Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10](=[NH:14])OCC)[CH2:9][CH2:8]2)[CH:6]=1.[S].C(O)(=O)C.C(N(CC)CC)C.N[C:28]1[C:33]([NH2:34])=[CH:32][N:31]=[C:30]([N:35]2[CH2:40][CH2:39][O:38][C@@H:37]([C:41]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:42])[CH2:36]2)[N:29]=1>>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]3[NH:14][C:32]4[C:33]([N:34]=3)=[CH:28][N:29]=[C:30]([N:35]3[CH2:40][CH2:39][O:38][C@@H:37]([C:41]([N:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)=[O:42])[CH2:36]3)[N:31]=4)[CH2:8][CH2:9]2)[CH:6]=1
Reactant: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Reactant: Nc1cnc(N2CCO[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: [S]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=C([C@H]1CN(c2ncc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)CCO1)N1CCCC1
Temperature: 100 °C

Procedure:
Ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate (0.13 g, 0.46 mmol), sulfur (15 mg), acetic acid (0.53 mL, 9.3 mmol) and triethylamine (0.39 mL, 2.79 mmol) were added to the filtrate containing (R)-(4-(4,5-diaminopyrimidin-2-yl)morpholin-2-yl)(pyrrolidin-1-yl)methanone, prepared in the previous step, at room temperature. The reaction mixture was heated to 100° C. for 24 h. The solvent was removed under reduced pressure and the resulting crude material was purified via preparative TLC to afford the title compound (13 mg). MS (ES+APCI) (M+H) 443.0; LCMS retention time 4.485 min (Method T1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:35][C:36]1[N:37]=[N:38][C:39](Cl)=[CH:40][CH:41]=1.[C:43]([O-:46])([O-])=[O:44].[K+].[K+]>CN(C=O)C.CO>[F:22][C:21]([F:24])([F:23])[C:43]([OH:46])=[O:44].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:39]4[N:38]=[N:37][C:36]([NH2:35])=[CH:41][CH:40]=4)=[CH:18][CH:19]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(Cl)nn1
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc(Oc2ccc(-c3nnc(Nc4ccc(Cl)c(C(F)(F)F)c4)[nH]3)cc2)nn1
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 19.2 %

Procedure:
4-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (120.0 mg, 0.338 mmol) was dissolved in 3 mL of anhydrous DMF in a 5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (81.0 mg, 0.406 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 15 min, then 3-amino-6-chloro-pyridazine (48.2 mg, 0.372 mmol) was added, followed by anhydrous K2CO3 (46.7 mg, 0.338 mmol). Then the vial was capped and microwaved at 200° C. for 30 min. After reaction was complete, the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (18.2 mg).
Reaction SMILES: Cl[Si](Cl)(C)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([S:18](Cl)(=O)=O)[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15].CN1CCN(C)C1=O>ClCCCl.[Zn]>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([SH:18])[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15]
Reactant: COc1cc(S(=O)(=O)Cl)cc(OC)c1OC
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: CN1CCN(C)C1=O
Solvent: ClCCCl
Product: COc1cc(S)cc(OC)c1OC
Temperature: 75 °C

Procedure:
A room temperature suspension of zinc powder (430 mg, 6.56 mmol) and dichlorodimethylsilane (0.80 mL, 6.59 mmol) in 1,2-dichloroethane (15 mL) was treated with a solution of 3,4,5-trimethoxybenzenesulfonyl chloride (500 mg, 1.87 mmol) and 1,3-dimethyl-2-imidazolidinone (647 mg, 5.67 mmol) in 1,2-dichloroethane (15 mL). The reaction was heated to 75° C. for 1 hour, cooled to room temperature, filtered, and concentrated. The concentrate was dissolved in methanol, concentrated, dissolved in methanol, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane to provide the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][C:16]([N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)([CH3:18])[CH3:17])[CH:9]=1>ClCCl.ClCCCl>[C:8]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][C:16]([N:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)([CH3:18])[CH3:17])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)CCc2cccc(-c3ccccc3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(CCc1cccc(-c2ccccc2)c1)N1CCNCC1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
0.65 ml (8.4 mmol) of trifluoroacetic acid is added to a solution of 0.35 g (0.86 mmol) of 1,1-dimethylethyl 4-(3-biphenyl-3-yl-1,1-dimethylpropyl)piperazine-1-carboxylate, prepared in step 5.3., in 5 ml of dichloromethane. The mixture is stirred for 2 hours and then 0.65 ml of trifluoroacetic acid is added. It is stirred for 2 more hours and then diluted with 10 ml of 1,2-dichloroethane and evaporated to dryness. The residue is taken up in a mixture of 50 ml of dichloromethane and 20 ml of 15% aqueous sodium hydroxide solution. The phases are separated and the aqueous phase is extracted with 2 times 20 ml of dichloromethane. The organic phases are washed with 10 ml of water and then with 20 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated, to give 0.25 g (0.81 mmol) of product in the form of a yellow oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[CH2:24][CH:23]([CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:28][CH2:27]3)[C:21](=[O:22])[C:16]2=[CH:17][C:18]=1[O:19][CH3:20]>C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[CH2:24][CH:23]([CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:30][CH2:31]3)[C:21](=[O:22])[C:16]2=[CH:17][C:18]=1[O:19][CH3:20].[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 25 °C

