Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](O)=[O:13])=[CH:2]1.C([N:24](CC)C(C)C)(C)C.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([NH2:24])=[O:13])=[CH:2]1
Reactant: O=C(O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: ClCCl
Product: NC(=O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a solution of 264 mg (1 mmol.) of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenyl-2-propenoic acid in 1.5 ml of THFd and 3 ml of DMFd was added 350 μl of N,N,-diisopropylethylamine and 154 mg (1.4 mmol.) of N-hydroxybenzotriazole ammonium salt. The obtained mixture was cooled to −20° C. and 266 mg (1.4 mmol.) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide were added. The reaction mixture was stirred for 2 hours at −20° C. and then warmed to room temperature. After additional 12 hours, the organic layer was diluted with dichloromethane, washed with saturated sodium bicarbonate, brine, dried over sodium sulphate and evaporated. The residual solid was triturated with EtOAc to afford 76 mg of the title compound as a white solid (yield 29%) m.p. 222-224° C. 1H-NMR (DMSO-d6) δ ppm: 11.79 (s, 1H, NH pyrrole); 8.19 (dd, 1H, pyridine); 7.82 (dd, 1H, pyridine); 7.76 (s, 1H, CH═C); 7.2-7.5 (m, 5H, ph); 7.04 (dd, 1H, pyridine); 6.3 (d, 1H, pyrrole); 7.1 (s, 1H, CONH2); 6.7 (s, 1H, CONH2). (M+H)+=264
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[F:24][C:25]([F:30])([F:29])[C@@H:26]([NH2:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(#N)C.[OH2:42]>>[C:26]([OH:21])([C:25]([F:30])([F:29])[F:24])=[O:42].[CH3:22][C:3]1[C:2]([NH:28][C@@H:26]([CH3:27])[C:25]([F:30])([F:29])[F:24])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: C[C@H](N)C(F)(F)F
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
Reactant: O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H](C)C(F)(F)F
Product: O=C(O)C(F)(F)F
Temperature: 100 °C
Yield: 0.1 %
Yield: 16 %

Procedure:
Prepared similarly to that described in Example 254 using 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 254c; 34 mg, 0.109 mmol), (S)-1,1,1-trifluoropropan-2-amine hydrochloride (32.5 mg, 0.217 mmol, SynQuest Laboratories, Alachua, Fla.), Pd(tBu3P)2 (Strem, Newburyport, Mass.; 5.56 mg, 10.87 μmol), and K3PO4 (92 mg, 0.435 mmol), heating at 100° C. for 2 h. Purification by silica gel (100% DCM to 4% 2 M NH3 in MeOH/DCM) then by rpHPLC (Phenomenex Gemini C18, 10 pan, 150×30 mm; 10-100% ACN/water with 0.1% TFA) provided (S)-2-(2-methyl-3-((1,1,1-trifluoropropan-2-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16% yield). MS (ESI, pos. ion) m/z: 390.2 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 1.61 (d, J=6.85 Hz, 3H) 2.66 (s, 3H) 2.96 (t, J=6.85 Hz, 2H) 3.66 (td, J=6.85, 2.54 Hz, 2H) 4.85 (s, 1H) 4.86-4.96 (m, 1H) 5.35 (br. s., 1H) 7.12 (d, J=2.35 Hz, 1H) 7.47 (t, J=7.82 Hz, 1H) 7.73 (dd, J=8.12, 1.27 Hz, 1H) 7.94 (dd, J=7.63, 1.17 Hz, 1H) 11.60 (br. s., 1H). 19F NMR (376 MHz, DMSO-d6) δ ppm −76.30 (3F, s).
