Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1cc(OC2CCNCC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
1,1-Dimethylethyl 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 3) (21.5 g, 56 mmol) was dissolved in DCM (50 ml) and trifluoroacetic acid (50 ml) was added very slowly. The mixture was stirred at room temperature for 1 h. The solvent was evaporated to dryness and the residue treated with saturated aqueous sodium carbonate solution. The mixture was extracted with EtOAc (×2), washed with water, and dried (MgSO4). The drying agent was removed by filtration and the filtrate was evaporated to dryness (22 g). This was still a trifluoracetic acid salt and was re-dissolved in EtOAc, washed with aqueous sodium carbonate, water, and dried (MgSO4). The drying agent was removed by filtration and the filtrate was evaporated to dryness to afford the title compound (15.9 g). LCMS RT=2.45 min, ES+ve m/z 285 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9]([C:6]1[NH:7][N:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:11]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Yield: 95 %

Procedure:
To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (1.13 g, 7.19 mmol) in anhydrous methanol (20 ml) at to 0° C. was added thionyl chloride (2.23 g, 1.37 ml, 18.7 mmol) dropwise. The resulting solution was heated to reflux for 2 h. The cooled solution was evaporated to dryness to give 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (1.17 g, 95%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3=[C:16]4[C:21](=[N:22][C:14]3=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH2:12]3)[NH:7]2)[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C[Si]([N:33]=[C:34]=[O:35])(C)C>C1COCC1>[NH2:33][C:34]([N:1]1[CH2:2][CH2:3][C:4]2([C:15]3=[C:16]4[C:21](=[N:22][C:14]3=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH2:12]3)[NH:7]2)[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH2:5][CH2:6]1)=[O:35]
Reactant: C1=CCC2=C3N=c4ccccc4=C3C3(CCNCC3)NC2=C1
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: NC(=O)N1CCC2(CC1)NC1=CC=CCC1=C1N=c3ccccc3=C12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4 g of 5,6-dihydrospiro[1H-indolo[3,2-c]quinoline-6,4'-piperidine] in 100 ml of THF were added 9.7 g of K2CO3 and 13.9 ml of trimethylsilyl isocyanate (32% xylene by weight). The mixture was stirred overnight at room temperature and filtered. Subsequently, an additional 5.6 ml of trimethylsilyl isocyanate was added and the resultant solution was stirred for 30 minutes at room temperature. Concentration gave a solid/gum mixture which was triturated with H2O to give 3.07 g of solid, m.p. 265°-267° dec.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:22])([F:21])[C:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]2[CH3:20])=[N:12][CH:13]=1)([OH:7])[CH3:6].C(Cl)Cl.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31](Cl)(=[O:33])=[O:32]>O>[F:22][C:4]([F:3])([F:21])[C:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([S:31]([C:27]3[S:26][CH:30]=[CH:29][CH:28]=3)(=[O:33])=[O:32])[CH2:16][C@@H:15]2[CH3:20])=[N:12][CH:13]=1)([OH:7])[CH3:6]
Reactant: C[C@H]1CNCCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
A 100 mL round-bottomed flask was charged with 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydro chloride (0.250 g, 0.763 mmol) and 10 mL of CH2Cl2. To this was added 2-thiophenesulfonyl chloride (0.153 g, 0.839 mmol, Sigma-Aldrich, St. Louis, Mo.). After 15 min, the mixture was diluted with water (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined extracts were dried (MgSO4), concentrated, and purified via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (0.125 g) as mixture of two isomers.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:2]2[S:16][C:15]([C:14]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=2[CH:6]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of 5.0 g of 2-fluoro-5-(trifluoromethyl)benzaldehyde, 3.3 g of methyl thioglycolate, 4.0 g of potassium carbonate and 50 ml of DMF was stirred at 60° C. for 2 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the mixture was extracted with tert-butyl methyl ether three times. The combined organic layers were washed with water and saturated saline, and dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was recrystallized from methanol, to obtain 6.3 g of methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (present condensed ring compound 1).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.[C:6](ON1C(=O)CCC1=O)([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]>O1CCOCC1>[N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: C1=CCNC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of 2,5-dihydro-1H-pyrrole (30 g, 434 mmol) in dioxane (0.43 M solution) was added CbzOSu (130 g, 521 mmol). After being stirred at room temperature for 18 h, the reaction mixture was concentrated to around 300 mL, diluted with 1000 mL of EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The desired benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate was obtained in 91% yield (80.0 g) as a colorless oil by flash column chromatography. 1H NMR (CDCl3, 400 MHz): δ 7.32 (5H, m), 5.80 (2H, m), 5.77 (2H, s), 4.22 (4H, m). LC/MS (uplc): MH+ 204.2, 160.1 (−44), 0.86 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:15]1[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[N:19]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Br:20][C:18]1[N:19]=[C:15]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[N:3]=[CH:4]3)[N:16]([CH3:21])[CH:17]=1
