Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[NH2:8][C@H:9]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:10](O)=[O:11].CO>C1COCC1>[NH2:8][C@H:9]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:10][OH:11]
Reactant: N[C@@H](C(=O)O)c1cccs1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: N[C@@H](CO)c1cccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
1.59 ml (3.18 mmol) of lithium borohydride (2 M in THF) were initially charged in 2.5 ml of dry THF, 0.80 ml (6.30 mmol) of chlorotrimethylsilane were added at RT and the mixture was stirred at RT for 5 min. Subsequently, 200 mg (1.27 mmol) of (2S)-amino(2-thienyl)acetic acid were added in portions and the reaction mixture was stirred at RT overnight. 2.5 ml of methanol were added dropwise to the reaction mixture, and the mixture was concentrated. The residue was admixed with 1.5 ml of a 20% aqueous potassium hydroxide solution and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated. 173 mg of the target compound were obtained (90% of theory).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:7]=1[O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1.C(N(C(C)C)CC)(C)C.[O:36]1CCOC[CH2:37]1>>[O:36]=[C:37]1[N:4]([CH2:5][C:6]2[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:7]=2[O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH2:3][CH2:2][O:1]1
Reactant: C1COCCO1
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNCCO)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN2CCOC2=O)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
(3-{2-[(2-Hydroxy-ethylamino)-methyl]-4-trifluoromethyl-phenoxy}-phenyl)-acetic acid (0.15 g, 0.41 mmol), N,N′-carbonyldiimidazole (0.1 g, 0.61 mmol), and diisopropylethylamine (1 mL) were combined in 1,4-dioxane (5 mL) and stirred at 70° C. for 2 hours. The mixture was concentrated and purified by preparative HPLC to give the desired product (0.01 g).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Cl.CS(C)=[O:18]>>[ClH:1].[NH2:14][CH2:13][CH2:12][CH:7]1[C:6]2[C:10](=[CH:11][C:3]([F:2])=[CH:4][CH:5]=2)[NH:9][C:8]1=[O:18]
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: CS(C)=O
Agent: Cl
Product: NCCC1C(=O)Nc2cc(F)ccc21
Temperature: 50 °C
Reaction time: 6 h
Yield: 47 %

Procedure:
To a solution of 2-(6-fluoro-1H-indol-3-yl)ethanamine hydrochloride (500 mg, 2.3 mmol) in DMSO (0.8 mL) was added hydrochloric acid (36%, 1.3 g, 12.8 mmol). The resulting reaction mixture was stirred at 50° C. in a sealed tube for 6 h. After cooling to room temperature, the reaction mixture was filtered. The resulting cake was stirred in EtOH (5 mL). The mixture was filtered and dried to give the desired product (250 mg, 1.28 mmol, 47% yield) as a yellow solid. MS (ESI) m/z 195.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[H-].[Na+].[Br:12][C:13]1[CH:14]=[C:15]([N+]([O-])=O)[C:16]([C:19]#[N:20])=[N:17][CH:18]=1.O>CN(C=O)C>[Br:12][C:13]1[CH:14]=[C:15]([O:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=2)[C:16]([C:19]#[N:20])=[N:17][CH:18]=1
Reactant: Cc1ccc(O)c(C)n1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2cc(Br)cnc2C#N)c(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.2 %

Procedure:
To a 0° C. solution of 2,6-dimethylpyridin-3-ol (10 g, 81.2 mmol) in DMF (50 ml) was added sodium hydride (60% dispersion in oil, 3.4 g, 85 mmol). After 15 minutes, 5-bromo-3-nitropicolinonitrile (18.5 g, 81 mmol) was added and the mixture was allowed to warm slowly to ambient temperature. The reaction mixture was slowly added to 500 mL of rapidly stirring water. A light red solid formed and then the material formed a gum. The gum was extracted into ethyl acetate, and the organics washed with brine, dried over MgSO4 and concentrated in vacuo to afford 5-bromo-3-(2,6-dimethylpyridin-3-yloxy)picolinonitrile (25 g, 82 mmol, 101% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9](F)[CH:10]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:16][C:4]1[CH:3]=[C:2]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:10]=2)[N:5]=1
Reactant: Cc1cc(Cl)c2cc(F)c([N+](=O)[O-])cc2n1
Reactant: C1CCNC1
Product: Cc1cc(N2CCCC2)c2cc(N3CCCC3)c([N+](=O)[O-])cc2n1
Yield: 86.1 %

