Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C(O[C:15](OCC)(OCC)[CH2:16][CH3:17])C>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:15]([CH2:16][CH3:17])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc(-c2ccc(Br)cc2)o1

Procedure:
A mixture of 4-bromobenzoic acid hydrazide (3.23 g) and triethylorthopropionate (25 ml) was heated at reflux for 7 hours. The mixture was evaporated to give a solid which was recrystallised from ethyl acetate to give 2-(4-bromphenyl)-5-ethyl-1,3,4-oxadiazole (3.65 g), as a solid, m.p. 101°-102° C.; microanalysis found: C, 47.3; H, 3.6; N, 10.9%; C10H9BrN2O requires: C, 47.5; H, 3.58; N, 11.1%; NMR(CDCl3): 1.44(3H,t), 2.96(2H,q), 7.65(2H,d) and 7.90(2h,D); m/z 253(M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[CH:24]([NH2:26])[CH2:23][CH2:22]2.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[CH:24]([NH:26][C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=3)[N:3]=1)[CH2:23][CH2:22]2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: COc1cccc2c1C(N)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cccc2c1C(Nc1ccc3cc([N+](=O)[O-])ccc3n1)CC2
Temperature: 140 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A mixture of 2-chloro-6-nitro-quinoline (1.8 g, 8.62 mmol) in 1-methyl-2-pyrrolidone (5 mL) with the above described 7-methoxy-indan-1-ylamine (1.69 g, 10.35 mmol) and N-ethyldiisopropylamine (2.22 mL, 12.94 mmol) was stirred at 140° C. for 2 h. Cooled to 23° C., poured onto water and extracted twice with ethyl acetate, dried over Na2SO4 and evaporated totally to give a crude product which was purified by silica gel column chromatography with heptane/dichloromethane followed by trituration with diethyl ether to give the title compound as a yellow solid (2.3 g, 80%); MS: m/e=336.3 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C)C=O.[C:21]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([NH2:34])=[CH:29][CH:28]=2)([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>S(Cl)(Cl)=O.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:34][C:30]4[CH2:31][C:32]5[C:27](=[CH:28][CH:29]=4)[N:26]=[C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:33]=5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(C)(C)c1cc2cc(N)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)C1=NC2=CC=C(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)CC2=C1
Reaction time: 0.5 h