Reactant: Cn1cc(Br)nc1Br
Reactant: Cn1ncc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(Br)nc1-c1ccc2c(cnn2C)c1
Temperature: 110 °C

Procedure:
In a 10-20 mL reaction vial, the 1-methyl-1H-indazol-5-ylboronic acid (169 mg, 0.966 mmol) and the 2,4-dibromo-1-methyl-1H-imidazole (300 mg, 1.25 mmol) were dissolved in dioxane (4 mL) and water (1 mL) under argon atmosphere. The mixture was bubbled with argon for 5 min and then potassium carbonate (400 mg, 2.895 mmol) and Pd(PPh3)4 (167 mg, 0.145 mmol) were added sequentially. The resulting reaction mixture was then sealed and heated in oil bath at 110° C. for 1.5 h. Reaction was then partitioned between EtOAc (30 mL) and water (30 mL).The organic phase was washed with water (3×20 mL) and was concentrated. Residue was purified on silica gel column with 0-50% EtOAc/Hex to afford the desired product. LCMS-ESI+: calc'd for: C12H11BrN4: 291.0, 293.0 (M+H+); found: 291.0, 293.0 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OC(=O)c2ccccc2)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 93.3 %

Procedure:
A solution of 8a (0.05 g, 0.13 mmol), benzoyl chloride (0.09 g, 0.92 mmol) and a catalytic amount of DMAP in CH2Cl2 (20 mL) was stirred at room temperature for 2 h. Absolute MeOH (15 mL) was added and the solvent was removed under reduced pressure. CH2Cl2 (25 mL) was added to the residue and the solution was washed with 10% HCl (3×20 mL) and saturated NaCl (3×20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded 13 (0.06 g, 98%) as a white solid, mp 165-170° C.; 1H NMR (CDCl3): δ 1.18 (3H, s, H-19); 1.47 (3H, s, H-20); 1.50-1.75 (4H, m, H-6β, H-7α,β and H-11β); 1.84 (1H, ddd, J=3.0, 3.0, 9.9 Hz, H-6α); 2.11 (1H, dd, J=2.4, 10.8 Hz, H-8); 2.26 (1H, s, H-10); 2.47 (2H, m, H-3α,β); 2.55 (1H, dd, J=5.1, 13.5 Hz, H-11α); 2.84 (1H, dd, J=6.9, 9.9 Hz, H-4); 3.75 (3H, s, CO2CH3); 5.40 (1H, dd, J=9.6, 10.5 Hz, H-2); 5.52 (1H, dd, J=2.1, 11.7 Hz, H-12); 6.39 (1H, dd, J=0.9, 1.8 Hz, H-14); 7.40 (1H, dd, J=1.5, 1.8 Hz, H-15); 7.42 (1H, dd, J=0.9, 1.5 Hz, H-16); 7.48 (2H, dt, J=7.2, 7.5 Hz, Ar-meta-H); 7.60 (1H, tt, J=1.2, 7.5 Hz, Ar-para-H); 8.09 (2H, dt, J=1.2, 7.2 Hz, Ar-ortho-H).
Reaction SMILES: [C:1]([O:5][CH:6](Cl)[CH3:7])(=[O:4])[CH2:2][CH3:3].[CH:9]([O:22][C:23]([CH2:25][O:26][N:27]=[C:28]([C:44]1[N:45]=[CH:46][S:47][CH:48]=1)[C:29]([NH:31][CH:32]1[C:42](=[O:43])[N:34]2[C:35]([C:39]([OH:41])=[O:40])=[CH:36][CH2:37][S:38][C@H:33]12)=[O:30])=[O:24])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[CH:9]([O:22][C:23]([CH2:25][O:26][N:27]=[C:28]([C:44]1[N:45]=[CH:46][S:47][CH:48]=1)[C:29]([NH:31][CH:32]1[C:42](=[O:43])[N:34]2[C:35]([C:39]([O:41][CH:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH3:7])=[O:40])=[CH:36][CH2:37][S:38][C@H:33]12)=[O:30])=[O:24])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCC(=O)OC(C)Cl
Reactant: O=C(CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1cscn1)OC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCC(=O)OC(C)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3cscn3)C(=O)N12
Temperature: 40 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
1-Chloroethyl propionate (0.6 g) was added to the mixture of 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) in dimethyl sulfoxide (13 ml) and potassium carbonate (0.3 g) and the mixture was stirred for 2 hours at 40° C. The reaction mixture was added to the mixture of ice-water and ethyl acetate and the mixture was adjusted to pH 7.5 with 20% aqueous solution of potassium carbonate. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated to give 1-propionyloxyethyl 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylate (syn isomer) (1.3 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][NH:23][O:24][CH3:25])=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:23]([CH2:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[O:24][CH3:25])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCCCc1ccc(F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(CCCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-[3-(4-fluorophenyl)-propyl]-O-methyl-hydroxylamine as described in the preparation of compound 1-C gave the title amide as white crystals (97% yield): mp 90-91° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.77 (6H, s, CH3), 1.98 (2H, m, CH2), 2.64 (2H, t, J=7.9 Hz, CH2), 3.71 (2H, t, J=7.6 Hz, NCH2), 3.73 (3H, s, OCH3), 6.41 (1H, broad s, CH), 6.98 (2H, m, aromatics), 7.16 (2H, m, aromatics). Anal. calcd for C17H20FNO5: C, 60.53; H, 5.98; N, 4.15. Found: C, 60.43; H, 5.99; N, 4.09.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10](Cl)=[O:11])[CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[O:11])[CH2:6]1