Procedure:
Tartaric acid (1.5 g, dissolved in 35 ml of acetone) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (200 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound.
Reaction SMILES: [C:1]1(=[O:44])[N:5]([CH:6]2[C:37](=[O:38])[N:8]3[C:9]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:10]([CH2:13][S:14][C:15]4[S:16][C:17]([CH3:20])=[N:18][N:19]=4)[CH2:11][S:12][C@H:7]23)[C:4](=[O:39])[C:3]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:2]12.C1C[O:48]CC1.[S-2].[Na+].[Na+].S(=O)(=O)(O)O>C(OCC)(=O)C.O>[C:1]([C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[C:4]([NH:5][CH:6]1[C:37](=[O:38])[N:8]2[C:9]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[O:39])([OH:48])=[O:44]
Reactant: C1CCOC1
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N4C(=O)c5ccccc5C4=O)[C@H]3SC2)s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)c4ccccc4C(=O)O)[C@H]3SC2)s1
Reaction time: 0.25 h

Procedure:
A solution of benzhydryl 7-phthalimido-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (2 mmol.) in 25 ml. of THF and 8 ml. of water is cooled in an ice-water bath, and 660 mg. of Na2S.9H2O are then added. The mixture is stirred for 15 minutes, and 10 ml. of water and 40 ml. of ethyl acetate are added. The layers are separated, and a neutral material is obtained from the ethyl acetate layer. The aqueous layer is acidified to pH 4.3 with 1N sulfuric acid and is extracted twice with ethyl acetate. The ethyl acetate extract is washed, dried, and evaporated to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[CH2:13]([O:15][C:16]([C:18]1([NH2:27])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:13]([O:15][C:16]([C:18]1([NH:27][C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3cc[nH]c23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 1H-indole-7-carboxylic acid (250 mg, 1.55 mmol), 2-Amino-indan-2-carboxylic acid ethyl ester (318 mg, 1.55 mmol), HATU (886 mg, 2.33 mmol) in anhydrous DMF (8 mL) is added DIPEA (385 μL, 2.33 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-60% EtOAc in heptane) to give a pure product (57) as white solid (378 mg, 70%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1C(F)(F)F

Procedure:
Heat a mixture of 2-chloro-3-trifluoromethyl-pyridine (1.8 g, 10 mmol) and sodium methoxide (4M, 5 mL, 20 mmol) in MeOH (20 mL) at reflux for 18 hours. Cool the mixture and remove the volatiles by rotary evaporation. Dissolve the residue in EtOAc (50 mL) and wash with water (50 mL), saturated NaHCO3(aq) (50 mL) and brine (50 mL). Dry the organic extract over MgSO4 and remove the solvent under reduced pressure to yield the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1.C[Si](Cl)(C)C.[SH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH:5]([C:4]1[CH:3]=[C:2]([CH:1]([S:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[S:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:9]=[CH:8][CH:7]=1)=[O:6]
Reactant: O=Cc1cccc(C=O)c1
Reactant: COC(=O)CCS
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of isophthalaldehyde (5.4 g) in CHCl3 (50 ml) and methyl 3 -mercaptopropanoate (9.2 ml) was added dropwise trimethylsilylchloride (6.5 ml). The reaction mixture was stirred 1 hour at room temperature, quenched with aqueous NH4OAc (25%), and extracted with ethylacetate. Flash chromatography of the residue using 1:1 ethylacetate hexane afforded the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)[C:2]#[CH:3].[CH2:20]=O.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C>[Cu]Cl.O1CCOCC1>[N:22]1([CH2:20][C:3]#[C:2][CH2:1][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: C=O
Reactant: C#CCN1c2ccccc2C(=O)Nc2cccnc21
Agent: Cl[Cu]
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(CC#CCN2CCCC2)c2ccccc21

