Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=O>>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:27]([C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([F:23])[CH:25]=3)[N:22]=[C:16]2[CH:17]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Nc1cc(Br)cc[n+]1N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Fc1cccc(-c2nc3cc(Br)ccn3n2)c1
Yield: 70.9 %

Procedure:
The product was prepared in the same manner as described in example 1b using 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (2 g, 5.15 mmol) and 3-fluorobenzoyl chloride (1.24 ml, 10.3 mmol) as starting materials. The reaction affords 7-Bromo-2-(3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (1.067 g, 70.9%) as pink solid. mp.: 186-188° C., MS: m/z=291.9/293.9 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[F:30])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1[C:42](O)=[O:43].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1[C:42]([NH:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:22]([F:30])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27])[CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:43]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Yield: 58.2 %

Procedure:
The procedure of Example 77 was followed using the product of Example 106 (197.0 mg, 0.44 mmol), 1-methylindole-2-carboxylic acid (152 mg, 0.87 mmol), NMM (0.047 ml, 0.44 mmol), HOBt (144 mg, 0.96 mmol), and EDAC (183 mg, 0.96 mmol) in methylene chloride to prepare the titled product (156 mg, 58%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:13]=2[O:17][CH2:18][CH2:19][CH3:20])[N:8]1[C:27](=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[C:27]([N:8]1[C:9]2[C:14](=[C:13]([O:17][CH2:18][CH2:19][CH3:20])[C:12]([CH:21]3[CH2:26][CH2:25][N:24]([C:2]([O:4][CH3:5])=[O:3])[CH2:23][CH2:22]3)=[CH:11][CH:10]=2)[CH2:15][CH2:16][C@@H:7]1[CH3:6])(=[O:29])[CH3:28]
Reactant: COC(=O)Cl
Reactant: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1c(C2CCN(C(=O)OC)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Methyl chloroformate (5 μL, 0.06 mmol) was added to a solution of (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (20 mg, 0.05 mmol) and triethylamine (0.04 mL, 0.27 mmol) in dichloromethane (0.5 mL), and the reaction stirred at room temperature overnight. The reaction was quenched via the addition of water (5 mL). The organic layer was collected and further washed with water (5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 10-20% methanol in ethyl acetate) to afford methyl (S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate (19 mg, 89%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94-1.07 (m, 6H), 1.17-1.26 (m, 1H), 1.43-1.57 (m, 2H), 1.60-1.79 (m, 4H), 2.01 (s, 3H), 2.16-2.31 (m, 2H), 2.68-2.91 (m, 3H), 2.95-3.03 (m, 1H), 3.58 (s, 3H), 3.61-3.73 (m, 2H), 4.04-4.15 (m, 2H), 4.56 (br d, J=6.45 Hz, 1H), 7.05 (br s, 2H). MS (ESI, pos. ion) m/z 389 [M+H]+.
Reaction SMILES: CN([CH:4]=[CH:5][C:6]([CH:8]1[CH2:10][CH2:9]1)=O)C.[N+:11]([CH2:14][C:15]([NH2:17])=[O:16])([O-:13])=[O:12].C([O-])(=O)C.[NH2+]1CCCCC1>O>[CH:8]1([C:6]2[NH:17][C:15](=[O:16])[C:14]([N+:11]([O-:13])=[O:12])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1
Reactant: CN(C)C=CC(=O)C1CC1
Reactant: NC(=O)C[N+](=O)[O-]
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: O