Reactant: CN(C)CCN
Reactant: O=C(Cl)N1CCC(Oc2cccc(Cl)c2Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)CCNC(=O)N1CCC(Oc2cccc(Cl)c2Cl)C1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution 11.8 g (0.04 mole) of 3-(2,3-dichlorophenoxy)-1-pyrrolidinecarbonyl chloride in 50 ml of chloroform was stirred at 5° C. in an ice bath while the following were added in order: 25 g of ice, 5.52 g of potassium carbonate and 3.87 g (0.044 mole) of N,N-dimethylethylenediamine. The resulting mixture was stirred for 20 hours and worked up by adding additional water followed by separation of the organic phase. The chloroform solution was dried over magnesium sulfate, filtered and concentrated in vacuo to a dark amber oil, 14 g, which solidified on standing. TLC analysis (10% methanol/chloroform) showed 3 spots; therefore, the crude product was chromatographed on 50 g of Fluorisil. Elution with chloroform gave a dark forerun which was discarded, the main portion was collected and rechromatographed through a 50 g Florisil column. The column was washed with 200 ml of methanol and the 2 fractions (chloroform and methanol) were combined before concentrating on a rotary evaporator to give a light amber oil which solidified. Recrystallization from isopropyl ether gave a beige crystalline product; 4.5 g (34%), m.p. 94°-95° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:24]3[CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22][CH2:23]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC1CCNCC1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1CCN(C2=Nc3cc(Br)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A mixture of 4.73 g (0.0150 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1000 ml of toluene was heated under nitrogen, with stirring, until a solution resulted. Then there was added 14.9 g (0.150 mole) of 4-methylpiperidine, followed by 8.54 g (0.045 mole) of titanium tetrachloride. The mixture was refluxed for 3 hours, cooled to room temperature and filtered. The filtrate was stirred with 500 ml of 2N sodium hydroxide solution for 15 minutes and the layers were separated. The aqueous phase was extracted with 250 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to an oil which solidified. The solid was triturated twice with hexane to afford 4.9 g (83%) of product. Recrystallization from ethyl acetate provided the analytical sample, mp 177°-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClCCl>CCOCC.F[B-](F)(F)F.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[NH:11])[O:10][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:23]=2)=[CH:6][CH:7]=1
Reactant: CC(C)C(C(N)=O)c1ccc(Cl)cc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C(C(=N)OCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
To a refluxing solution of 2.72 g (12.9 mmol) of 2-(4-chlorophenyl)-3-methylbutyramide and 2.27 g (8.6 mmol) of 3-phenoxybenzyl bromide in a solution of 15 ml dichloromethane and 3 ml ethyl ether is added a solution of 1.83 g (9.5 mmol) of silver tetrafluoroborate in ether. The mixture is refluxed for 2 hours and then separated by pouring into ice cold aqueous ethyl acetate/sodium bicarbonate. The organic phase is washed with water, dried and stripped of solvent. The residue is triturated with ether and filtered. The filtrate is concentrated and chromatographed on silica gel, eluting with 25% ethyl acetate/-hexane, and then on plates using 35% ethyl acetate/hexane, to yield 3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutanimidate, MS m/e 393 (M-hu +(M+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]=O.Cl.[C:16]([O:20][C:21](=[O:28])[C@H:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:23])([CH3:19])([CH3:18])[CH3:17].[Na]>O1CCCC1.C(OCC)(=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][NH:23][C@H:22]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:28])[C:24]([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](NCCN1C(=O)c2ccccc2C1=O)C(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A solution of the product of Example 111-1 (46.5 g, 246.0 mmol) in tetrahydrofuran (900 mL) was treated with L-tert-leucine-t-butyl ester hydrochloride salt (66.1 g, 295.2 mmol, 1.2 equivalents) stirred at 20° C. for 2 hours, treated with sodium triacetoxyborohydrodride (78.2 g, 369.0 mmol, 1.5 equivalents) portionwise over 5 minutes (slightly exothermic), stirred at 20° C. for 2 hours, diluted with ethyl acetate (1 L) and washed with water (1 L). The organic layer was washed with water (1 L), 10% NaHCO3 (2×1 L) and brine (1 L). The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (87 g, 98.2% yield). 1H NMR (CDCl3): δ 7.82 (m, 2 H), 7.70 (m, 2 H), 3.77 (t, 2 H), 2.92 (m, 1 H), 2.73(s, 1H), 2.68(m, 1H), 1.44(s, 9H), 0.86(s, 9H).
