])([F:39])[F:38])=[C:32]([C:34](O)=[O:35])[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:34]([C:32]3[N:33]=[C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:30][C:31]=3[C:37]([F:39])([F:40])[F:38])=[O:35])=[CH:16][C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2C#N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
Crude 4-(4-amino-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester from above was dissolved in methylene chloride (10 mL) and to the resulting solution was added 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (454 mg), triethylamine (247 μL) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCl, 337 mg). The reaction mixture was stirred at room temperature for 3 hr. Another portion of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.5 eq) was added. The reaction mixture was stirred at 50° C. for 3 hr and at room temperature for 3.5 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography afforded 4-{2-cyano-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (240 mg, 25% yield) as a yellow solid. LCMS calcd for C27H26F3N5O4 (m/e) 541, obsd 542 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]3[O:16][C:15]([CH3:17])=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C:13]=3[C:25]=2[CH3:26])=O)=[CH:4][CH:3]=1>C(O)C>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:8][C:9]2[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]3[O:16][C:15]([CH3:17])=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C:13]=3[C:25]=2[CH3:26])=[CH:4][CH:3]=1
Reactant: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccc(F)cc1
Solvent: CCO
Product: Cc1oc2c(C)c(C)c(NCc3ccc(F)cc3)c(C)c2c1-c1ccc(F)cc1
Yield: 66 %

Procedure:
By using 4-fluoro-N-[3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-yl]benzamide, the title compound was synthesized according to Example 2b. Yield: 66%. Melting point: 107-109° C. (Ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.Cl[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:30]([CH:29]=[CH2:28])(=[O:32])=[O:31])[CH2:16][CH2:15]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide (500 mg, 1.3 mmol) in methylene chloride at room temperature, triethylamine (0.44 mL, 3.2 mmol) and 2-chloroethylsulfonyl chloride (0.168 mL, 1.6 mmol) were added. The reaction mixture was stirred for 30 min. Removed the solvent, the residue was purified by combiflash to give the title compound (150 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2.[NH2:17][CH2:18][CH2:19][CH2:20][NH2:21].C(O)CCCC.C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:17][CH2:18][CH2:19][CH2:20][NH2:21])=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2
Reactant: Clc1ccc2c(Cl)c3c(nc2c1)CCCC3
Reactant: NCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCO
Product: NCCCNc1c2c(nc3cc(Cl)ccc13)CCCC2
Yield: 87 %

Procedure:
To a sealed tube was charged a mixture of 6,9-dichloro-1,2,3,4-tetrahydroacridine (1.0 g, 3.97 mmoL), 1,3-diaminopropane (1.67 mL, 19.83 mmoL) and 4 mL 1-pentanol. The mixture was heated to 160 degree Celsius for 24 h. After cooled down and saturated sodium bicarbonate was added, the mixture was extracted with dichloromethane three times. The combined extract was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel with 10-20% MeOH/CH2Cl2 (1% ammonium hydroxide) to give the desired product as brown oil (1.0 g, 87%).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1)=[CH:7]2.O1CCCC1.[C:25]([C@H:29]1[CH2:34][CH2:33][C@H:32](O)[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Br:1][C:2]1[C:11]([O:12][C@H:32]2[CH2:33][CH2:34][C@H:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:30][CH2:31]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1)=[CH:7]2
Reactant: C[C@@]1(c2ccc3c(Br)c(O)ccc3c2)COC(=O)N1
Reactant: CC(C)(C)[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Br)CC1
Reaction time: 0.08 h

