Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[N:27]1([CH2:32][CH2:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][N:35]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([CH2:33][CH2:32][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:35][CH:36]=3)[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Reactant: O=C(O)c1ccc(CCN2CCCC2)nc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1ccc(CCN3CCCC3)nc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (150 mg, 0.21 mmol) was dissolved in DMF (2 mL), and 6-(2-pyrrolidin-1-ylethyl)nicotinic acid (92 mg, 0.42 mmol) was added. PYBOP (217 mg, 0.42 mmol) and diisopropylethylamine (73 μL, 0.42 mmol) were subsequently added, and the mixture was stirred at rt overnight. The solids that formed were isolated by vacuum filtration and washed copiously with ethyl acetate to give the title compound (81 mg, 69%): HPLC MS RT=1.05 min, MH+=562.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 9.30 (1H, s), 8.99 (0.5H, m), 8.50 (1H, d), 8.24 (0.5H, m), 8.06 (1H, d), 7.53 (1H, d), 7.46 (1H, d), 4.55 (2H, t), 4.35 (2H, t), 4.24 (2H, t), 4.01 (3H, s), 4.00 (2H, m), 3.68 (2H, m), 3.60 (4H, m), 3.51 (2H, m), 3.29 (4H, m), 3.11 (2H, m), 2.26 (2H, m), 2.02 (3H, m), 1.87 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[C:9](C(O)=O)[CH:10]=[C:11]([CH:25]=3)[O:12][CH2:13][CH2:14][S:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][CH:17]=3.C([N:31](CC)CC)C.C1(OP(=O)OC2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([NH2:31])[CH:10]=[C:11]([CH:25]=3)[O:12][CH2:13][CH2:14][S:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][CH:17]=3
Reactant: O=C(O)c1cc2cc(c1)OCCSc1cccc(c1)Nc1nc(ncc1Cl)N2
Reactant: CCN(CC)CC
Agent: O=[PH](Oc1ccccc1)Oc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cc2cc(c1)OCCSc1cccc(c1)Nc1nc(ncc1Cl)N2
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).1(9,13)]tetracosa-1(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxylic acid (0.40 g, 0.95 mmol) in tetrahydrofuran (10 mL) at 0° C. was treated with triethylamine (0.53 mL, 3.8 mmol) and diphenylphosphonic acid (0.45 mL, 2.1 mmol) and stirred at 20° C. for 2 h. The reaction mixture was poured into water (50 mL) and ethyl acetate (150 mL). The ethyl acetate layer was separated, diluted with water (50 mL) and heated at 100° C. for 8 h. The reaction mixture was filtered and the organic layer from the filtrate was separated and washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude yellow. This material was treated with ethyl acetate and filtered. The filtrate was concentrated to give the desired product (0.29 g, 78%) as a tan solid. LCMS for C18H17ClN5OS (M+H)+: m/z=385.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:22][CH:21]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(Cl)cc1
Yield: 87.9 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.243 g, 1.0 mmol) and 4-chlorophenyl isothiocyanate (0.174 g, 1.03 mmol). Trituration in hexanes/ethyl acetate (1:1) gave the product (0.362 g); m.p. 179-180° C.
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]>C(O)(=O)C.[Pd]>[NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 97.6 %

Procedure:
III (7.8 g, 0.0123 mole) was taken in acetic acid (80 ml) and hydrogenated in the presence of 10% Pd-C (1 g) at 40 psi. After filtering the catalyst with the aid of celite, the solvent was removed under reduced pressure, triturated with ether, filtered, washed with ether then pet. ether and dried to obtain 6.5 g of the product (yield: 97.3%), m.p. shrinks at 127° C. and decomp. at 145° C. Rf3, 0.24; Rf4, 0.11. Anal. Calcd. for C25H43N5O10.1/2H2O: C 54.52, H 8.05, N 12.7%. Found: C 54.32, H 8.02, N 12.59%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][NH2:19])[C:11]=2[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][NH:19][S:35]([CH3:34])(=[O:37])=[O:36])[C:11]=2[CH2:20][C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)n1nc(CN)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1nc(CNS(C)(=O)=O)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution containing 35 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3-methylamine in 3 ml of anhydrous dichloromethane at room temperature under nitrogen was treated with 0.024 ml of triethylamine and 0.007 ml of methane sulphonyl chloride. The mixture was stirred at room temperature for 0.5 h. The mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate then extracted three times. Combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (1:19) for the elution to give 21 mg of N-[[5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazol-3-yl]methyl]methanesulfonamide as a brown solid. Mass spectrum (ESI) m/z 465 [M+H]+. 1H NMR (DMSO) 1.30 (d, 6H), 2.90 (s, 3H), 3.92 (s, 2H), 4.20 (d, 2H), 4.73 (m, 1H), 6.89 (s, 2H), 7.11 (d, 2H), 7.38 (s, 1H), 7.56 (t, 1H), 8.30 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1>C(O)(C)C.CC(C)=O.C(#N)C.O=[Mn]=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: OCc1ccc(O)cn1
Agent: O=[Mn]=O
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: CC#N
Product: O=Cc1ccc(O)cn1
Reaction time: 20 h
Yield: 21.8 %

