Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[O:3][CH2:4][CH:5]([OH:7])[CH3:6].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[Cl-].[NH4+]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:14][C:11]([CH3:13])([O:10][C:8](=[O:9])[N:2]([CH3:1])[O:3][CH2:4][CH:5]([CH3:6])[O:7][C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH3:12]
Reactant: O=C1CCC(=O)O1
Reactant: CC(O)CON(C)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(CON(C)C(=O)OC(C)(C)C)OC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
To a solution of N-methyl-N-boc-(2-hydroxypropyl)hydroxylamine (227 mg, 1.11 mmol) in dichloromethane (4 mL) were added DMAP (41 mg, 0.333 mmol) and succinic anhydride (167 mg, 1.67 mmol). The resulting mixture was stirred for 20 h at room temperature. The reaction mixture was poured into a saturated solution of ammonium chloride (15 mL) and extracted with DCM (3×40 mL). The combined organic layer was washed with water and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by silica flash column chromatography using 40% EtOAc/hexane as eluent to give the product as a white solid (227 mg, 0.744 mmol, 67%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6](B(O)O)=[C:5]([CH3:11])[CH:4]=1)=O.IC1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.[C:26]([O-])([O-])=[O:27].[Na+].[Na+]>CCO.COCCOC.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>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:1]([C:3]3[S:7][C:6]([CH:26]=[O:27])=[C:5]([CH3:11])[CH:4]=3)[C:21]=12
Reactant: Cc1cc(C=O)sc1B(O)O
Reactant: O=C([O-])[O-]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1cc(-c2nn(C(C)C)c3ncnc(N)c23)sc1C=O
Temperature: 80 °C
Yield: 38 %

Procedure:
A solution of 5-Formyl-3-methylthiophene-2-boronic acid (26 mg, 0.14 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA34 (14.7 mg, 38% yield). ESI-MS (M+H)+ m/z calcd 302.1, found 302.0.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C@@H:6]([OH:20])[C@@H:7]([NH:9]C(=O)OCC1C=CC=CC=1)[CH3:8].[ClH:26]>C(O)C.C(OCC)C.[Pd]>[Cl-:26].[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C@@H:6]([OH:20])[C@@H:7]([NH3+:9])[CH3:8]
Reactant: Cl
Reactant: C[C@H](NC(=O)OCc1ccccc1)[C@H](O)COc1ccc(F)cc1F
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: C[C@H]([NH3+])[C@H](O)COc1ccc(F)cc1F
Product: [Cl-]
Yield: 94 %

Procedure:
Benzyl (2S,3S)-4-(2,4-difluorophenoxy)-3-hydroxybutan-2-ylcarbamate (426 mg, 1.21 mmol) in ethanol (20 mL) was hydrogenated over Pd (10% on carbon) (40.0 mg) at r.t. and atmospheric pressure overnight. The mixture was filtered through celite, evaporated, dissolved in ethanol and filtered through a syringe filter. On evaporation a white solid was obtained. This was dissolved in ethanol (4 mL) and diethyl ether (6 mL) and 1M HCl in diethyl ether was added (1.5 mL) under stirring. Evaporation, coevaporation from dichloromethane/diethylether gave the title compound as a solid, (290 mg, 94%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:36])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:35][C:31]1[CH:30]=[C:29]([C:27]2[CH2:26][C:25](=[O:36])[NH:24][C:9]3[CH:10]=[C:11]([C:20]([F:22])([F:23])[F:21])[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])=[CH:13][C:8]=3[N:7]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(Br)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2