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (1.09 g, 5.30 mmol) was dissolved in 2 mL of thionyl chloride under nitrogen. A catalytic amount (0.3 mL) of N,N-dimethylformamide (DMF) was added and the reaction mixture was stirred for 30 minutes. The excess thionyl chloride was evaporated and the resulting residue was dissolved in 15 mL of dichloromethane. This solution was slowly added to a solution of 2-tert-butyl-1H-indol-5-amine (1.0 g, 5.3 mmol) in 10 mL of dichloromethane containing triethylamine (1.69 mL, 12.1 mmol). The resulting solution was allowed to stir for 10 minutes. The solvent was evaporated to dryness and the crude reaction mixture was purified by silica gel column chromatography using a gradient of 5-50% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a pale pink powder (1.24 g 62%). ESI-MS m/z calc. 376.18, found 377.3 (M+1)+. Retention time of 3.47 minutes. 1H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 8.39 (s, 1H), 7.56 (d, J=1.4 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.05-6.87 (m, 4H), 6.03 (s, 3H), 1.44-1.37 (m, 2H), 1.33 (s, 9H), 1.05-1.00 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]([CH3:43])=[C:16]([N:28]([CH3:42])[CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[CH:17]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([CH:26]=O)=[CH:24][CH:25]=2)[CH:19]=1)=[O:13].[NH:44]1[CH2:49]COC[CH2:45]1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:13])[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([CH2:26][N:44]([CH3:49])[CH3:45])=[CH:24][CH:25]=2)[CH:17]=[C:16]([N:28]([CH3:42])[CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)[C:15]=1[CH3:43]
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)nc3)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a stirred solution of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-formylpyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate (1 equiv.) and morpholine (5 equiv.) in methanol (5 mL for 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 4 h. Then reducing agent NaBH3CN (1 equiv.) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and residue purified by column chromatography over silica gel affording desired tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-((dimethylamino)methyl)pyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate. This compound was then dissolved in DCM (5 mL) and cooled to 0° C. TFA (2 mL) was added to it. The reaction mixture was stirred at room temperature for 1 h. On completion, reaction was concentrated to dryness. Residue was purified by solvent washings to afford the title compound (0.06 g, 40%). LCMS: 517.25 (M+1)+; HPLC: 99.07% (@ 254 nm) (Rt; 3.913; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.48 (s, 1H), 10.08 (bs, 1H), 8.97 (s, 1H), 8.57 (bs, 1H), 8.23 (d, 2H, J=7.6 Hz), 8.18 (s, 1H), 7.60 (d, 1H, J=8 Hz), 7.50 (s, 1H), 7.34 (s, 1H), 5.87 (s, 1H), 4.49 (d, 2H), 4.30 (s, 2H), 3.25 (d, 2H), 3.16 (s, 1H), 2.89 (m, 2H), 2.83 (s, 6H), 2.64 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.81 (bs, 4H).
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:4](O)=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:22]>ClCCCl>[Cl:22][C:4]1[C:5]2[CH2:9][CH2:8][CH2:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1CCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Clc1ncnc2c1CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a solution of 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.87 g, 72.5 mmol) in DCE (200 ml) was added DIEA (15 mL, 86.1 mmol). The mixture was stirred at room temperature for 30 minutes and then added POCl3 (15 mL, 163.9 mmol) was added slowly. The mixture was stirred at room temperature for 1 hour and then refluxed for 12 hour. After cooling, the solvent was removed and the residue was dissolved in CHCl3 (200 ml). The mixture was basified by adding ice-cooled concentrated aqueous ammonia (15 mL). The organic phase was separated. The aqueous phase was washed with CHCl3 (3×100 mL). The organic phase was combined, dried and concentrated. The residue was subject to chromatography on silica gel, eluted by Hexanes/ethyl acetate (4:1) to afford 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.7 g, 51%). 1H NMR (CDCl3, 400 MHz) δ 8.76 (s, 1H), 3.12-3.01 (m, 4H), 2.23-2.14 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5]2.O.[CH3:20][N:21](C=O)C>[NH4+].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5]2)#[N:21]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(Br)cc2C1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NC1Cc2ccc(C#N)cc2C1
Temperature: 110 °C
Reaction time: 21 h