Procedure:
A mixture of 5-hydroxy-2-hydroxymethylpyridine (14 g) and MnO2 (100 g) in isopropylalcohol (600 mL) was stirred under N2 for 20 h. The reaction mixture was filtered and filtrate concentrated under vacuum affording a crude product as a solid (12 g). It was suspended in acetone/acetonitrile (25 mL each) and the solid residue was filtered off. It was washed with cold acetone/acetonitrile 1:1 mixture to give pure 5-hydroxypyridine-2-carboxaldehyde (3 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2].[CH:30]([NH:32][NH:33][CH:34]=O)=O.Cl[Si](C)(C)C.C(N(CC)CC)C>N1C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:34]=[N:33][N:32]=[CH:30]3)=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(N)cc2)n1-c1ccc(C(N)=O)cc1C
Reactant: O=CNNC=O
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2ccc(-n3cnnc3)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 100 °C
Yield: 82 %

Procedure:
Under a nitrogen atmosphere, 3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (11A, synthesis described in Scheme 4 where R1=4-carbamoyl-2-methylphenyl) (102 mg, 0.26 mmol) was dissolved in 4 mL pyridine. 1,2-diformylhydrazine (69 mg, 0.78 mmol) was added. Chlorotrimethylsilane (0.5 mL, 3.9 mmol) was added dropwise. Triethylamine (0.25 mL, 1.82 mmol) was added dropwise. The reaction was heated to 100° C. for 24 hrs. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative tlc plate (1500 microns, 10% IPA/CH2Cl2). The desired band (rf=0.3) was isolated and dried under high vacuum to yield 3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,4]triazol-4-yl-phenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (11B) (95 mg, 82%, light tan powder).
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[Cl:27][C:28]1[CH:53]=[CH:52][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][N:37]([S:40]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]3[C:49](O)=[O:50])(=[O:42])=[O:41])[CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1.C1C[C@H](C(O)=O)NCC1>C(Cl)Cl.C(OCC)(=O)C>[C:2]([O:6][NH:7][C:49]([C@H:44]1[CH2:45][CH2:46][CH2:47][CH2:48][N:43]1[S:40]([N:37]1[CH2:36][CH2:35][CH:34]([C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([Cl:27])=[CH:53][CH:52]=2)[CH2:39][CH2:38]1)(=[O:42])=[O:41])=[O:50])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(S(=O)(=O)N2CCCC[C@@H]2C(=O)O)CC1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)[C@H]1CCCCN1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)ONC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 65 %

Procedure:
O-tert-butylhydroxylamine hydrochloride (127 mg, 1.01 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (129 mg, 0.67 mmol), N,N imethylaminopyridine (41 mg, 0.34 mmol), and N-methylmorpholine (0.15 ml, 1.3 mmol) were added to a solution of 1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (140 mg, 0.34 mmol), [prepared by proceeding as described in Example 9, but replacing D-valine and 4-(4-chlorophenoxy)piperidinesulfamoyl chloride with D-pipecolinic acid and 4-(4-chlorobenzoyl-piperidinesulfamoyl chloride, respectively], in methylene chloride (2 ml). After stirring overnight, the reaction mixture was diluted with ethyl acetate, washed with 1M HCl, and brine, and dried over MgSO4. The organics were evaporated in vacuo and the residue was chromatographed (FMLC, SiO2, 40% ethyl acetate/hexane) to give N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide as a white solid (65%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[N:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1.[CH3:19][I:20]>>[I-:20].[Br:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]2=[N:3][N+:2]([CH3:19])([CH3:1])[CH3:18])=[CH:12][CH:13]=1
Reactant: CI
Reactant: CN(C)N=C1CCCCC1Cc1ccc(Br)cc1
Product: C[N+](C)(C)N=C1CCCCC1Cc1ccc(Br)cc1
Product: [I-]