Product: O=c1[nH]c(C2CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of crude b-N,N-dimethylaminoethenylcyclopropyl ketone (12 g, <86 mmol), nitroacetamide (9 g, 86 mmol) and aqueous piperidinium acetate (10 ml) [prepared from glacial acetic acid (42 ml), water (100 ml) and piperidine (72 ml)] was stirred at room temperature overnight. Following dilution with water (20 ml), the yellow precipitate was isolated via filtration and drying in vacuo to yield the title compound: 1H NMR (CDCl3) d 1.15 (m, 2 H), 1.36 (m, 2 H), 2.10 (m, 1 H), 6.02 (br d, J=8.0 Hz, 1 H), 8.41 (d, J=8.0 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(C(C)C)CC)(C)C.[C:28](OCC)(=[O:30])[CH3:29]>ClCCl>[C:12]([O:7][C:6]1[CH:8]=[C:2]([CH3:1])[C:3]([O:11][C:28](=[O:30])[CH3:29])=[C:4]([CH3:10])[C:5]=1[CH3:9])(=[O:14])[CH3:13]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1cc(C)c(OC(C)=O)c(C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of trimethylhydroquinone (10.0 g) and acetic anhydride (10 mL) in dichloromethane (50 mL) was added diisopropylethylamine (10 mL) at room temperature. The solution was stirred at room temperature for 18 hours, diluted with ethyl acetate, washed with water and brine. Evaporation gave the 2,3,5-trimethyl-1,4-phenylene diacetate as solid.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15]2[CH2:19][C@:18]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH:7]1[CH2:10][S:9][CH2:8]1)=[O:5].C1C=C(Cl)C=C(C(OO)=[O:41])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:14]=[C:13]([C:15]2[CH2:19][C@:18]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=3)([C:20]([F:21])([F:22])[F:23])[O:17][N:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH:7]1[CH2:8][S+:9]([O-:41])[CH2:10]1)=[O:5]
Reactant: Cc1cc(C2=NO[C@@](c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C2=NO[C@@](c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1C[S+]([O-])C1
Reaction time: 0.17 h

Procedure:
To a suspension of 2-methyl-N-(thietan-3-yl)-4-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide in dichloromethane (92 mL) was added m-CPBA (24.3 mmol, 5.58 g) portion wise at 0-5° C., and the reaction mixture was stirred for 10 min. A saturated Na2S2O3 solution was added, and the mixture was stirred for 10 min. The organic layer was washed with sat. NaHCO3 solution, water and brine, dried over MgSO4, filtered and evaporated. Purification over silica gel (eluent: CH2Cl2/EtOAc) yielded the title compound. LCMS (Method GR) 1.13 min, M+ 539/541; 1H NMR (400 MHz, CDCl3) 2.50 (s, 3H), 3.28 (m, 1H), 3.70 (d, 1H), 4.10-4.20 (m, 4H), 4.70 (m, 1H), 6.50 (d, 1H), 7.40-7.70 (1d+4s, 5H), 19F-NMR (CDCl3, 376 MHz): −79.43. Chiral HPLC Method Column: Daicel CHIRALPAK® IB, 3 μm, 0.46 cm×10 cm Mobile phase: Heptan/EtOH 80/20 Retention times of eluting isomers: 4.85 min (8.2%) 5.66 min (91.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:34])[CH3:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][C:32](=[O:34])[CH3:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(=O)Nc1ccccc1Br
Product: CC(=O)Nc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and N-(2-bromophenyl)acetamide. MS (ESI): mass calcd. for C18H15FN4O, 322.12; m/z found, 322.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.91 (m, 1H), 7.53-7.21 (m, 6H), 6.73 (s, 2H), 1.92 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[C:21](#[N:25])[CH2:22][C:23]#[N:24].N1CCCCC1>C(O)C>[NH2:25][C:21]1[O:1][CH:2]2[C:3]3[C:7](=[CH:8][CH:9]=[C:10]2[CH:16]([C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH3:11])[CH:14]=2)[C:22]=1[C:23]#[N:24])[N:6]=[CH:5][CH:4]=3
Reactant: N#CCC#N
Reactant: COc1cccc(C=O)c1
Reactant: Oc1cccc2[nH]ccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(C2C3=CC=C4N=CC=C4C3OC(N)=C2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
To a solution of 4-hydroxyindole (500 mg, 3.76 mmol), 3-methoxybenzaldehyde (511 mg, 3.76 mmol) and malononitrile (250 mg, 3.76 mmol) in ethanol (10 mL) was added piperidine (0.18 mL, 1.62 mmol). The solution was stirred at room temperature overnight and the solvent was removed in vacuo. The crude material was purified by flash column chromatography (3:1 hexane:ethyl acetate) to yield 300 mg (25%) of title compound as white solids. 1H NMR (CDCl3): 8.26 (brs, 1H), 7.26–7.18 (m, 2H), 7.09–7.06 (m, 1H), 6.84–6.74 (m, 4H), 6.65–6.63 (m, 1H), 4.80 (s, 1H), 4.65 (brs, 2H), 3.76 (s, 3H).