Procedure:
A flask charged with 1,1-dimethylethyl (5-bromo-2,3-dihydro-1H-inden-2-yl)carbamate (3.0 g, 9.26 mmol; step 1 above), dppf (645 mg, 1.16 mmol), Pd2 dba3 (532 mg, 0.58 mmol), ZnCN2 (1.50 g, 12.8 mmol) and water in 50 mL DMF was evacuated/backfilled with nitrogen (×4), and stirred at 110° C. for 21 hours. Upon cooling, the mixture was diluted with satd NH4Cl and extracted with ethyl acetate. The organic extract was washed with (water 3×, brine), dried over MgSO4 and concentrated in vacuo. The residual oil was purified by flash chromatography (ethyl acetate/hexanes) affording title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.45 (d, 1H, J=7.9 Hz), 7.28 (d, 1H, J=7.7 Hz), 4.69 (br.s, 1H), 4.47 (br. s, 1H), 3.33-3.25 (m, 2H), 2.86-2.80 (m, 2H), 2.79 (s, 9H).
Reaction SMILES: O.NN.C([NH:7][C:8]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])(=O)C.C(O)(=O)C.[Cl-].[Na+]>C(OCC)(=O)C>[NH2:7][C:8]1[CH:16]=[C:15]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CC(=O)Nc1cc(Oc2ccccc2)ccc1C(=O)O
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A suspension of hydrazine monohydrate 5.0 mL of 2-(acetamido)-4-phenoxybenzoic acid 1.5 g was heated and refluxed for 4 hours. After the reaction mixture was cooled to room temperature, acetic acid 10 mL, ethyl acetate and saturated sodium chloride aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, solid matter was filtrated to give 2-amino-4-phenoxybenzoic acid 1.2 g of white solid.
Reaction SMILES: [Sn](Cl)Cl.[N+:4]([C:7]1[C:8](=[O:20])[N:9]([CH2:17][CH:18]=[CH2:19])[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)([O-])=O.[OH-].[Na+]>Cl.C1COCC1>[NH2:4][C:7]1[C:8](=[O:20])[N:9]([CH2:17][CH:18]=[CH2:19])[C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1
Reactant: C=CCn1c(C(F)(F)F)ccc([N+](=O)[O-])c1=O
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCn1c(C(F)(F)F)ccc(N)c1=O
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A solution of tin(II) chloride (924 mg, 4.09 mmol) in concentrated HCl (2.5ml) was added dropwise to a stirred solution of 3-nitro-6-trifluoromethyl-1-allyl-2-pyridinone (127 mg, 0.512 mmol) in THF(6.5 ml) at -10° C. After 1 h at 0° C., the reaction was poured into a mixture of 50% sodium hydroxide and ice. The product was extracted into ethyl acetate, dried (Na2SO4), and evaporated invacuo to give the title compound (106 mg): 1H NMR (CDCl3) selected signals at δ 4.63 (br s, 2H, NH2), 4.74 (d, J=5.4 Hz, 2H), 5.11-5.23 (m, 2H), 5.86-5.99 (m, 1H), 6.42 (d, J=7.7 Hz, 1H), 6.64 (d, J=7.7 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:26])=[N:8][N:9]2[C:14]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])=[CH:13][C:12]([CH3:25])=[CH:11][C:10]=12)=[O:5])C.[OH-].[Na+].CS(C)=O>O1CCOCC1>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[CH2:16][O:15][C:14]1[N:9]2[N:8]=[C:7]([CH3:26])[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[CH:11]=[C:12]([CH3:25])[CH:13]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3Cl)cc(C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(F)cccc2Cl)n2nc(C)c(C(=O)O)c2c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
A solution of 198 mg (0.62 mmol) of 7-(2-chloro-6-fluorobenzyloxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (Example 136A) in 6.7 ml of 1,4-dioxane was admixed with 2 M sodium hydroxide solution (2.5 ml). The mixture was stirred at 90° C. for a further 18 hours. The reaction mixture was admixed with 0.8 ml of dimethyl sulphoxide and stirred at 90° C. for a further 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was admixed with acetonitrile (5 ml) and trifluoroacetic acid (0.8 ml), and then with water and dichloromethane. The organic phase was removed and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (mobile phase: dichloromethane/methanol, gradient 80% to 100%), which gave 105 mg (27% yield, 56% pure) of the target compound, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C@H:19]([CH3:28])[CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:32]=[C:33]([CH2:37][C:38](O)=[O:39])[CH:34]=[CH:35][CH:36]=1.CCN(C(C)C)C(C)C>>[CH3:28][C@@H:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:41])([F:29])[F:42])[CH:32]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)[CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1
Reactant: C[C@H](COC1CCCCO1)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](COC1CCCCO1)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cncnc21

Procedure:
Prepared according to the method described above for Example 1, using (5-aminopyridin-3-yl){7-[(1R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (Preparation 36) and 3-trifluoromethylphenylacetic acid with DIPEA as base.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CCN(C)C)cc1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(CCN(C)C)cc1
Yield: 26.7 %