Procedure:
2-[(4-bromophenyl)methyl]-cyclohexanone dimethylhydrazone (16.2 g) (0.052 mol) and methyl iodide (60 ml) were stirred overnight at RT. The precipitate was filtered, washed twice with ethyl ether, then with EtOH, and finally with pentane After drying, 2-[2-[(4-bromophenyl)methyl]-cyclohexylidene]-1,1,1-trimethyl-hydrazinium iodide was obtained as a white solid (11.9 g, mp=173° C.). 1H NMR (CDCl3): 7.40 (2H, d), 7.05 (2H, d), 3.7 (9H, s), 3.3-3.1 (1H, m), 3.05 (1H, dd), 2.85-2.45 (3H, m), 2.15-1.4 (6H, m).
Reaction SMILES: CN(C)C=O.[C:6]([NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])(=[O:8])[CH3:7].[CH2:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O.C(Cl)(Cl)Cl>[CH2:22]([S:26]([NH:29][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([NH:9][C:6](=[O:8])[CH3:7])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=1)(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCCCS(N)(=O)=O
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCS(=O)(=O)NC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
N,N′-carbonyldiimidazole (9.40 g) is added to an N,N-dimethylformamide (300 ml) solution of 4-acetylamino-3-nitro-benzoic acid (10.0 g), and the solution is stirred for 1 hour at room temperature. Then, 1-butanesulfonamide (7.92 g) and diazabicycloundecene (8.83 g) are added into the solution, and the solution is stirred for 72 hours at 100° C. After chloroform and water are added into the solution and the solution is separated into layers, the residue, which is obtained by concentrating the organic layer, is purified using silica gel column chromatography (eluate: ethyl acetate/methanol=4/1), and thus, N-(1-butanesulfonyl)-4-acetylamino-3-nitrobenzamide (10.75 g) is obtained. 1H-NMR (DMSO-d6, δ): 0.87 (3H, t, J=7.4 Hz), 1.37-1.44 (2H, m), 1.64-1.71 (2H, m), 2.12 (3H, s), 3.52 (2H, t, J=7.7 Hz), 7.83 (1H, d, J=8.6 Hz), 8.21 (1H, dd, J=8.6 and 2.1 Hz), 8.54 (1H, d, J=2.2 Hz), 10.56 (1H, s), 12.32 (1H, s).
Reaction SMILES: [CH:1]([C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1)=O.[CH3:26][NH2:27]>ClCCl.CO.C(O)C>[CH3:26][N:27]=[CH:1][C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1
Reactant: CN
Reactant: O=CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CN=CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Reaction time: 24 h

Procedure:
2.0 g (5.9 mmol) of 8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine is dissolved in 100 ml of a 1:1 mixture of dichloromethane-methanol-mixed with 40 ml of a 33% solution of methylamine in ethanol and allowed to stand for 24 hours at room temperature. Then, the solvent is drawn off, and the residue is boiled with 25 ml of ethanol. After filtration, 1.95 g (93%) of the title compound with a melting point of 245-247° C. (decomposition) is obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([O:16]C)=[O:15].C[O-].[Na+].CO.Cl>O>[CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[S:5][C:4]=1[C:14]([OH:16])=[O:15]
Reactant: CNc1cc(-c2ccncc2)sc1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNc1cc(-c2ccncc2)sc1C(=O)O
Yield: 67.9 %

Procedure:
A mixture of methyl 3-(methylamino)-5-(pyridin-4-yl)thiophene-2-carboxylate (0.533 g, 2.15 mmol), sodium methoxide (0.348 g, 6.45 mmol), methanol (8.0 mL) and water (2.0 mL) was heated at reflux for 4 h. The mixture was cooled in an ice-bath and conc. HCl (0.533 mL, 6.45 mmol) was added to adjust the pH to 4. The resultant yellow precipitate was collected by filtration and washed with water and methanol to afford the title compound (0.342 g, 68%) as a yellow solid:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].Cl>O1CCCC1.CO>[CH3:17][O:11][C:10]([C@@H:9]1[CH2:13][C@@H:14]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of trans-1-t-butoxycarbonyl-4-hydroxy-L-proline (8.5 g) in tetrahydrofuran (110 ml) at -30° C., triethylamine (12.8 ml) and methanesulfonyl chloride (6.27 ml) are added. The mixture is stirred at the same temperature for 30 minutes. To the mixture triethylamine (5.13 ml) and methanol (30 ml) are added. The mixture is stirred for 30 minutes. The reaction mixture is acidified with 1N-hydrochloric acid (37 ml) and extracted with ethyl acetate. The extract is successively washed with water, aqueous sodium hydrogen carbonate, water and saturated brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography and recrystallized from toluene-petroleum ether to give (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylic acid methyl ester (9.16 g). Colorless crystals. Yield: 77%. mp. 86° to 87° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.[ClH:24].CO>O1CCOCC1.C(Cl)Cl>[F:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1.[ClH:24]
Reactant: COc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(OC2CCNCC2)c(F)c1
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-(2-fluoro-4-methoxyphenoxy)piperidine-1-carboxylate (2.78 g, 8.54 mmol) in dioxane (21.36 mL) was treated with HCl (4 M in dioxane, 21.36 mL, 85 mmol) at room temperature and the resulting reaction mixture stirred overnight. Flash silica gel chromatography using a gradient of 5% to 30% MeOH in DCM gave the title compound as its HCl salt (1.7 g, 76%) as a white solid. ESI-MS m/z [M+H]+ 226.20.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[C:4]([Cl:11])[CH:3]=1.[CH3:12][OH:13].Cl.[OH2:15]>>[CH3:12][O:13][C:9](=[O:15])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:11]
Reactant: O
Reactant: N#CCc1ccc(Br)cc1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(Br)cc1Cl
Temperature: 0 °C
Yield: 80 %