Reaction SMILES: N[CH:2](CC1CCCCC1)[CH:3](O)[CH:4](C1CCCCC=1)[OH:5].C(S(C[C@@H](CC1C=CC=CC=1)C(N[C@H](C(O)=O)C[C:34]1[N:38]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][C:40]=2[N+:48]([O-:50])=[O:49])[CH:37]=[N:36][CH:35]=1)=O)(=O)=O)(C)(C)C.C([N:63](CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[N+:48]([C:40]1[CH:41]=[C:42]([N+:45]([O-:47])=[O:46])[CH:43]=[CH:44][C:39]=1[N:38]1[CH:34]=[C:35]([CH2:2][CH2:3][C:4]([NH2:63])=[O:5])[N:36]=[CH:37]1)([O-:50])=[O:49]
Reactant: CCN(CC)CC
Reactant: NC(CC1CCCCC1)C(O)C(O)C1=CCCCC1
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cncn1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: NC(=O)CCc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 100 mg (0.37 mmol) of (1S or R,2R,3S)-3-amino-4-cyclohexyl-1-(1-cyclohexen-1-yl)-1,2-butanediol and 257 mg (0.41 mmol) of N-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamoyl]-3-(2,4-dinitrophenyl)-L-histidine in 15 ml of acetonitrile is treated under argon in succession at room temperature with 83 mg (0.82 mmol) of triethylamine, 67 mg (0.41 mmol) of HOBT and 168 mg of HBTU and the reaction mixture is thereafter stirred at room temperature for 3 hours. For the working-up, the reaction mixture is concentrated under reduced pressure to about 1/4 of the original volume, then diluted with 50 ml of ethyl acetate and washed in succession with water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated under reduced pressure, and the residue is chromatographed on silica gel with a 98:2 mixture of methylene chloride and methanol as the eluting agent, whereby there are obtained 140 mg (0.17 mmol) of (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamido]-N-[(1S, 2R,3S or R)-1-(cyclohexylmethyl)-3-(1-cyclohexen-1-yl)-2,3-dihydroxypropyl]-1-(2,4-dinitrophenyl)imidazole-4-propionamide in the form of a yellow foam, MS: 838 (M+H)+. This is dissolved in 3 ml of dimethylformamide and stirred at room temperature for 3 hours with 0.15 ml (1.7 mmol) of thiolactic acid. Thereafter, the reaction solution is evaporated in a high vacuum, the residue is dissolved in 15 ml of ethyl acetate and the reaction solution is washed in succession with saturated sodium carbonate solution, water and saturated sodium chloride solution. The yellowish coloured ethyl acetate phase is dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue (120 mg) is chromatographed on silica gel with a 95:5 mixture of methylene chloride and methanol, which contains 0.1% ammonium hydroxide, as the eluting agent. After lyophilization from dioxan there are obtained 85 mg of (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-3-(1-cyclohexen-1-yl)-1-(cyclohexylmethyl)-2,3-dihydroxypropyl]imidazole-4-propionamide as a yellowish powder, MS: 671 (M+H)+.