Procedure:
Following general procedure D, 1-(6-bromo-4-(4-(2-(dimethylamino)ethyl)phenyl amino)quinolin-3-yl)ethanone (76 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (76 mg, 0.28 mmol) to afford the desired product (23 mg, 27%) as a yellow-green solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.30 (s, 1H), 8.19 (dd, J=8.8, 2.0 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.76 (d, J=2.1 Hz, 1H), 7.60 (d, J=8.3 Hz, 2H), 7.50 (d, J=8.3 Hz, 2H), 6.99-6.92 (m, 2H), 3.46-3.39 (m, 2H), 3.27-3.19 (m, 2H), 3.00 (s, 6H), 2.82 (s, 3H); ESI MS m/z 478 [C27H25ClFN3O2+H]+; HPLC 98.4% (AUC), tR=10.91 min.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29](O)=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:65]1[CH2:70][CH2:69][CH:68]([N:71]2[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]2)[CH2:67][CH2:66]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)[C:29](=[O:30])[N:74]3[CH2:73][CH2:72][N:71]([CH:68]4[CH2:69][CH2:70][O:65][CH2:66][CH2:67]4)[CH2:76][CH2:75]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Reaction time: 16 h

Procedure:
A solution of 70 mg (0.15 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 51 mg (0.16 mmol) TBTU and 25 μL (0.18 mmol) triethylamine in 1 mL DMF was stirred for 1 h at RT. Then 25 mg (0.15 mmol) 1-(tetrahydropyran-4-yl)-piperazine was added and the reaction solution was stirred for 16 h. The reaction solution was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH2:21][NH2:22].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1>[O:29]=[C:28]1[NH:22][CH2:21][C:3]2[C:2](=[CH:7][CH:6]=[C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH2:9]3)[CH:4]=2)[NH:1]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(CN)c2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)CNC(=O)N3)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 66.2 %

Procedure:
To a solution of compound 17 (1.38 g, 4.5 mmol) in THF (20 mL) at room temperature was CDI (0.80 g, 4.95 mmol) and the reaction was stirred at 80° C. for 6 hr. The mixture was cooled to room temperature and the solid formed was filtered, washed with diethyl ether to afford 0.99 g (72%) of compound 10 as an off-white foam. IR (KBr) vmax. cm−1: 3210, 3162 (NH), 3032 (Ar—H), 1691 (C═O), 1607, 1515, 1419 (C═C). 1H NMR (500 MHz, CDCl3) δ=1.47 (s, 9H, (CH3)3C); 3.06 (m, 4H, 2CH2); 3.52 (m, 4H, 2CH2); 4.49 (s, 2H, CH2); 6.69 (m, 2H, aromatic-H), 6.74 (m, 1H, aromatic-H); 7.82 (br.s, 1H, NH); 13C NMR (125.7 MHz, CDCl3) δ=28.60 (CH3)3C), 43.35 (CH2), 43.90 (CH2), 50.66 (CH2), 80.10 (CH3)3C), 112.11 (aromatic-C), 112.28 (aromatic-C), 117.19 (aromatic-C), 130.18 (aromatic-C), 134.88 (aromatic-C), 143.18 (aromatic-C), 154.62 (CO), 155.93 (C═O). Calculated (%) for C17H24N4O3 (332.18); C, 61.43; H, 7.28; N, 16.86. found (%) C, 61.38; H, 7.32; N, 16.81.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[O:7][C@H:8]1[C@H:12]2[O:13][CH2:14][C@@H:15]([OH:16])[C@H:11]2[O:10][CH2:9]1.C(Cl)Cl>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[O:7][C@@H:8]1[CH2:9][O:10][C@@H:11]2[C:15](=[O:16])[CH2:14][O:13][C@H:12]12
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: O=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1.4 g (5.0 mmol) (3R,3aR,6R,6aR)-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (III.1), 2.5 g molecular sieves 4 Å in DCM 1.2 g (10.0 mmol) N-methyl-morpholin-N-oxide and after 5 min 0.1 g (0.25 mmol) tetrapropylammonium perruthenate are added. The reaction mixture is stirred at RT for 30 min and purified by FC.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=1)[CH2:4][CH3:5])[CH3:2].Cl[C:21](OCC)=[O:22]>O1CCOCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][N:8]1[C:9]2[N:10]=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[N:15]=[C:21]1[OH:22])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CCNc1nc(OC)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CCN(CC)CCn1c(O)nc2ccc(OC)nc21
Temperature: 180 °C
Reaction time: 1 h