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.[H-].[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>CN(C)C=O>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[S:26]([N:13]1[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=3)[C:9]=2[CH:11]=[CH:12]1)(=[O:27])=[O:28]
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(S(=O)(=O)n2ccc3c4c(N)nc(N)nc4ccc32)c1
Reaction time: 1.5 h

Procedure:
A solution of 11.97 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine, as prepared in Example 1, in 750 ml. dry dimethylformamide is stirred under nitrogen as 3.18 g. of ca. 50% sodium hydride-mineral oil is added carefully. After stirring for 1.5 hours and chilling with an ice-water bath, a solution of 13.51 g. 2,5-dimethylbenzenesulfonyl chloride in 50 ml. dry dimethylformamide is added dropwise to the chilled stirring suspension. Stirring is continued for 4 hours, while the reaction slowly warms to ambient temperature, and is quenched with 30 ml. isopropanol. After removal of solvent (in vacuo), the residue is stirred thoroughly with excess aqueous potassium carbonate solution and filtered. The solids are collected, washed well with water, rinsed with hexane, and dried. The crude product is dissolved in 2.5 liters of boiling methanol, treated with charcoal, and filtered through Celite. The filtrate is concentrated to ca. 1 liter and chilled. The crystalline solid is collected and again recrystallized from methanol and dried to afford 9.68 g. of the title compound, m.p. 271.5°-272.5° C., NMR (d DMSO): δ2.35 (singlet, 5--CH3), 2.39 (singlet, 2--CH3), 5.93 (singlet, 3--NH2), 6.88 (singlet, 1--NH2), 7.16 (doublet, J=9 cps, 5H), 7.48 (doublet, J=31/2 cps, 9H), 8.9 (doublet, J=31/2 cps, 8H) p.p.m.; λmax95%EtOH 242 shoulder (ε28,300), 257 (ε31,700), 288 shoulder (ε12,500), 350 (ε4,900) nm; λmin95%EtOH 320 (ε2,700) nm.
Reaction SMILES: FC1C(OC2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:48]([OH:50])=O)[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=[O:30])([CH3:27])([CH3:26])[CH3:25].[NH:51]1[CH2:69][CH2:68][CH2:67][C@H:52]1[C:53]([NH:55][C@H:56]([C:64]([OH:66])=[O:65])[CH2:57][CH2:58][CH2:59][NH:60][C:61](=[NH:63])[NH2:62])=[O:54]>O1CCOCC1.O>[C:24]([O:28][C:29]([NH:31][C@H:32]([C:48]([N:51]1[CH2:69][CH2:68][CH2:67][C@H:52]1[C:53]([NH:55][C@H:56]([C:64]([OH:66])=[O:65])[CH2:57][CH2:58][CH2:59][NH:60][C:61](=[NH:62])[NH2:63])=[O:54])=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])=[O:30])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O
Agent: Fc1c(F)c(F)c(Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
To a solution of 53 g (0.1 mol) of pentafluorophenyl ether of tert.butyloxycarbonyl-Nε -benzyloxycarbonyl-lysine in 300 ml of dioxane there is added, under vigorous stirring, a solution of 23 g (0.08 mol) of prolyl-arginine II in 100 ml of water. After two hours the solvent is evaporated and the residue is dissolved in 150 ml of dimethylformamide. The solution is stirred for 48 hours at room temperature (25° C.), dimethylformamide is distilled-off to 1/3 volume, whereafter the reaction mixture is poured into 1 liter of diethyl ether. A further treatment is effected as described in the case of compound I. After recrystallization of the product from a mixture of ethylacetate-ethanol-diethyl ether (3:1:30) there are obtained 47 g (75%) of tert.butyloxycarbonyl-Nε -benzyloxycarbonyl-lysyl-prolyl-arginine having the following properties: M.p. 90° C., [L]D20 -39° (c 1.0; 10% CH3COOH); Rf =0.51/A, "Eastman"/, 0.82/B, "Eastman"/; Ehis =0.34 (pH 2.4).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]([CH2:34][CH3:35])[C:23]3[C:28]([C:29]=2[C:30]#[N:31])=[CH:27][CH:26]=[C:25]([O:32][CH3:33])[CH:24]=3)=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[C:30]([C:29]1[C:28]2[C:23](=[CH:24][C:25]([O:32][CH3:33])=[CH:26][CH:27]=2)[N:22]([CH2:34][CH3:35])[C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][NH:11][CH:8]=[O:10])=[CH:16][CH:17]=1)#[N:31]
Reactant: CCn1c(-c2ccc(OCCN)cc2)c(C#N)c2ccc(OC)cc21
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCn1c(-c2ccc(OCCNC=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