Reaction SMILES: [Na].[C:2]([C:5]1[N:6]2[CH:9]([S:10][CH2:11][C:12]=1[CH2:13][S:14][C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[CH:8]([NH:21][C:22](=[O:30])[CH2:23][C:24]1[S:25][C:26](=[O:29])[S:27][CH:28]=1)[C:7]2=[O:31])([OH:4])=[O:3].[C:32]([O:35][CH2:36]I)(=[O:34])[CH3:33].O>CN(C)C=O>[C:32]([O:35][CH2:36][O:3][C:2]([C:5]1[N:6]2[CH:9]([S:10][CH2:11][C:12]=1[CH2:13][S:14][C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[CH:8]([NH:21][C:22](=[O:30])[CH2:23][C:24]1[S:25][C:26](=[O:29])[S:27][CH:28]=1)[C:7]2=[O:31])=[O:4])(=[O:34])[CH3:33]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Reactant: CC(=O)OCI
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCOC(=O)C1=C(CSc2nnnn2C)CSC2C(NC(=O)Cc3csc(=O)s3)C(=O)N12
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
The sodium salt of 2-carboxy-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (5.08 g.) is dissolved in dimethylformamide (100 cc.) at 5° C. A solution of iodomethyl acetate (2 g.) in dimethylformamide (10 cc.) is added to this solution and the reaction mixture is stirred for 10 minutes at 5° C. It is then poured into water (500 cc.) and extracted twice with ethyl acetate (200 cc.). The combined organic phases are washed with water (100 cc.), saturated sodium bicarbonate solution (100 cc.), a 5% sodium bisulphite solution (100 cc.) and a saturated sodium chloride solution (100 cc.). The organic phase is dried over magnesium sulphate, filtered in the presence of decolourising charcoal and concentrated to dryness under reduced pressure (15 mm Hg). This gives a white product (5 g.) which is recrystallised from acetonitrile (50 cc.). 2-Acetoxymethoxycarbonyl-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (3 g.) is thus obtained as white crystals m.p. 154° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)[CH:15]=2)[CH:11]=[CH:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[OH:53][C:54]([C:57]1[CH:58]=[C:59]([CH:63]=[C:64]([S:66]([F:71])([F:70])([F:69])([F:68])[F:67])[CH:65]=1)[C:60](O)=[O:61])([CH3:56])[CH3:55].N>CN(C=O)C>[OH:53][C:54]([C:57]1[CH:58]=[C:59]([CH:63]=[C:64]([S:66]([F:71])([F:67])([F:68])([F:69])[F:70])[CH:65]=1)[C:60]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][NH:20][CH:21]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:61])([CH3:55])[CH3:56]
Reactant: CC(C)(O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(C(C)(C)O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound from Example 7A (2.63 g, 9.45 mmol) was dissolved in 55 ml of DMF. HATU (7.91 g, 20.8 mmol) and N-methylmorpholine (8.31 ml, 75.6 mmol) were added, and the mixture was stirred at RT for 30 min. The mixture was then cooled to −5° C. and the compound from Example 19A (5.79 g, 18.9 mmol) was added. The mixture was stirred for a further 45 min, concentrated aqueous ammonia solution was then added and the mixture was stirred for another 15 min. The mixture was then extracted with ethyl acetate, and the organic extract was washed with conc. sodium chloride solution, dried over sodium sulphate and concentrated. The crude product was purified by preparative HPLC [column: Waters Sunfire C-18.5 μm, 250 mm×20 mm; ternary gradient water/acetonitrile/1% TFA in water: 0-6.7 min 45:50:5, ramp, 6.9-9.0 min 0:95:5]. This gave 3.86 g (72% of theory) of the title compound.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27]Br.O>O1CCCC1>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([CH2:27][CH2:26][O:25][CH3:24])[C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COCCBr
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCC(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
Dibenzyl malonate (28.43 g, 0.1 mole) was added dropwise over 1 hour to a stirred suspension of sodium hydride (3.15 g, 80% dispersion in oil; 0.105 mole) in dry tetrahydrofuran (100 ml) under nitrogen, the temperature being allowed to rise to 40° C. 2-Methoxyethyl bromide (13.9 g, 0.1 mole) was added to the resulting clear solution, which was stirred at room temperature for two hours, and then refluxed overnight. Water was added, and the mixture extracted with methylene chloride. The organic extract on washing with water, drying (MgSO4) and evaporation under vacuum gave a crude liquid (30.94 g). Chromatography on silica gel (700 g) eluting with a mixture of ether and hexane (2:8 by volume) gave 2-methoxyethyl-malonic acid dibenzyl ester as a colourless liquid (15.6 g). This was dissolved in dioxan (150 ml) and a solution of potassium hydroxide (2.55 g, 45.44 mmole) in water (40 ml) added at 0° C. with stirring. The mixture was stirred overnight at room temperature and the solvent was evaporated under vacuum. Water was added and the mixture was extracted with ether to remove unreacted diester. The aqueous phase was then acidified with 2N hydrochloric acid (50 ml) and extracted with ether. The organic extract on washing with water, drying (MgSO4) and evaporation under vacuum gave the mono-ester as a colourless oil (8.95 g, 78%).
