Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([F:15])=[CH:4][C:3]=1[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(OC(=O)C)(=O)C.C(OCC)(OCC)OCC>[CH2:18]([O:20][CH:21]=[C:17]([C:16](=[O:23])[C:3]1[CH:4]=[C:5]([F:15])[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[CH:7][C:2]=1[F:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:17]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(C2CCN(C)CC2)cc1F
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCN(C)CC2)cc1F

Procedure:
A solution of 3 25 g (10 mmoles) of ethyl 2,5-difluoro-4-(1-methyl-4-piperidinyl)-β-oxobenzenepropionate in 20 ml of acetic anhydride and 2.5 ml of triethyl orthoformate was refluxed 11/4 hours and evaporated under vacuum to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12](O)=[O:13])[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33][CH:32]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:12](=[O:13])[C@@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:33][CH:32]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC3=C(Oc4cccc(OC)c4C3)C2=O)nc1
Yield: 18.3 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 0.54 mmol) (Example 7, Step 2c), commercially available 6-amino-nicotinic acid methyl ester (98 mg, 0.64 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (113 mg, 0.59 mmol), and N-hydroxybenzotriazole (HOBt) (80 mg, 0.59 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded 6-[(S)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionylamino]-nicotinic acid methyl ester (50 mg, 18.4%), as a white solid. 1H NMR (DMSO-d6) δ: 11.32 (br. s., 1H), 8.87 (br. s., 1H), 8.28 (d, J=8.8 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.10 (br. s., 1H), 4.38 (d, J=18.6 Hz, 1H), 4.04 (d, J=19.1 Hz, 1H), 3.84 (d, J=15.7 Hz, 6H), 3.55 (br. s., 2H), 1.48-1.89 (m, 7H), 0.85-1.29 (m, 6H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C@@H:6]([O:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C@H:5]([CH3:23])[O:4][C:3]1=[O:24].[OH:25][C:26]1[C:27]([C:34](O)=[O:35])=[N:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:12]([O:11][C@@H:7]1[C@@H:6]([O:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C@H:5]([CH3:23])[O:4][C:3](=[O:24])[C@@H:2]([NH:1][C:34](=[O:35])[C:27]2[C:26]([OH:25])=[C:31]([O:32][CH3:33])[CH:30]=[CH:29][N:28]=2)[CH2:10][O:9][CH2:8]1)[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: CC(C)CCO[C@H]1[C@H](C)OC(=O)[C@@H](N)COC[C@@H]1OCCC(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCCC(C)C)[C@@H](OCCC(C)C)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Yield: 42.3 %

Procedure:
(3S,7S,8S,9S)-3-amino-7,8-bis(isopentyloxy)-9-methyl-1,5-dioxonan-2-one (130 mg, 0.376 mmol) and 3-hydroxy-4-methoxypicolinic acid (70.0 mg, 0.414 mmol) were diluted with DCM (3763 μl). PyBOP (215 mg, 0.414 mmol) was added, followed by N-ethyl-N-isopropylpropan-2-amine (216 μl, 1.242 mmol), and the mixture was stirred at room temperature until thin layer chromatography (TLC) indicated complete consumption of starting material. The reaction mixture was purified by column chromatography (SiO2; hexanes/EtOAc) to furnish the title compound (79.1 mg, 0.159 mmol, 42.3% yield) as a white solid: mp 61-70° C.; IR (thin film) 3530, 3371, 2955, 2873, 1750, 1649, 1529, 1262 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.94 (s, 1H), 8.67 (d, J=8.1 Hz, 1H), 8.01-7.98 (m, 1H), 6.87 (d, J=5.2 Hz, 1H), 5.04 (ddd, J=8.2, 6.8, 5.0 Hz, 1H), 5.01-4.89 (m, 1H), 4.05 (dd, J=11.9, 6.8 Hz, 1H), 3.94 (s, 3H), 3.92-3.85 (m, 1H), 3.85-3.78 (m, 2H), 3.66-3.58 (m, 2H), 3.57-3.48 (m, 2H), 3.26-3.14 (m, 2H), 1.69 (dp, J=13.4, 6.7 Hz, 2H), 1.51-1.38 (m, 7H), 0.90 (dt, J=6.2, 2.7 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 170.30, 168.94, 155.32, 148.72, 140.66, 130.22, 109.56, 85.02, 83.63, 75.28, 73.94, 73.17, 72.48, 69.35, 56.09, 52.12, 39.23, 38.95, 24.96, 22.91, 22.67, 22.62, 22.50, 18.59; HRMS-ESI (m/z) [M+Na]+ calcd for C25H40N2NaO8, 519.2677, found 519.2687.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH:9]=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>>[N+:23]([C:22]1[C:17]([N:13]2[CH2:12][CH2:11][C:10](=[CH:9]/[CH:8]=[CH:7]/[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:15][CH2:14]2)=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: C(/C=C/c1ccccc1)=C1CCNCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1N1CCC(=C/C=C/c2ccccc2)CC1
Yield: 95.7 %