Procedure:
The mixture of 8.5 g (0.034 mol) of 5,11-dihydro-11-(prop-2-ynyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 50 ml of anhydrous dioxan, 1.08 g (0.036 mol) of paraformaldehyde, 2.77 g (0.039 mol) of pyrrolidine and 0.2 g of copper (I) chloride was refluxed for 1 hour with stirring and then, after cooling, evaporated down in a water jet vacuum. The residue was partitioned between water and ethylacetate, the ethylacetate solution obtained was mixed with 2 g of animal charcoal, dried over sodium sulphate, filtered and evaporated down. The residue was purified by column chromatography on silica gel using first ethyl acetate and then dichloromethane/cyclohexane/methanol/conc. ammonia 68/15/15/2 (v/v/v/v) as eluant. The crude product obtained after evaporation of the suitable eluates was recrystallised once more from ethylacetate. Yield: 1.6 g (14% of theory) of colourless crystals, m.p. 153° C.; RF 0.5 (Merck, ready-made TLC plates, silica gel 60 F-254; eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 68/15/15/2 v/v/v/v).
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.B1(C=C)OB([CH:39]=[CH2:40])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]([O:27][C:26](=[O:32])[NH:25][C@@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][O:18][C:17]1[C:2]([CH:39]=[CH2:40])=[CH:3][C:4]2[C:13]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[CH:16]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=Cc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 33.5 %

Procedure:
A mixture of (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.250 g, 0.496 mmol) (prepared as described in Example 3, Part B) 2,4,6-trivinylcyclotriboroxane pyridine complex (0.239 g, 0.991 mmol), Na2CO3 (0.158 g, 1.487 mmol) and Pd(PPh3)4 (0.029 g, 0.025 mmol) in toluene (1 mL) water (0.1 mL), and ethanol (0.3 mL) was purged with nitrogen gas and heated at 90° C. for 16 h. After cooling, the reaction mixture was transferred to separatory funnel containing water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (60% ethyl acetate: petroleum ether) to afford a (S)-tert-butyl(4-methyl-1-((6-methyl-5-oxo-9-vinyl-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.150 g, 0.166 mmol, 34% yield) as a yellow solid. LC/MS (ESI) m/e 452.4, [(M+H)+, calcd for C26H34N3O4, 452.2]; LC/MS retention time (method D): tR=0.95 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-])=O.[C:8]([C:11]1[C:12]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13][N:14]([C:16]2([CH2:20][C:21]#[N:22])[CH2:19][NH2+:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].FC(F)(F)S(OCC(F)(F)F)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[C:21]([CH2:20][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:13]2)[CH2:17][N:18]([CH2:3][C:2]([F:7])([F:6])[F:1])[CH2:19]1)#[N:22]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)C[NH2+]C1
Reactant: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CN(CC(F)(F)F)C1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidinium trifluoroacetate (Intermediate #38-2) (23 mg, 0.078 mmol) in dioxane (2 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (36 mg, 0.15 mmol), followed by K2CO3 (23 mg, 0.078 mmol). The resulting mixture was heated to 110° C. and allowed to stir for 2 hours. The reaction was then cooled to ambient temperature, water was added and the reaction mixture was extracted with EtOAc (3×). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound, Example #19. 1H NMR (600 MHz, CDCl3): δ 8.78 (s, 1H), 7.75 (s, 1H), 7.48 (d, J=7.7 Hz, 2H), 7.26 (t, J=7.9 Hz, 2H), 6.90 (t, J=7.3 Hz, 1H), 5.62 (s, 2H), 3.81 (d, J=8.6 Hz, 2H), 3.74 (d, J=8.6 Hz, 2H), 3.34 (s, 2H), 3.09 (q, J=9.1 Hz, 2H). LRMS (ESI) calc'd for C17H17F3N6O [M+H]+: 379. Found: 379.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][CH2:20][CH:21]([OH:50])[CH2:22][NH:23][C:24](=[O:49])[C@H:25]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:26]C(OCC1C=CC=CC=1)=O)=[O:18].[H][H]>COCCOC.CN(C)C=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][CH2:20][CH:21]([OH:50])[CH2:22][NH:23][C:24](=[O:49])[C@H:25]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[NH2:26])=[O:18]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(O)CNC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)NCC(O)CNC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl

Procedure:
1.80 g (2.46 mmol) of Nα -benzyloxycarbonyl-Nε -tert.-butoxycarbonyl-L-lysine-3-{2-[2-(2,6-dichlorophenylamino)-phenyl]-acetylamino}-2-hydroxypropylamide are dissolved in 100 ml of 1,2-dimethoxyethane/dimethylformamide (9:1) and after the addition of 0.40 g of palladium-on-carbon (10%) the whole is treated for 11/4 hours with hydrogen. The catalyst is filtered off, the filtrate is concentrated by evaporation at 30° in a rotary evaporator and the residue is lyophilised after being taken up in 100 ml of dioxan/water (7:3). Nε -tert.-butoxycarbonyl-L-lysine-3-{2-[2-(2,6-dichlorophenylamino)-phenyl]-acetylamino}-2hydroxypropylamide is obtained in the form of a colourless powder which is immediately processed further; Rf =0.52 (acetonitrile:water=3:1), Rf =0.66 (ethyl acetate:n-butanol:pyridine:acetic acid:water=42:21:21:6:10).
Reaction SMILES: C(C=O)=O.[OH-].[NH4+:6].[Cl:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=1.ClC1C=CC=[C:19]([CH3:23])[N:18]=1>CO>[Cl:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([C:14]2[NH:6][CH:23]=[CH:19][N:18]=2)[N:13]=1
Reactant: [NH4+]
Reactant: Cc1cccc(Cl)n1
Reactant: O=Cc1cccc(Cl)n1
Agent: O=CC=O
Agent: [OH-]
Solvent: CO
Product: Clc1cccc(-c2ncc[nH]2)n1
Temperature: 25 °C

Procedure:
Glyoxal (40% w/w H2O, 20 mL) and ammonium hydroxide (con. 40 mL) are added to a solution of 6-chloro-pyridine-2-carbaldehyde (0.127 mol; prepared from 2-chloro-6-methyl-pyridine essentially as described by Vacher et al. (1998) J. Med. Chem. 41:5080) in MeOH (620 mL) at 0° C. The mixture is allowed to warm gradually to room temperature over an 18 hour period. The solvent is removed. Water (125 mL) is added to the residue and the mixture is extracted with methylene chloride (5×150 mL). The combined organic layers are washed with brine (2×100 mL), dried and solvent removed. The crude product is triturated with ethyl ether (200 mL) to give 2-chloro-6-(1H-imidazol-2-yl)-pyridine as a solid.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:17][O:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][CH2:13]2)(=O)=O)=CC=1.CN(C=O)C.[N-:29]=[N+:30]=[N-:31].[Na+]>O>[N:29]([CH:12]1[CH2:17][O:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:14][CH2:13]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC2COC(c3ccccc3)OC2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1COC(c2ccccc2)OC1
Temperature: 105 °C
Reaction time: 48 h
Yield: 84.1 %

Procedure:
To a 1 L round bottom flask was added 2-phenyl-1,3-dioxan-5-yl 4-methylbenzenesulfonate (40 g, 120 mmol) and DMF (500 mL). NaN3 (31.3 g, 478 mmol) was added as a solution in water (150 mL). The reaction was stirred at 105° C. for 2 days. The reaction was then concentrated to dryness. The solid was dissolved in water (700 mL) and extracted into EtOAc (3×500 mL). The combined organic layers were washed with water (5×) and concentrated to dryness to afford an orange solid. The material was then recrystallized from hexanes to afford 20.7 g (84% yield) of 22 as a pale brown solid. 1H NMR (CDCl3, 400 MHz), δ: 3.67 (2H, pseudo t, J=11.59 Hz), 3.78-3.88 (1H, m), 4.36-4.04 (2H, m), 7.36-7.39 (3H, m), 7.45-7.47 (2H, m). Mass Spec (lo-res): Calc'd for C10H11N3O2: 205.09; found: 178.1 (M+H−N2).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[CH:13][NH:12][C:11]2=O>S1(CCCC1)(=O)=O>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: COc1cc2ncnc(Cl)c2cc1OC
Temperature: 120 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Sulfolane (250 ml) and phosphorus oxychloride (250 ml=412.5 g, 2.69 mol) were added to 6,7-dimethoxy-4-quinazolone (50.1 g, 0.24 mol), and the mixture was stirred at 120° C. for one hr. The reaction mixture was cooled to room temperature, and the excess phosphorus oxychloride was then removed by distillation under the reduced pressure. The residue was poured into ice water (1000 ml), and chloroform (1000 ml) was added thereto. The aqueous layer was adjusted to pH 6.5 by the addition of a 20% sodium hydroxide solution, followed by the separation of the organic layer from the aqueous layer. The separated organic layer was washed with water (1000 ml×six times), was dried over sodium sulfate, and was then concentrated under the reduced pressure. Tetrahydrofuran (470 ml) was added to the residue, and the mixture was refluxed. The reaction solution was cooled to −5° C. to −10° C. and was filtered and dried to give 38.5 g (yield 71.4%) of the target product.