Reaction SMILES: Br[C:2]1[CH2:3][CH:4]2[C:9](=[CH:10][CH:11]=1)[N:8](C(C(OCC)=O)=O)[CH:7]([CH:19]([C:21](OC)=O)C)[CH2:6][CH2:5]2.F[B-](F)(F)F.[O:30]=[N+]=O.[N+]([O-])([O-])=O.[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.C(Cl)(Cl)Cl>[C:19]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[N:8]=1)(=[O:30])[CH3:21]
Reactant: CCOC(=O)C(=O)N1C2=CC=C(Br)CC2CCC1C(C)C(=O)OC
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(=O)c1ccc2ccccc2n1

Procedure:
The title compound was prepared by the route outlined in Example 22-6 to 7 starting with 6-bromo-N-ethoxalyl-2-(1-methoxycarbonylethyl)tetrahydroquinoline (less polar). In nitration step of Example 22-6, conditions of nitronium tetrafluoroborate in dichloromethane at room temperature were employed instead of those of refluxing ammonium nitrate-trifluoroacetic anhydride in chloroform: mp 242° C.; 1H NMR (270 MHz, DMSO-d6) δ12.08 (s, 1H), 7.21 (s, 1H), 7.17 (s, 1H), 4.93 (bd, 1H, J=10 Hz), 3.40 (s, 3H), 2.89 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.80 (dm, 1H, J=17.1 Hz), 2.60 (qd, 1H, J=7, 10 Hz), 2.23 (dm, 1H, J=13.5 Hz), 1.72~1.91 (m, 1H), 1.11 (d, 3H, J=7 Hz).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1>CN(C=O)C>[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Nc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5ccccc5F)nc34)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.2 %

Procedure:
To NaH (60 wt % in mineral oil; 0.071 g, 1.763 mmol) in 1 mL DMF was added 2-fluoroaniline (0.196 g, 1.763 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added as a solid and the reaction became dark red. After 30 min, the reaction was heated at 70° for 2 h. The reaction mixture was then cooled to RT and partitioned between saturated aq. NH4Cl and EtOAc. The organic layer was washed with saturated aq. NaHCO3 (1×), water (1×), saturated aq. NaCl (1×), and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was suspended in DCM and filtered, rinsing 2×DCM, dried in vacuo to give 2-(2-((2-fluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.021 g, 0.056 mmol, 22% yield) as a dull-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.04 (1H, br. s.), 9.32 (1H, s), 8.14 (1H, s), 7.97 (1H, dd, J=7.5, 1.5 Hz), 7.84-7.93 (1H, m), 7.56-7.62 (1H, m), 7.34-7.44 (1H, m), 7.22-7.33 (3H, m), 7.15-7.21 (1H, m), 6.86-6.95 (2H, m), 3.32-3.41 (2H, m), 2.51-2.57 (2H, m). m/z (ESI, +ve) 373.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH:20]([OH:22])[CH2:19][CH:18]1[CH2:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](Cl)(C1C=CC=CC=1)([C:35]1[CH:42]=[CH:41][C:38]([O:39][CH3:40])=[CH:37][CH:36]=1)[C:27]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[CH:29][CH:28]=1>N1C=CC=CC=1.CN(C1C=CC=CN=1)C>[CH2:1]([O:8][C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH:20]([OH:22])[CH2:19][CH:18]1[CH:23]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:24][CH:26]([C:27]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[CH:29][CH:28]=1)[C:35]1[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[CH:41][CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCCCN1CC(O)CC1CO)OCc1ccccc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2CCCCCCNC(=O)OCc2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 436.1 %

Procedure:
Compound 29 (6 g, 17 mmol) was co-evaporated with anhydrous pyridine three times and then dissolved in pyridine (60 mL). To this solution dimethylamino pyridine (0.207 g, 1.7 mmol) and DMT-Cl (6 g, 17.9 mmol, 1.05 equiv.) were added at room temperature. The reaction mixture was stirred at room temperature for 16 h. The excess DMT-Cl was quenched by the addition of methanol (25 mL). The solution was dried under reduced pressure. To the residue was suspended in ethyl acetate (300 mL) and washed with saturated bicarbonate solution, brine and water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. 24.2 g of the crude product was obtained after removal of the solvent. Upon purification over silica gel using 2% MeOH/DCM compound 30 (8.7 g, 79%) was obtained as white foamy solid.