Procedure:
The filtrated hydrogenation solution from 28 grams of 2-(diethylaminoethylamino)-3-nitro-6-methoxypyridine in 450 ml of dioxane (10 grams Raney nickel, 50 bar and 65° C.) were treated under stirring with 11.25 grams of ethyl chloroformate. After 3 hours stirring the open carbethoxy compound was filtered off and heated to 180° C. under stirring and held at this temperature for one hour. The cooled melt was recrystallized from isopropanol.
Reaction SMILES: [CH2:1](C1C=C2C(COC2=O)=CC=1)[CH3:2].Br[C:14]1[C:15]([O:36][CH3:37])=[C:16]([C:22]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(B(CC)CC)C>>[CH2:1]([C:14]1[C:15]([O:36][CH3:37])=[C:16]([C:22]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:2]
Reactant: CCc1ccc2c(c1)C(=O)OC2
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC
Agent: CCB(CC)CC
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(CC)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from ethyl 3-bromo-6-(4-fluorobenzenesulphonylmethyl)-2-methoxy-benzoate (Intermediate 85) and triethyl borane.
Reaction SMILES: [CH:1]1([O:6]/[N:7]=[C:8](\[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)/[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[NH:20][C:9](=[O:11])/[C:8](=[N:7]/[O:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)/[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(O)/C(=N/OC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2ccccc2s1)/C(=N/OC1CCCC1)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 67 %

Procedure:
(E)-Cyclopentyloxyimino-(3,4-dichloro-phenyl)-acetic acid (prepared as in Example 18, 100 mg, 0.33 mmol), 2-aminobenzothiazole (50 mg 0.33 mmol) and N,N-diisopropylethylamine (173 μL, 0.99 mmol) were combined in methylene chloride (1.6 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (126 mg, 0.33 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-cyclopentyloxyimino-2-(3,4-dichloro-phenyl)-acetamide (96 mg, 67%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C20H17Cl2N3O2S [M+] 433.04, found 434 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 4.93 (m, 1 H, OCH), 7.34 (ddd, Jo=8.0, Jo=7.3, Jm=1.2 Hz, 1 H, Ar), 7.40 (dd, Jo=8.4, Jm=2.0 Hz, 1 H, Ar), 7.47 (ddd, Jo=8.3, Jo=7.3, Jm=1.3 Hz, 1 H, Ar), 7.53 (d, Jo=8.4 Hz, 1 H, Ar), 7.67 (d, Jm=2.0 Hz, 1 H, Ar), 7.83 (m, 2H, Ar), 10.20 (s, 1 H, NH).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(Cl)=[S:17]>C(OCC)(=O)C>[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:16]=[S:17]
Reactant: S=C(Cl)Cl
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: S=C=NCc1ccccc1

Procedure:
Benzylamine (1.5 g) and triethyl amine (2.9 g) were dissolved in anhydrous ethyl acetate (50 ml) and stirred under ice cooling. Thiophosgene (4.9 g) dissolved in ethyl acetate (50 ml) was slowly added to the stirred solution. The solution was heated at reflux for 2 hr and filtered. Evaporation of the solvent afforded (isothiocyanatomethyl)-benzene which was used in the next step without purification. 1H NMR, CDCl3, 4.72 (2H, s), 7.30-7.40 (5H, m).