Procedure:
A well homogenised mixture of Compound 255b (175 mg, 0.878 mmol), 2-chloro-3-nitropyridine (153 mg, 0.966 mmol) and triethylamine (0.139 mL, 0.97 mmol) was stirred at 25° C. for 24 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether 8:2) affording the title product (270 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](I)[CH3:13].O[Li].O>CCO>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:13]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CCI
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A 500 mL 3-neck flask fitted with a stir-bar, condenser, and an Ar inlet was charged with 4-amino-3-nitrophenol (12.0 g, 77.9 mmol), ethyl iodide (15.2 g, 8.00 mL, 97.3 mmol), LiOH.H2O (6.55 g, 156 mmol), and EtOH (120 mL). The resultant solution was heated at 60° C. overnight. Another 3 mL of ethyl iodide and 1 g of LiOH.H2O were added, and the mixture was stirred at 60° C. overnight again. The solution was cooled and partitioned with EtOAc (250 mL) and H2O (200 mL). The organic phase was washed with 1% aqueous LiOH (2×200 mL), H2O (200 mL), and brine (200 mL), filtered through phase separation paper, and concentrated in vacuo to a dark red solid. The crude solid was triturated with hexanes:EtOAc 8:1 (50 mL). The solid was filtered, pressed with rubber dam, and rinsed with hexanes (3×10 mL). The material was dried to give 10.7 g of 46a as a red solid (75%). 1H NMR (60 MHz, CDCl3): δ 7.5 (d, 1H), 7.0 (dd, 1H), 6.7 (d, 1H), 5.9 (bs, 2H), 4.0 (qt, 2H), 1.4 (t, 3H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 96% with a retention time of 4.2 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cc(Cl)ccn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.6 %