Procedure:
(R)-4-(5-Bromo-6-hydroxy-naphthalen-2-yl)-4-methyl-oxazolidin-2-one (2.16 g, 6.70 mmol) was dissolved in tetrahydrofuran (22.50 mL, 277.4 mmol) in a capped 250 mL round-bottom flask equipped with a magnetic stir bar. trans-4-tert-Butyl-cyclohexanol (2.095 g, 13.41 mmol) and triphenylphosphine (3.517 g, 13.41 mmol) were added and the mixture was stirred for 5 minutes. Diisopropyl azodicarboxylate (2.640 mL, 13.41 mmol) was then slowly added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, diluted in methylene chloride and adsorbed onto silica gel under reduced pressure, then purified by flash chromatography (0-55% EtOAC in hexanes) to give 1.37 g of the title compound (45% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:23]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[C:22](=[O:33])[N:13]3[C:14]=2[C:15]([O:17]C(C)(C)C)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[C:1]1([CH2:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:23]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[C:22](=[O:33])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1=C(CCc2ccccc2)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(CCc3ccccc3)CS[C@H]12
Reaction time: 0.5 h

Procedure:
The cephem (XXIV) (29 mg) was dissolved in trifluoroacetic acid (0.5 ml) and the solution was stood at room temperature for 30 minutes. The solution was evaporated and the residual gum re-evaporated from dry benzene (4 × 1 ml). The residual gum was dissolved in dry ether and evaporated to give the desired cephem carboxylic acid (XXVI) as a dark yellow solid foam (24 mg, 94%). νmax (CHCl3) 1775 cm-1 (β-lactam); 1675 cm-1 (amide).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]#[N:14])(=[O:4])=[O:3]>CO.[Pd]>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][NH2:14])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccccc1CC#N
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1ccccc1CCN
Reaction time: 48 h

Procedure:
(2-Methanesulfonylaminophenyl)acetonitrile (300 mg) was mixed with 10% palladium/carbon (catalytic amount) in methanol (20 ml) and the mixture was stirred under hydrogen gas atmospheres for 48 hours. After confirming the completion of the reaction using TLC, the resulting mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The following procedure was carried out using the concentrate which was not purified.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[CH3:14])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[BrH:19].BrBr>C(O)(=O)C>[Br:19][C:7]1[CH:6]=[C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[CH3:14])[CH:4]=[C:3]([C:15]([F:18])([F:17])[F:16])[C:2]=1[NH2:1]
Reactant: Cc1cn(-c2ccc(N)c(C(F)(F)F)c2)c(C)n1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1cn(-c2cc(Br)c(N)c(C(F)(F)F)c2)c(C)n1

Procedure:
1-(4-Amino-3-trifluoromethylphenyl)-2,4-dimethylimidazole (10 g) was dissolved in glacial acetic acid (70 cm3). A solution of 45% w/w hydrogen bromide in glacial acetic acid (7.4 cm3) was added. A solution of bromine (2.1 cm3) in glacial acetic acid (30 cm3) was then added dropwise. The mixture was heated at 70° for 3 hours, cooled, concentrated to a small volume by evaporation in vacuo, and basified to pH 8 by addition of aqueous sodium carbonate solution. The aqueous phase was extracted with chloroform (3×200 cm3) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]), eluting with ethyl acetate. Combination and evaporation of appropriate fractions afforded 1-(3-bromo-4-amino-5-trifluoromethylphenyl)-2,4-dimethylimidazole (4.76 g), a small sample of which was recrystallised from ethyl acetate/hexane, m.p. 149°.
Reaction SMILES: COC[CH2:4][CH2:5][O:6][C:7]1[N:12]=[C:11]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31]([OH:33])=[O:32])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)=[CH:9][CH:8]=1.[CH3:34][O:35]CCO>>[CH3:34][O:35][CH2:4][CH2:5][O:6][C:7]1[N:12]=[C:11]([O:13][CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:10]([NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31]([OH:33])=[O:32])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)=[CH:9][CH:8]=1
Reactant: COCCCOc1ccc(Nc2ncnc3sc(C(=O)O)c(C)c23)c(OC2CCOCC2)n1
Reactant: COCCO
Product: COCCOc1ccc(Nc2ncnc3sc(C(=O)O)c(C)c23)c(OC2CCOCC2)n1

Procedure:
Prepared as described for 4-(6-(3-methoxypropoxy)-2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid except that 2-methoxyethanol was used in place of 3-methoxypropan-1-ol in the first step.