Procedure:
) The title compound was prepared from the above described {2-[3-(3-bromo-phenyl)-3-oxo-propionylamino]-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (1.01 g, 1.72 mmol) and TFA (6.5 mL) in DCM (20 mL) according to general procedure I step 2. Obtained as a white solid (0.65 g, 81%). MS (ISP) 468.0 [(M+H)+]; mp 186° C. (dec).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([CH2:12][N:13]([C@:20]2([OH:35])[C@H:26]([OH:27])[C@@H:25]([CH2:28][OH:29])[O:24][C@:22]([CH2:30][CH2:31][CH2:32][CH3:33])([OH:23])[C@@H:21]2[OH:34])[C:14](=[O:19])[NH:15][CH2:16][CH2:17][Cl:18])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[N+:36]([O-])([N+]([O-])=O)=[O:37].CCCCCC>O1CCCC1.C(O)(=O)C>[CH:6]1([CH2:12][N:13]([C@:20]2([OH:35])[C@H:26]([OH:27])[C@@H:25]([CH2:28][OH:29])[O:24][C@:22]([CH2:30][CH2:31][CH2:32][CH3:33])([OH:23])[C@@H:21]2[OH:34])[C:14](=[O:19])[N:15]([CH2:16][CH2:17][Cl:18])[N:36]=[O:37])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCC[C@]1(O)O[C@H](CO)[C@@H](O)[C@@](O)(N(CC2CCCCC2)C(=O)NCCCl)[C@H]1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCCC[C@]1(O)O[C@H](CO)[C@@H](O)[C@@](O)(N(CC2CCCCC2)C(=O)N(CCCl)N=O)[C@H]1O
Reaction time: 0.08 h
Yield: 37.3 %

Procedure:
Anhydrous sodium acetate (15 g) was added to a solution of 3-cyclohexylmethyl-3-(n-butyl α-D-glucopyranose-3-yl)-1-(2-chloroethyl)urea (3.94 g, 9.02 mmol) in a mixture of tetrahydrofuran (120 ml) and acetic acid (20 ml), and dinitrogen tetraoxide gas (4 g) was introduced into the mixture with well stirring at 0° to 5° C. spending 5 minutes. After the mixture was stirred at the same temperature for further 30 minutes to complete reaction, n-hexane (200 ml) was added and insoluble matter was filtered off. The filtrate was vacuum-concentrated at 25° C. and fractionated by column chromatography (packing: silica gel; eluent: ethyl acetate/chloroform/methanol (2:10:1) to isolate the objective product. Thus, 1.62 g of 3-cyclohexylmethyl-3-(n-butyl α-D-glucopyranose-3-yl)-1-(2-chloroethyl)-1-nitrosourea was obtained; yield 38.5%, m.p. 75°-77° C., [α]D20 +47.2° (C 1.0, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5](C(O)=O)=[CH:4][N:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:18])C=CC=CC=1.C([N:30]([CH2:33]C)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([N:30]=[C:33]=[O:18])=[CH:4][N:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-chloro-nicotinic acid (0.468 g, 3 mmol) (Aldrich) in toluene (15 mL) was added diphenylphosphoryl azide (0.958 g, 3.5 mmol) (Aldrich), followed by the addition of triethylamine (0.35 g, 3.6 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes and the mixture became clear. Then the mixture was heated at 80° C. for 2 hours. The mixture was cooling down to room temperature to give crude 2-chloro-5-Isocyanato-pyridine as 0.2 M solution of toluene and used for the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:20](O)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH2:40].O>CN(C=O)C>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH:40][C:20]([C:4]1[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=2)[C:7]([CH3:8])=[C:2]([I:1])[CH:3]=1)=[O:21]
Reactant: Cc1c(I)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(I)cc(C(=O)NCCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a suspension of 5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (10 g, 23.64 mmol) in DMF (20 mL) was added a solution of carbonyldiimidazole (5.14 g, 30.72 mmol) in DMF (30 mL) over a period of 40 min at 25° C. After stirring the mixture for 30 minutes, was added a solution of N,N-dimethylpropane-1,3-diamine (3.62 g, 35.45 mmol) in DMF (10 mL) over a period of 20 min at 25° C. and stirred for 40 minutes. After completion of the reaction, water (100 mL) was charged at 25° C. over a period of 1 h. The resulting suspension was stirred for 4 h and filtered. The cake was washed with water (50 mL) and dried under vacuum at 50° C. for 12 h to afford the title product as a light brown solid (10 g, 83%); 1H NMR (400 MHz, CDCl3) δ 9.36 (bs, 1 H), 8.87 (s, 1 H), 7.82 (d, J=7.53 Hz, 1 H), 7.76 (t, J=7.78Hz, 1 H), 7.49 (s, 1 H), 7.41 (d, J=8.03 Hz, 1 H), 3.43 (q, J=6.86 Hz, 2 H), 2.30-2.35 (m, 2 H), 2.29 (s, 3 H), 2.20 (s, 6 H), 1.74 (p, J=7.28 Hz, 2 H); LCMSm/z: 508 [M+].
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N+:12]([C:15]1C=CC=CC=1)([O-:14])=[O:13].CN>CO>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:15][N+:12]([O-:14])=[O:13])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: CN
Solvent: CO
Product: CN(C)c1ccc(C=C[N+](=O)[O-])cc1
Reaction time: 72 h
Yield: 41.1 %