Procedure:
To a cold (0° C.) solution of 4-chloro-2-picoline (5.0 g, 39 mmol) and ethyl 4-fluorobenzoate (6.6 g, 39 mmol) in tetrahydrofuran (100 mL) was added lithium bis(trimethylsilyl)amide (80 mL 1.0 M in tetrahydrofuran, 80 mmol) dropwise via a pressure equalizing funnel over 30 minutes. Upon complete addition, the cold bath was removed and the resulting solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and methanol was added to the reaction, resulting in the formation of a white precipitate. The precipitate was collected by filtration and dried to give 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 99%) as a white solid. 1H-NMR (DMSO-d6): δ 7.90 (m, 3H), 7.11 (t, 2H), 6.56 (s, 1 H), 5.67 (s, 1H), 4.14 (m, 2H); 19F-NMR (DMSO-d6): δ −115.67; MS m/z 250 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][NH:8][C:9]1[CH:14]=[C:13](F)[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:23])[CH2:7][NH:8][C:9]1[CH:14]=[C:13]([N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)CNc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1cc(-n2ccnc2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of 9.36 g (27.7 mmol) of N-(5-fluoro-2-nitro-4-trifluoromethylphenyl)glycine tert-butyl ester, 7.54 g of imidazole and 30 ml of DMF was stirred for 2 hours on an oil bath at 60° C. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was poured into water and the compound so precipitated was collected by filtration. The resulting compound was washed successively with water and ethyl ether and then dried under reduced pressure to give 8.95 g (84%) of N-[5-(1H-imidazol-1-yl)-2-nitro-4-trifluoromethylphenyl)glycine tert-butyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([NH:36][S:37](Cl)(=[O:39])=[O:38])=[O:35]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:37]([NH:36][C:34]([C:30]2[O:29][CH:33]=[CH:32][CH:31]=2)=[O:35])(=[O:38])=[O:39])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(NS(=O)(=O)Cl)c1ccco1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCCNS(=O)(=O)NC(=O)c2ccco2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.5 g) in chloroform (dried over alumina) and triethylamine (2 ml) was added 2-furoylsulphamoyl chloride in one portion and the mixture stirred at room temperature for 17 hours. After evaporation to dryness, the resultant oil was partitioned between 5% aqueous sodium bicarbonate and methylene chloride. The combined organic liquors were dried (MgSO4), filtered and evaporated to give 0.35 g of solid which was crystallised from diisopropyl ether to give pure title compound (0.2 g), m.p. 138° C. Found: C, 51.30; H, 5.23; N, 7.41. C25H28ClN3O9S requires C, 51.59; H, 4.85; N, 7.22%.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:19](=[O:20])[N:18]2[C@@H:12]1[CH2:13][C:14](=O)[CH2:15][CH:16]=[C:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[C:45](F)(F)[S:46](OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:19](=[O:20])[N:18]2[C@@H:12]1[CH2:13][C:14]([S:46][CH3:45])=[CH:15][CH:16]=[C:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCC(=O)C[C@H]12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSC1=CC=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2C1
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 48.7 %

Procedure:
To a solution of 4-nitrobenzyl (7R,8S)-8-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-5,9-dioxo-1-azabicyclo[5.2.0]non-2-ene-2-carboxylate (1.5 g, 3.07 mmol) in acetonitrile (15 ml) was added at 0° C. N,N-diisopropylethylamine (1.1 ml, 6.45 mmol). The reaction mixture was cooled at -40° C. and trifluoromethanesulfonic anhydride (0.57 ml; 3.38 mmol) was added. After 5 minutes, further N,N-diisopropylethylamine (1.1 ml, 6.45 mmol) was added to the reaction mixture. Methylmercaptan was then bubbled through the solution at -40° C. during a few seconds. The mixture was allowed to warm to ambient temperature over 1.5 hours. The solvent was evaporated and the residue purified by chromatography on silica gel eluting with ethyl acetate/dichloromethane 3:97 to give 4-nitrobenzyl (7R,8S)-8-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]5-methylthio-9-oxo-1-azabicyclo[5.2.0]non-2,4-diene-2-carboxylate (776 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:12]=O)[CH:10]=[O:11])=[CH:5][CH:4]=1.Cl.[NH2:15]O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:12]=[N:15][O:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C=O)C=O)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cnoc2)cc1
Reaction time: 8 h

Procedure:
The (4-methoxyphenyl)malonaldehyde (2.5 g, 14 mmol) was heated under reflux with hydroxylamine hydrochlorid (1.46 g, 21 mmol) in ethanol (28 mL) for 2 hours. Ethanol was removed under vacuum and the residue was purified by column chromatography through a 115 gram biotage silica gel cartridge eluting with 20-50% EtOAc/hexanes to give pale oil, which solidified upon standing overnight.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:16]=[CH:17][N:18]=[C:4]2[N:3]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([NH:24][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:5]2[N:16]=[CH:17][N:18]=[C:4]2[N:3]=1
Reactant: Cc1ccc(-c2c(Cl)nc3ncnn3c2Cl)cc1
Reactant: NC1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2c(Cl)nc3ncnn3c2NC2CCCC2)cc1
Reaction time: 3 h
Yield: 86.4 %