Procedure:
A solution of 0.29 g (1.21 mmol) of 4-chloro-6-fluoro-2-methyl-7-nitro-quinoline in pyrrolidine (2 ml, 24 mmol) was heated at 80° C. (bath temperature) for 18 h. The excess pyrrolidine was removed in vacuo, the residue taken up in methylene chloride, which was washed with water, brine and then dried over magnesium sulfate. The solvent was removed in vacuo to give 0.34 g (79%) of the desired 2-methyl-7-nitro-4,6-di-pyrrolidin-1-yl-quinoline as dark red solid. ISP mass spectrum, m/e: 327.3 (M+1 calculated for C18H22N4O2: 327).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:4]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.[NH2:21][C@@H:22]([CH3:39])[CH2:23][N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:36]=[C:35]([F:37])[C:32]([C:33]#[N:34])=[C:31]([Cl:38])[CH:30]=2)=[N:25]1>>[Cl:38][C:31]1[CH:30]=[C:29]([C:26]2[CH:27]=[CH:28][N:24]([CH2:23][C@@H:22]([NH:21][C:8]([C:6]3[N:7]=[C:3]([C:2]([F:1])([F:20])[F:19])[N:4]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=3)=[O:10])[CH3:39])[N:25]=2)[CH:36]=[C:35]([F:37])[C:32]=1[C:33]#[N:34]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1C(F)(F)F
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(F)(F)F)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (0.97 mmol, 300 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.97 mmol, 269 mg). The product was purified by flash-chromatography. Yield 230 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.13 (s, 9H), 0.65-0.77 (m, 2H), 1.17 (d, 3H), 3.36-3.43 (m, 2H), 4.21-4.42 (m, 3H), 5.75 (q, 2H), 7.01 (s, 1H), 7.64 (s, 1H), 7.83-7.88 (m, 2H), 7.95 (s, 1H), 8.65 (d, 1H). LC-MS: [M+1]=571.01.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[C:11]([CH:13]([O:15][C:16]([C:18]1[NH:19][CH:20]=[C:21]([CH2:25][CH3:26])[C:22]=1[CH2:23][CH3:24])=[O:17])[CH3:14])#[N:12].C([O-])(=O)C.[Na+]>ClC(Cl)C>[C:11]([CH:13]([O:15][C:16]([C:18]1[NH:19][C:20]([CH:8]=[O:9])=[C:21]([CH2:25][CH3:26])[C:22]=1[CH2:23][CH3:24])=[O:17])[CH3:14])#[N:12]
Reactant: CN(C)C=O
Reactant: CCc1c[nH]c(C(=O)OC(C)C#N)c1CC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCc1c(C=O)[nH]c(C(=O)OC(C)C#N)c1CC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
15 ml (160 mmol) phosphorous oxychloride were added dropwise for a period of 20 minutes to 13 ml (160 mmol) dimethylformamide at a temperature of 0° C. The mixture was stirred for another 15 minutes at room temperature and then 100 ml of dichloroethane were added. A solution of 10 g (40 mmol) of compound 11 in 50 ml dichloroethane were added dropwise. After gentle reflux for 15 minutes, the mixture was poured into 500 ml of a 4-molar sodium acetate solution and heated for a further 15 minutes. The organic layer was separated, washed with water and yielded after evaporation of the solvent, a brown oil, which was directly used for the next step without purification.
Reaction SMILES: [CH2:1]([C:5]1([CH2:36][CH3:37])[CH2:11][S:10](=[O:13])(=[O:12])[C:9]2[CH:14]=[CH:15][C:16]([N:18]([CH3:20])[CH3:19])=[CH:17][C:8]=2[CH:7]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH:24]=[CH:25][CH:26]=2)[CH:6]1[OH:35])[CH2:2][CH2:3][CH3:4].[NH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH:49]([C:50]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=3)[CH:48]([CH2:58][CH2:59][CH:60]([OH:67])[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:47]2=[O:68])=[CH:42][CH:41]=1>CN(C)C=O>[CH2:1]([C:5]1([CH2:36][CH3:37])[CH2:11][S:10](=[O:13])(=[O:12])[C:9]2[CH:14]=[CH:15][C:16]([N:18]([CH3:20])[CH3:19])=[CH:17][C:8]=2[CH:7]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N:46]4[C:47](=[O:68])[CH:48]([CH2:58][CH2:59][CH:60]([OH:67])[C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)[CH:49]4[C:50]4[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=4)=[CH:42][CH:41]=3)[CH:24]=[CH:25][CH:26]=2)[CH:6]1[OH:35])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(CN)cc2)cc1
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)CCCCBr)c2)C1O
Solvent: CN(C)C=O
Product: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)CCCCNCc3ccc(N4C(=O)C(CCC(O)c5ccccc5)C4c4ccc(OC)cc4)cc3)c2)C1O
Temperature: 80 °C