Procedure:
A mixture of 4-dimethylaminobenzaldehyde (1.5 g, 10 mmol) in 3 mL methanol, 0.61 g (10 mmol) nitrobenzene and 0.15 mL of 22% methylamine aqueous solution was stirred for 3 days. The dark red solid obtained after filtration was recrystallized from nitromethane and rinsed with cold methanol to yield 0.79 g (41.1%) of red crystals, mp 180.6-180.9° C. (ref mp 181° C. (see Richter-Egger, D. L. et al. J. Chem. Educ. 2001, 78, 1375-1378)). 1H NMR 3.08 (s, 6H, Ar—N(CH3)2); 6.68 (2H, d, JHH 8.7 Hz, Ar—H); 7.43 (2H, d, JHH 9.0 Hz, Ar—H); 7.50 (1H, d, JHH 13.2 Hz, Ar—CH); 7.97 (1H, d, JHH 13.5 Hz, CH—NO2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[C:25]([F:28])([F:27])[F:26]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[C:25]([F:26])([F:27])[F:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Fc1cccc2c1CCNC2C(F)(F)F
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2c(F)cccc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=3)[C:5]2=[O:16])[CH2:3][CH2:2]1.[Sn](Cl)(Cl)(Cl)Cl>CCO.O>[NH2:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:16])[N:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:12]2
Reactant: O=C1c2ccc([N+](=O)[O-])cc2CN1C1CC1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CN(C1CC1)C2=O
Temperature: 79 °C
Reaction time: 2 h

Procedure:
The 2-cyclopropyl-5-nitroisoindolin-1-one (50 mg, 0.23 mmol) was dissolved in EtOH (1.1 ml) with heating, and tin chloride (117 mg, 0.52 mmol) added. The solution was stirred at 79° C. for 2 hours. The mixture was cooled to RT, diluted with 4:1 water:saturated sodium bicarbonate (aq, 100 ml), extracted with EtOAc (3×100 ml), the organics combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 5% MeOH:DCM+1% TEA to give the titled compound.
Reaction SMILES: [Br:1][Si](C)(C)C.CS(C)=O.[CH:10]1([C:15]([OH:17])=[O:16])[CH2:14][CH:13]=[CH:12][CH2:11]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[Br:1][CH:12]1[CH:13]2[CH2:14][CH:10]([C:15](=[O:17])[O:16]2)[CH2:11]1
Reactant: C[Si](C)(C)Br
Reactant: O=C(O)C1CC=CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C1OC2CC1CC2Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Bromotrimethysilane (3.1 mL, 0.023 mol) was added dropwise to a solution of dimethyl sulfoxide (1.6 mL, 0.023 mol) in chloroform (38.0 mL) in a round-bottom flask at 0° C. The resulting mixture was stirred at 0° C. for 2 hours. To the reaction mixture was added dropwise a solution of cyclopent-3-ene-1-carboxylic acid (2.00 g, 0.0178 mol) in chloroform (12 mL) over a period of 15 minutes and the reaction mixture was stirred at 0° C. for 10 minutes. N,N-diisopropylethylamine (4.0 mL, 0.023 mol) was then added and the resulting mixture was stirred at 0° C. After 10 minutes, the mixture was heated to reflux for 16 hours. The reaction mixture was diluted with chloroform, washed with water, brine, dried (MgSO4), and stripped in vacuo. The residue was purified by chromatography on silica gel using 30% EtOAc/hexanes as eluent to give the product. 1HNMR (400 MHz, CDCl3): δ 4.88 (brs, 1H), 4.34 (m, 1H), 2.90 (m, 1H), 2.66 (m, 1H), 2.31 (m, 1H), 1.93 (m, 1H), 1.83 (m, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[C:17](=[O:22])[NH:18][CH2:19][CH2:20][CH:21]=1.[CH3:24]Br>C1COCC1>[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[C:17](=[O:22])[N:18]([CH3:24])[CH2:19][CH2:20][CH:21]=1
Reactant: COC(=O)CCC1=CCCNC1=O
Reactant: CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCC1=CCCN(C)C1=O
Reaction time: 0.5 h
Yield: 72 %