Acetic anhydride (700 μL) and 98% formic acid (280 μL) were heated at 65° C. for 1 h. This was cooled to 0° C. 2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, was taken up in THF (400 μL), and added to the mixed anhydride. This was stirred at 0° C. for 45 minutes. The mixture was then portioned between EtOAc and aqueous NaHCO3. The organic layer was dried and concentrated. Purification by silica gel chromatography (4/1, CH2Cl2/acetone) yielded N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]-ethyl} formamide (28 mg, 86%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[CH2:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[O:10][C:9]1([CH3:21])[CH3:20].[H-].[Na+].Cl[CH2:28][C:29]1[S:30][C:31]2[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:32]=2[N:33]=1.O>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[CH2:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:28][C:29]3[S:30][C:31]4[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:32]=4[N:33]=3)[CH:15]=2)[O:10][C:9]1([CH3:20])[CH3:21]
Reactant: COc1ccc(N)cc1CC1C(=O)c2cc(O)ccc2OC1(C)C
Reactant: Fc1cc2nc(CCl)sc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N)cc1CC1C(=O)c2cc(OCc3nc4cc(F)c(F)cc4s3)ccc2OC1(C)C
Temperature: 0 °C
Yield: 62 %

Procedure:
To a stirred solution of 2.36 (7.21 mmole) of the product of Example 102 in 25 mL DMF at 0° C. was added 332 mg (8.29 mmole) 60% sodium hydride. The mixture was stirred at 0° C. then a solution of 2.06 g (9.37 mmole) 2-(chloromethyl)-5,6-difluorobenzothiazole in 15 mL DMF was added dropwise. The mixture was slowly warmed to room temperature and stirred for 18 hours. The mixture was poured into water and then extracted with ethyl acetate. The ethyl acetate extract was washed successively with 1N KOH, water and brine and then dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes gave 2.3 g (62%) of the title product as a solid. NMR (CDCl3): δ1.45 (d, 6H); 2.90 (m, 3H); 3.69 (s, 3H); 5.39 (s, 2H). MS (Cl, NH3) m/e: 528 (M+ +18), 511 (M+ +1,100).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][C:17]([N:19]([CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH:28]1([N:19]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:17](=[O:18])[CH2:16][NH:14][CH:9]2[CH:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: COc1ccc(N(C(=O)CBr)C2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNC2C=CC=CC2Nc2ccccc2)C2CCCC2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
2.03 g (10.7 mmol) N-Phenyl-o-phenylene diamine, 3.50 g (11.2 mmol, 1.05 equiv) 2-Bromo-N-cyclopentyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, 1.62 g (11.7 mmol, 1.1 equiv) Potassium carbonate, and 177 mg (1.1 mmol, 0.1 equiv) Potassium Iodide were combined in 35 mL DMF and stirred 18 h at 60° C. The reaction mixture is filtered and the solvent removed in vacuo. The residue is taken into EtOAc (150 mL), washed with 1N HCl (2×50 mL), H2O (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by flash chromatography on 50 g silica gel eluted with EtOAc/Hexanes (3:17, 1 L). Appropriate fractions were combined and concentrated in vacuo to give 2.53 g (6.09 mmol) of N-Cyclopentyl-N-(4-methoxy-phenyl)-2-(6-phenylamino-cyclohexa-2,4-dienylamino)-acetamide as a yellow oil: 1H NMR (Acetone-d6, 300 MHz) δ7.26-6.50 (m, 13H), 6.22 (d, 1H, J=7.9), 5.29 (s, br, 1H), 4.82 (m, 1H), 3.87 (s, 3H), 3.41 (d, 2H, J=4.4), 1.83 (m, 2H), 1.48 (m, 4H), 1.33 (m, 2H); TLC Rf =0.14 (EtOAc/Hexanes, 3:17).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Si]([O:29][CH:30]([CH2:41][CH2:42][CH2:43][CH3:44])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32])(C(C)(C)C)(C)C.O.CCOC(C)=O>C1COCC1>[OH:29][CH:30]([CH2:41][CH2:42][CH2:43][CH3:44])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32]
Reactant: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(O)C(=O)Nc1ccc(C)cn1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Tetrabutylammoniumfluoride trihydrate (302 mg, 0.96 mmol) was added to a stirred solution of 2-{[tert-butyl(dimethyl)silyl]oxy}-N-(5-methylpyridin-2-yl)hexanamide (Step 2) (215 mg, 0.64 mmol) in THF (5 mL). The reaction mixture was kept at ambient temperature for 1 h. Water and EtOAc were added and the two phases were separated. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with DCM/EtOAc:2/1) to give the title compound as a colourless solid (135 mg), 1H NMR (300 MHz, CDCl3) δ 9.46 (br s, 1H), 8.20 (d, 1H), 8.04 (d, 1H), 7.55 (dd, 1H), 5.47 (br s, 1H), 4.29 (m, 1H), 2.31 (s, 3H), 1.98 (m, 1H), 1.76 (m, 1H), 1.52 (m, 2H), 1.38 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](Cl)=[O:6].FC1C=C(F)C(F)=CC=1C(O)=[O:18]>>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:18])=[O:6]