Procedure:
(4-Bromo-2-chloro-phenyl)-acetonitrile (1.98 g, 8.6 mmoles) was dissolved into MeOH (50 mL) and water (5 mL), and the resulting homogeneous mixture was chilled to 0° C. To this stirring (cold) mixture was slowly (carefully) added concentrated HCl (25 mL). After the addition was complete the mixture was refluxed for 16 hours. After this period the reaction mixture was combined with ice and the resulting heterogeneous mixture was extracted with diethyl ether (3×50 mL). The combined ethereal layer was washed with brine, dried over anhydrous MgSO4, and evaporated in vacuo to yield clean (4-bromo-2-chloro-phenyl)-acetic acid methyl ester (2.3 g, 80%). 1H-NMR (CDCl3): δ 7.56 (d, J=2.0 Hz, 1H), 7.37 (dd, J′=8.3 Hz, J″=2.0 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 3.73 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: O1CCCC1.[O:6]([CH2:13][C:14]([NH:16][CH:17]1[C:43](=[O:44])[N:19]2[C:20]([C:27]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[C:21]([CH:25]=O)[CH2:22][S:23](=[O:24])[C@H:18]12)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:45][N:46]1[C:50]([CH:51]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:49][N:48]=[N:47]1.Cl>CO.C(OCC)(=O)C>[O:6]([CH2:13][C:14]([NH:16][CH:17]1[C:43](=[O:44])[N:19]2[C:20]([C:27]([O:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:28])=[C:21]([CH:25]=[CH:51][C:50]3[N:46]([CH3:45])[N:47]=[N:48][N:49]=3)[CH2:22][S:23](=[O:24])[C@H:18]12)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S(=O)C1
Reactant: Cn1nnnc1C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nnnc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S(=O)C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
To 130 ml of anhydrous tetrahydrofuran was added 5.35 g of benzhydryl 7-phenoxyacetamido-3-formyl-3-cephem-4-carboxylate-1-oxide, and, after cooling to -5°--10° C., further added 4.3 g of (1-methyl-1H-tetrazol-5-yl)methylenetriphenylphosphorane. The mixture was stirred at that temperature for 5 hours and poured into a mixture of ethyl acetate and ice-water. The resulting mixture was then made acidic with 10 ml of 5% hydrochloric acid. The organic layer was washed with five portions of a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave a solid residue. The residue was, after addition of approximately 30 ml of methanol, stirred at room temperature for 20 minutes and filtered leaving a precipitate. There was obtained 3.62 g of benzhydryl 7-phenoxyacetamido-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylate-1-oxide as a crystalline powder. The filtrate was evaporated under redueced pressure to dryness, and the obtained residue was developed through silica gel column with ethyl acetate to give 600 mg of the crystals additionally.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[N:12]([O-])=[O:13].[Na+].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[N:12]([N:7]1[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:10])[F:11])[CH2:9][CH2:8]1)=[O:13]
Reactant: FC(F)(F)CN1CCNCC1
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=NN1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,2,2-trifluoroethyl)piperazine (4.88 g, 29.0 mmol) in water (4.9 mL) that cooled with ice bath, a solution of sodium nitrite (4.04 g, 58.6 mmol) in water (20 mL) and acetic acid (5.0 mL, 87.0 mmol) were added dropwise slowly, then the mixture was stirred for 1 h. The reaction mixture was all owed to warm to ambient temperature, stirred for further 2 h. The reaction mixture was adjusted to pH9 using sodium carbonate, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated to afford 1-nitroso-4-(2,2,2-trifluoroethyl)piperazine as oil (5.57 g, y. 97%).