Procedure:
0.22 ml of 1.0M NaHMDS solution in THF (0.22 mM) was added to 0.5 ml of THF solution containing 80 mg 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl ester (f) prepared from the step 1 in Example 3 (0.44 mM) in a dropwise manner at −79° C. and then stirred for 30 min. After 0.48 ml of methyl bromide (0.48 mM) was added to the reaction mixture, the solution was stirred at 0° C. for 3 hrs. The reaction mixture was quenched by 2 ml of sat. NH4Cl solution and then the organic layer was extracted with ethyl acetate (7 ml). The combined organic layer was washed with 2 ml of sat. NH4Cl solution (2 ml) and 2 ml of sat. NaCl solution subsequently. Then the organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with EtOAc solvent as an eluant to give 62 mg of the title compound (i2) (yield: 72%).
Reaction SMILES: C(N(CC)CC)C.C(C1C=CC(S([N:20]=[N+:21]=[N-])(=O)=O)=CC=1)(O)=O.[N:23]([CH:26]1[CH:29]([CH2:30][C:31](=[O:43])[CH2:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[NH:28][C:27]1=[O:44])=[N+:24]=[N-:25]>C(#N)C.C(OC(=O)C)C>[N:23]([CH:26]1[CH:29]([CH2:30][C:31](=[O:43])[C:32]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[N+:20]=[N-:21])[NH:28][C:27]1=[O:44])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=NC1C(=O)NC1CC(=O)CC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1C(=O)NC1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
Triethylamine (15 mmol) is added to an ice-cold stirring suspension of p-carboxybenzene sulfonylazide (5 mmol) and 3-azido-4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one (5 mmol) in anhydrous acetonitrile (30 ml). The resulting mixture is stirred at room temperature for 90 mins, then diluted with ethylacetate and filtered. The filtrate is washed with water, 0.5 N sodium hydroxide, water, and brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to give 3-azido-4-(3-benzyloxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].BrC(C)COC1C2C(=CC(OC)=CC=2)N=CC=1.Br[CH2:29][CH:30]([O:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[N:36]=[CH:35][CH:34]=1)[CH3:31]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:31][CH:30]([O:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([O:43][CH3:44])=[CH:40][CH:41]=3)[N:36]=[CH:35][CH:34]=2)[CH3:29])[CH:7]=1
Reactant: COc1ccc2c(OC(C)CBr)ccnc2c1
Reactant: O=c1ccc(Br)c[nH]1
Agent: COc1ccc2c(OCC(C)Br)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(OC(C)Cn3cc(Br)ccc3=O)ccnc2c1
Reaction time: 0.17 h

Procedure:
To a stirring solution of 5-bromo-2(1H)-pyridone (100 mg, 575 μmol) in DMF (1 mL) under nitrogen was added sodium hydride (60% dispersion in mineral oil; 27.6 mg, 1149 μmol) and stirred for 10 min. To this suspension was added 4-(2-bromopropoxy)-7-methoxyquinoline (170 mg, 575 μmol) and 4-(1-bromopropan-2-yloxy)-7-methoxyquinoline (170 mg, 575 μmol) mixture in DMF (1 mL). The mixture was stirred at 40° C. for 48 h. The reaction was quenched with 5% NaHCO3 and extracted with CH2Cl2 (4×10 mL). The combined organics were dried over MgSO4, concentrated to a residue from toluene, and purified on 12 grams of silica eluting with 30-60% of 5% (MeOH/CH2Cl2). MS (ESI pos. ion) m/z (MH+): 389/391. Calc'd exact mass for C18H17BrN2O3: 388. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.52 (d, J=6.26 Hz, 3H) 3.90-4.01 (m, 4H) 4.48 (dd, J=13.60, 3.23 Hz, 1H) 5.05-5.14 (m, 1H) 6.45 (d, J=9.59 Hz, 1H) 6.67 (d, J=5.48 Hz, 1H) 7.18 (dd, J=9.19, 2.54 Hz, 1H) 7.24-7.31 (m, 1H) 7.37 (d, J=2.15 Hz, 1H) 7.53 (d, J=2.54 Hz, 1H) 8.01 (d, J=9.19 Hz, 1H) 8.61 (d, J=5.48 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) 8 ppm 17.29, 54.82, 55.55, 71.78, 97.82, 100.08, 107.03, 116.03, 118.81, 121.93, 122.66, 138.56, 143.08, 151.11, 151.41, 160.12, 161.17.
Reaction SMILES: C(Br)(Br)[Br:2].[CH3:5][CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8]>O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)(Cl)Cl>[Br:2][C:6]([CH3:5])([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(C)C(=O)OC
Reactant: BrC(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Br)C(=O)OC
Yield: 89.4 %