Procedure:
5,7 Dichloro-6-(4-methylphenyl)-1,2,4-triazolo-[1,5-a]pyrimidine (1.8 g, 6 mmol) was dissolved in tetrahydrofuran. A solution of cyclopentylamine (0.51 g, 6 mmol) and triethylamine (0.61 g, 6 mmol) in tetrahydrofuran (2 ml) was then added with stirring and the stirring continued for a further 3 hours at ambient temperature (20° C.). The reaction mixture was then evaporated in vacuo and the residue extracted with dichloromethane and water (100 ml each). The organic layer was dried over sodium sulphate and the solvent evaporated in vacuo. The residue was crystallized from ethyl acetate to give 1.7 g 5-chloro-6-(4-methylphenyl)-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine as yellowish crystals, m.pt. 158° C. Yield: 87% of theoretical 1H-NMR: δ=1.3-1.75 (2 m, 8H); 2.43(s,1H); 3.73 (m,1H); 5.97 (d,1H); 7.25 (m,4H); 8.25(s,1H) ppm
Reaction SMILES: O.N.[C:3]([C:5]1[CH:6]=[C:7]([NH:11][CH:12]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][S:23]3(=[O:28])=[O:27])=[C:18]([CH3:29])[CH:17]=2)=[O:14])[CH:8]=[CH:9][CH:10]=1)#[N:4]>CO>[NH2:4][CH2:3][C:5]1[CH:6]=[C:7]([NH:11][CH:12]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][S:23]3(=[O:28])=[O:27])=[C:18]([CH3:29])[CH:17]=2)=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(NC(=O)C(Nc2cccc(C#N)c2)c2ccccc2)ccc1N1CCCS1(=O)=O
Agent: N
Solvent: O
Solvent: CO
Product: Cc1cc(NC(=O)C(Nc2cccc(CN)c2)c2ccccc2)ccc1N1CCCS1(=O)=O

Procedure:
200 mg of water-moist Raney nickel and 1.0 ml of methanolic ammonia solution are added to a solution of 200 mg (0.434 mmol) of 2-(3-cyanophenylamino)-N-[4-(1,1-dioxoisothiazolidin-2-yl)-3-methylphenyl]-2-phenylacetamide in 3 ml of methanol, and the mixture is hydrogenated at 50° C. The reaction mixture is filtered, and the filtrate is evaporated, giving 2-(3-aminomethylphenylamino)-N-[4-(1,1-dioxoisothiazolidin-2-yl)-3-methylphenyl]-2-phenylacetamide as a colourless solid; ESI 465.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=[O:22])=[CH:16][CH:15]=1>>[C:9]1([C@H:20]2[C@H:20]([C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=3)[C:21](=[O:22])[NH:23][C:21]2=[O:22])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:19][CH2:14][CH2:15][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccc(Cl)cc1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(Cl)cc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(4-chlorophenyl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 4-chlorophenylacetamide. Yield 32.7 mg, 9.0%. 1H NMR (DMSO-d6) 400 MHz δ: 11.54 (s, 1H), 7.40 (m, 4H), 7.33 (s, 1H), 7.15 (dd, 1H, J=6.8 0.8 Hz), 6.86 (m, 2H), 4.54 (d, 1H, J=8.0 Hz), 7.38 (d, 1H, J=7.6 Hz), 4.10 (t, 2H, J=5.6 Hz), 2.90 (t, 2H, J=6.0 Hz), 2.11 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]([CH2:27][CH2:28][CH2:29][CH3:30])[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:15]=2[C:16](O)=[O:17])[N:11]([CH3:13])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[N:31]([CH2:34][C@@H:35]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][NH:36]1)=[N+:32]=[N-:33]>>[N:31]([CH2:34][C@@H:35]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][N:36]1[C:16]([C:15]1[CH:19]=[C:20]([CH:21]=[CH:22][C:14]=1[C:10]1[N:11]([CH3:13])[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:1][CH2:2][CH2:3][CH3:4])[N:9]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:17])=[N+:32]=[N-:33]
Reactant: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)OC)cc2C(=O)O)n1
Reactant: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])n1
Yield: 86.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271H, 2-(4-(dibutylcarbamoyl)-1-methyl-1H-imidazol-2-yl)-5-(methoxycarbonyl)benzoic acid (230 mg, 0.55 mmol) and (S)-3-(azidomethyl)-1,2,3,4-tetrahydroisoquinoline (135 mg, 0.72 mmol) were converted to the title compound (280 mg, 91%). MS(ESI+) m/z 586.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1>>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[S:30][C:31]=2[CH3:37])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: Cc1sc(-c2ccc(F)cc2)nc1CCO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Product: Cc1sc(-c2ccc(F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
Intermediate 48 was prepared from 224 mg of N-(Boc)-L-Tyrosine methyl ester and 180 mg of Intermediate 11 to yield 149 mg (51% overall yield) of the title compound as a solid: 1H NMR (DMSO-d6, 400 MHz) δ7.82 (dd, 2H, J=8.6, 5.5), 7.23 (t, 2H, J=8.7), 7.08 (d, 2H, J=8.4), 6.8 (d, 2H, J=8.5), 4.56 (br s, 1H), 4.19 (t, 2H, J=6.5), 3.56 (m, 1H), 3.03 (t, 2H, J=6.6), 2.95 (m, 1H), 2.79 (dd, 1H, J=14.5, 7.5), 2.37 (s, 3H); low resolution MS (ES+)m/e 400.9 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:7]=2[CH2:6]1.[OH-].[K+]>C(O)C.O>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:8]2[O:9][CH:5]([CH2:4][C:3]([OH:16])=[O:2])[CH2:6][C:7]=2[CH:13]=1
Reactant: COC(=O)CC1Cc2cc(OC)ccc2O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CC(CC(=O)O)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
110 g of 5-methoxy-2,3-dihydro-3-benzofuranacetic acid methylester dissolved in 400 ml of ethanol were added during 20 minutes to a solution of 55 g of KOH in 70 ml of water and 500 ml of ethanol at reflux temperature. Reflux was continued for 0.5 hours. Ethanol was evaporated and 600 ml of water were added, and the mixture was acidified with cold conc. hydrochloric acid and subsequently extracted with dichloromethane (3×300 ml). The combined organic phases were washed with brine, dried (MgSO4) and evaporated to a volume of 200 ml. 700 ml of n-heptane were added, and excess dichloromethane evaporated. The mixture was cooled to 0° C., and the precipitated carboxylic acid filtered off. Yield: 91 g. M.P. 111°-112° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4c(c3)OCO4)n2)c1