Reaction SMILES: [NH2:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([OH:9])[CH2:3]2.N1C=CC=CC=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH3:16])[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:2]23[CH2:8][CH:5]([CH2:6][CH2:7]2)[CH:4]([OH:9])[CH2:3]3)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: NC12CCC(C1)C(O)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC23CCC(C2)C(O)C3)cc1
Reaction time: 2 h

Procedure:
0.7 g of A1 are dissolved in 7 ml of dichloromethane and mixed with 0.9 ml of pyridine. 1.05 g of p-toluenesulfochloride are added whilst cooling with ice, and the reaction mixture is stirred for 2 hours. The mixture is diluted with 50 ml of dichloromethane, washed with water (1×), dried over MgSO4 and concentrated by evaporation on a rotary evaporator. From the residue, the title compound A5 is obtained as a white solid by flash chromatography (SiO2 60F/dichloromethane/methanol 20:1) and subsequent recrystallisation from toluene (0.53 g, 35% of theory). Melting point: 110-111° C. 1H-NMR (400 Hz, DMSOd6) δ: 0.92 (2H); 1.14 (2H); 1.90 (4H); 2.40 (3H); 3.70 (1H); 4.22 (1H); 5.72 (1H); 7.40 (2H); 7.50 (1H); 7.70 (2H).
Reaction SMILES: [N+:1]([CH:4](O)[CH3:5])([O-:3])=[O:2].[C:7]([OH:10])(=[O:9])[CH3:8].C1C=CC=CC=1>OS(O)(=O)=O.O>[N+:1]([CH2:4][CH2:5][O:10][C:7](=[O:9])[CH3:8])([O-:3])=[O:2]
Reactant: CC(O)[N+](=O)[O-]
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)OCC[N+](=O)[O-]

Procedure:
64 g nitroethanol, 50 ml glacial acetic acid, 250 ml benzene and 5 drops conc. H2SO4 were refluxed, using a water separator for 8 hours; 12 ml of H2O were collected. The solution was evaporated and vacuum distilled (1 mm at 60° C) yielding 89 g colorless nitroethylacetate.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][S:7][C:8]1[N:13]=[CH:12][C:11](N)=[CH:10][CH:9]=1.N([O-])=[O:16].[Na+].C(=O)(O)[O-].[Na+]>O>[CH3:6][S:7][C:8]1[N:13]=[CH:12][C:11]([OH:16])=[CH:10][CH:9]=1
Reactant: O=N[O-]
Reactant: CSc1ccc(N)cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CSc1ccc(O)cn1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of 5.5 ml of concentrated sulfuric acid and 8 ml of water is added to 1.9 g (13.55 mM) of 6-(methylthio)-3-pyridinamine. The reaction medium is brought to −6° C. and a solution of 1.59 g (23.03 mM) of sodium nitrite in 3 ml of water is added dropwise without exceeding 0° C. The mixture is stirred for 1 hour 30 min between 0° C. and −4° C. and then refluxed for 1 hour. The cooled reaction medium is poured in the presence of sodium bicarbonate and the mixture is then extracted with ethyl acetate. The organic phase is concentrated under reduced pressure and the residue is then chromatographed on silica gel (dichloromethane/ethyl acetate, 90/10; v/v) to give the expected product in the form of a white powder with a yield of 60%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2].[H][H]>O.Cl.CO.[Pt](=O)=O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1ccccn1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOC(=O)CC1CCCCN1

Procedure:
Platinum(IV) oxide (15 mg) was added to a mixture of 2-(2-pyridyl)acetic acid ethyl ester (1.652 g) in water (1.25 mL) and concentrated hydrochloric acid (1.25 mL) in methanol (15 mL), and the resultant mixture was stirred in a hydrogen atmosphere at room temperature for 15 hours. The catalyst was filtered off. The solvent was evaporated under reduced pressure, and ethanol was added to the residue, and then the solvent of the mixture was evaporated again under reduced pressure. To the residue, a small amount of water, diethyl ether (about 100 mL), and an excessive amount of potassium carbonate were added, and the resultant mixture was stirred, followed by filtration. The solvent of the filtrate was evaporated under reduced pressure, to thereby give the title compound as an oily product (1.322 g, 77%).