Procedure:
Bromoform (1.01 g, 0.4 mol), 1.46 g dimethyl methylmalonate, 200 mg tetra-n-butylammonium fluoride trihydrate (0.632 mmol), and 5 mL carbon tetrachloride were mixed at 24° C. for 2 h. The solution was found to contain 2.01 g (89% yield) of dimethyl α-bromo-α-methylmalonate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][CH2:18][C:19]3[S:23][C:22]([C:24]#[N:25])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.CO>[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][CH2:18][C:19]3[S:23][C:22]([C:24](=[NH:44])[NH2:25])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)s1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)s1)n2C)c1ccccn1
Yield: 53 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(2-cyanothiophen-5-yl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 53% of theory, C26H28N6O3S (504.6); Rf value: 0.22 (silica gel; dichloromethane/methanol=5:1); EKA mass spectrum: (M+H)+=505; (M+H+Na)++=264.
Reaction SMILES: ClC1C=CC2N(C3C[O:13][CH2:12]3)C(CCl)=NC=2C=1.[Cl:17][C:18]1[CH:47]=[CH:46][C:21]2[N:22]([C@@H:39]3[CH2:43][CH2:42]S(=O)(=O)C3)[C:23]([CH2:25][N:26]3[C:30]4=[CH:31][N:32]=[CH:33][CH:34]=[C:29]4[C:28]([S:35]([CH3:38])(=[O:37])=[O:36])=[N:27]3)=[N:24][C:20]=2[CH:19]=1.CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:17][C:18]1[CH:47]=[CH:46][C:21]2[N:22]([CH2:39][CH:43]3[CH2:12][O:13][CH2:42]3)[C:23]([CH2:25][N:26]3[C:30]4=[CH:31][N:32]=[CH:33][CH:34]=[C:29]4[C:28]([S:35]([CH3:38])(=[O:37])=[O:36])=[N:27]3)=[N:24][C:20]=2[CH:19]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCS(=O)(=O)C2)c2cnccc12
Reactant: ClCc1nc2cc(Cl)ccc2n1C1COC1
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CC2COC2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-oxetan-3-yl-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole (Example 2-1) instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][C@@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1)#[N:17]>N1C=CC=CC=1>[C:16]([C:18]1[CH:19]=[C:20]([S:24]([N:11]2[C@H:10]([CH3:15])[CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][C@@H:12]2[CH3:14])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1)#[N:17]
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1S(=O)(=O)c1cccc(C#N)c1

Procedure:
A solution of cis-4-benzyl-2,6-dimethylpiperazine (1 g), 4-N,N-dimethylaminopyridine(0.54 g), 3-cyanobenzenesulphonyl chloride (2.13 g) in pyridine (3 ml) were stirred at ambient temperature. After 1 h the mixture was partitioned between dichloromethane and water. The organic phase further washed with brine, collected, dried, (MgSO4) and solvent evaporated under reduced pressure to leave the subtitle compound as an orange gum. Yield: 1 g
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=O)[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1[CH3:20].C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C(O)C.[Pd]>[OH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[C:3]=1[CH3:20]
Reactant: Cc1ccc(-c2coc3c(C)c(O)ccc3c2=O)cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc(C2COc3c(ccc(O)c3C)C2)cc1

Procedure:
7-Hydroxy-8-methyl-3-(4-methylphenyl)-4H-1-benzopyran-4-one (400 mg) in a mixture of dioxane and ethanol 1:1 (200 ml) is hydrogenated for 64 h at room temperature over palladium 10% on active charcoal (100 mg) in the presence of p-toluenesulfonic acid monohydrate (120 mg). After filtration of the catalyst, the filtrate is evaporated under reduced pressure to a volume of about 50 ml. Water (150 ml) is added and the solution is extracted with dichloromethane (3×100 ml). The combined organic solutions are washed with water, dried and evaporated. The product is dried in vacuo to constant weight to yield 3,4-dihydro-7-hydroxy-8-methyl-3-(4-methylphenyl)-2H-1-benzopyran, m.p. 136°-137°.