Reactant: O=C(Cl)c1cc(F)c(F)c(Cl)c1F
Reactant: O=C(O)c1cc(F)c(F)cc1F
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F

Procedure:
A process for the preparation of 3-chloro-2,4,5-trifluorobenzoyl chloride, which comprises chlorinating 2,4,5-trifluorobenzoic acid to give 3-chloro-2,4,5-trifluorobenzoic acid, and reacting the latter with thionyl chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][CH3:50])=[C:45]([Pb+3])[CH:44]=2)=[CH:39][CH:38]=1>ClCCl.Cl>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][CH3:50])=[C:45]([CH:6]3[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]3=[O:9])[CH:44]=2)=[CH:41][CH:42]=1
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (described in U.S. Pat. No. 5,089,046A) (0.303 g, 1.78 mmol) and N,N-dimethylaminopyridine (1.09 g, 8.90 mmol) is added anhydrous chloroform (20 ml), followed by stirring at room temperature until dissolution. To this solution is added anhydrous toluene (5 ml), followed by 4′-chloro-4-ethylbiphenyl-3-yllead triacetate (1.17 g, 1.96 mmol) in one portion and the mixture heated at 80° C. for 1-2 hours. The mixture is allowed to cool to room temperature, then diluted with dichloromethane (150 ml) and dilute aqueous hydrochloric acid (30 ml), followed by stirring for 5 minutes and filtration through diatomaceous earth to remove inorganic residues (additional washing with solvents). All organic fractions are combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product is purified by column chromatography (100% hexane to hexane/ethyl acetate 5:1 ratio) then triturated with hexanes to afford 4-(4′-chloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.46 g) as a cream powder.
Reaction SMILES: C(O[C:5](=[O:16])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13]CC)C=C.N1C(=O)CC(=O)NC1=O.[C:26]([NH:34][CH:35]1[C:42](=[O:43])[N:41]2[CH:44](C(O)=O)[CH2:45][CH2:46][CH:40]2[CH2:39][CH:38](C)[CH2:37][CH2:36]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(O)(C(F)(F)F)=O>ClCCl.O>[OH:13][CH:8]1[CH:7]([NH:6][C:5]([C@H:44]2[N:41]3[C:42](=[O:43])[C@@H:35]([NH:34][C:26](=[O:33])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]3[CH2:46][CH2:45]2)=[O:16])[CH2:11][C:10](=[O:12])[O:9]1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCC
Reactant: CC1CCC(NC(=O)c2ccccc2)C(=O)N2C(CCC2C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C1CC(=O)NC(=O)N1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C1CC(NC(=O)[C@@H]2CC[C@@H]3CCCC[C@H](NC(=O)c4ccccc4)C(=O)N32)C(O)O1
Reaction time: 0.17 h

Procedure:
To a solution of (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester (183 mg, 0.8 mmol) in dichloromethane (6 mL) is added barbituric acid (300 mg, 1.9 mmol) and tetrakis triphenylphosphine palladium (92 mg, 0.08 mmol). The solution is stirred for 10 minutes and 6-benzoylamino-9-methyl-5-oxo-decahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid, 20, (105 mg, 0.32 mmol) is added followed by HOBt (99 mg, 0.74 mmol) and EDCI (141 mg, 0.74 mmol). The solution is stirred for 6 hours. Water is added and the organics are washed with NaHSO4, Brine, NaHCO3, and water. The organics are dried with MgSO4 and concentrated under reduced pressure. The residue is purified over silica to afford an oil which is dissolved in dichloromethane and treated with TFA (5 mL) and water (1 mL). The solution is stirred for 2 hours and the solvent is removed. The residue is purified over silica to afford the desired product as a white powder. 1H NMR (CDCl3): δ 7.83 (m, 2H), 7.56–7.39 (m, 3H), 7.26 (m, 2H), 5.51 (d, J=5.2, 1H), 5.16 (m,1H), 4.72 (m, 1H), 4.56 (t, J=8.1 Hz, 1H), 4.35 (m, 1H), 3.95 (m, 1H), 3.71 (m, 2H), 2.90 (m, 1H), 2.52–2.38 (m, 2H), 2.26–2.05 (m, 4H), 1.87–1.61 (m, 5H), 1.32 (t, J=6.9 Hz, 3H). 13C NMR (CDCl3): δ 173.7, 172.2, 171.7, 166.6, 131.9, 128.8, 127.3, 101.3, 65.9, 60.8, 59.5, 50.6, 48.6, 36.9, 36.3, 33.1, 32.4, 25.7, 25.6, 23.6, 15.2. ESI MS: 458.16 (M+H), 480.11 (M+Na).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:16])[CH:4]=[CH2:5].[C:17]1([OH:23])C=CC=[CH:19][CH:18]=1.S(C1C=CC(C)=CC=1)(OC[C@@H]1OC1)(=O)=O>>[CH2:3]([O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[O:16][CH2:19][CH:18]1[CH2:17][O:23]1)[CH:4]=[CH2:5]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1O