Procedure:
The title compound was prepared according to method C using benzo[d][1,3]dioxole-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 6.22 (s, 2H), 7.20 (d, J=8.1 Hz, 1H), 7.61-7.69 (m, 2H), 7.81 (dd, J=8.1, 1.7 Hz, 1H), 8.42 (dt, J=8.2, 1.9, 1.7 Hz, 1H), 8.81 (dd, J=4.7, 1.7 Hz, 1H), 9.24 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 268 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[CH:9][S:8][C:7]=3[C:6]=2[N:15]=1.C(O)(=O)C.[Br:20]N1C(=O)CCC1=O>C(Cl)Cl>[Br:20][C:9]1[S:8][C:7]2[C:6]3[N:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc2c(n1)-c1sccc1CCO2
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccc2c(n1)-c1sc(Br)cc1CCO2
Temperature: 2.5 °C
Reaction time: 18 h

Procedure:
9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (4.33 g, 18.2 mmol) was dissolved in methylene chloride (40 mL, 600 mmol)/acetic acid (40 mL, 700 mmol). The solution was cooled down to 0-5° C. and added a solution of N-Bromosuccinimide (3.57 g, 20.0 mmol) in 10 mL of DCM slowly. The reaction mixture was stirred for 18 hours. After removal of the solvents, the residue was partitioned between ethyl acetate and saturated sodium carbonate aqueous solution. The organic layer was washed with water, brine and dried over sodium sulfate. After filtration, the filtrate was concentrated to give 2-Bromo-9-chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene. 1HNMR (DMSO, 400 MHz): δ 7.48 (d, J=8.4 Hz, 1H, ArH), 7.28 (d, J=8.4 Hz, 1H, ArH), 7.18 (s, 1H, ═CH), 4.32 (t, J=4.4 Hz, 2H, CH2), 3.17 (t, J=4.4 Hz, 2H, CH2).