Reactant: Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Product: C=CCOc1cc([N+](=O)[O-])ccc1OCC1CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 g (0.50 mole) of 60% NaH/mineral oil was placed in a two liter flask and washed with 500 ml of hexane. 1 L of DMF was added, followed by 77 g (0.40 mole) of the 2-allyloxy-4-nitrophenol prepared in the previous step. Addition of the phenol was performed in portions under argon. After stirring the mixture for 30 minutes at room temperature under argon, 108 g (0.48 moles) of (R)-glycidyl tosylate was added and the mixture heated at 70°-75° C. under nitrogen overnight. Upon cooling, the DMF was removed in vacuum and replaced with one liter of methylene chloride. This was washed with 500 ml portions of 2N HCl, saturated sodium bicarbonate and saturated brine and dried over sodium sulfate. The mixture was filtered, concentrated to an oil in vacuum and column chromatographed on silica gel using 1:1 hexane/methylene chloride as eluant. This gave 43 g of product contaminated with traces of the two starting materials, followed by 21 g of pure product as a pale yellow solid. The impure material was recrystallized from 1.2 L of 10% ethyl acetate/hexane to give 34 g of pure (homogeneous on silica gel tlc with 1:1 hexane/methylene chloride) (R)-2-(2-allyloxy-4-nitrophenoxymethyl)-oxirane (m.p. 64° C).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[CH:7]=1)[CH3:2].[CH:14](=O)[CH2:15][CH3:16]>>[CH2:1]([C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[C:7]=1[CH2:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCC=O
Reactant: CCOC(=O)c1[nH]c(CC)cc1C
Product: CCCc1c(CC)[nH]c(C(=O)OCC)c1C

Procedure:
The crude product, obtained as in Example 74 but using 2-ethyl-4-methyl-5-carbethoxypyrrole and propionaldehyde, was sublimed (80° C. 1 × 10-4 mm), m.p. 86°-87° C. (50%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:25])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22](Br)[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1>>[CH3:26][C:27]1[CH:32]=[C:31]([C:22]2[N:23]=[C:17]3[CH:16]=[C:15]([NH:14][C:12]([C:11]4[N:10]([CH3:25])[N:9]=[CH:8][C:7]=4[C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])=[O:13])[CH:20]=[CH:19][N:18]3[N:21]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Product: Cc1cc(-c2nc3cc(NC(=O)c4c(C(=O)N5CCC5)cnn4C)ccn3n2)ccn1
Yield: 22 %

Procedure:
The product was prepared in the same manner as described in example 66 using 4-(azetidine-1-carbonyl)-N-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (150 mg, 371 μmol) and 2-methylpyridin-4-ylboronic acid (76.2 mg, 557 μmol) as starting materials. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate/methanol 10% as eluent affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(2-methyl-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (34 mg, 22.0%) as an off-white solid. mp: 210-211° C., MS: m/z=417.4 (M+H+)
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26](Cl)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>>[CH3:14][O:15][C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26]1[S:38][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1cccc(CCC(=O)Cl)c1OC
Product: COc1cccc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)c1OC

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg; 1 mmol), TEA (0.153 ml; 1.1 mmol), 2,3-dimethoxyphenylpropionylchloride (228 mg, 1.1 mmol) and Lawesson's reagent (606 mg; 1.5 mmol) as described in method 1; yield: 0.025 g (6.8%); MS m/z: 367.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.07 (t, 2H, 3J=7.9 Hz); 3.38 (t, 2H, 3J=7.9 Hz); 3.73 (s, 3H); 3.79 (s, 3H); 6.84 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 6.91 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 6.98 (t, 1H, 3J=8.3 Hz); 7.71 (d, 1H, 3J=8.3 Hz); 7.77 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 8.12 (d, 1H, 4J=1.7 Hz); 8.37 (s, 1H); HPLC (METHOD [A]): rt 12.03 min (95.8%)