Procedure:
100 mg of N-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]-5-bromopentanamide and 70 mg of 1-(4-aminomethylphenyl)-3-(3-hydroxy-3-phenylpropyl)-4-(4-methoxyphenyl)azetidin-2-one are dissolved in 5 ml of dimethylformamide and, with stirring, heated at 80° C. for about 2 to 3 hours. After the reaction has ended (monitored by thin-layer chromatogram or HPLC-MS), the solvent is removed under reduced pressure and the residue is purified by chromatography. This gives product 1 of molecular weight 929.24 (C55H68N4O7S); MS (FAB): 929 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].CN(C=O)C.[C:19](Cl)(=O)[C:20](Cl)=O.C([Zn]CC)C.[Cl-].[NH4+]>C(OCC)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCCC1.ClCCl>[C:11]([C@H:8]1[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1)(=[O:13])[CH2:19][CH3:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC[Zn]CC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(=O)[C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
A dry round bottom flask was charged with trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.00 g, 10.74 mmol) and the reaction vessel was placed under an atmosphere of argon (3× vacuum/argon cycle). Dichloromethane (11 mL) was added followed by DMF (0.01 mL, 0.129 mmol). The reaction was cooled to 0° C. in an ice bath, then oxalyl chloride (1.00 mL, 11.42 mmoles) was added drop-wise. The ice bath was removed after 1 hour and the reaction was stirred at ambient temperature for 14 hours as gradual gas evolution occurred. [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (236.0 mg, 0.322 mmol) was then added to the reaction flask followed by tetrahydrofuran (11 mL) then a solution of diethylzinc in tetrahydrofuran (1.0 M, 12.9 mL, 12.9 mmol). The reaction was stirred at ambient temperature for two hours and was then poured into cold saturated aqueous ammonium chloride (100 mL). The resulting biphasic solution was diluted with diethyl ether (100 mL). The organic phase was separated and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford methyl trans-4-propanoylcyclohexanecarboxylate as a clear oil. 1H NMR (500 MHz, CDCl3) δ 3.67 (s, 3H), 2.47 (q, J=7.3 Hz, 2H), 2.40-2.21 (m, 2H), 2.12-2.00 (m, 2H), 1.94 (d, J=13.9 Hz, 2H), 1.53-1.20 (m, 4H), 1.03 (t, J=7.3 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[N:13][N:12]2[CH:31]=1.[OH-].[Na+].C(N(CC)CC)C.Cl[C:42]([O:44][CH3:45])=[O:43]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([O:29][CH3:30])[C:22]=1[O:27][CH3:28])[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]2[N:12]([CH:31]=[C:9]([NH:8][C:42](=[O:43])[O:44][CH3:45])[N:10]=2)[N:13]=1
Reactant: COC(=O)Cl
Reactant: COc1cc(COc2ccc3nc(N)cn3n2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Nc1cn2nc(OCc3cc(OC)c(OC)c(OC)c3)ccc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 22.9 %

Procedure:
The product of stage (a) (1.0 g, 3.03 mmol) was suspended in dichloromethane and shaken with dilute sodium hydroxide solution. The organic phase was dried (Na2SO4) and evaporated to give a brown oil which was dissolved in dichloromethane and treated, with stirring, with triethylamine (0.42 ml, 3.03 mmol), methyl chloroformate (0.23 ml, 3.03 mmol) and 4-dimethylaminopyridine (18 mg, 0.3 mmol). The mixture was stirred at ambient temperature for 17 h then heated under reflux for 2 h and evaporated in vacuo. The resulting solid was partioned between chloroform and water, the organic phase was separated, dried (Na2SO4) and evaporated to give a solid which was chromatographed on SiO2 eluting with 2% methanol-chloroform. The product was recrystallised from DMF-H2O to give the title compound (0.27 g), mp. 210°-212°, NMR identical to the product of Example 1.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[H-].[Na+].Cl[CH2:18][CH:19]1[CH2:21][CH2:20]1.O>CN(C)C=O.C1COCC1>[CH:19]1([CH2:18][O:1][CH2:2][CH:3]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]2)[CH2:21][CH2:20]1
Reactant: ClCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCC2CC2)C1
Reaction time: 0.75 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (Preparation 65, 46.6 g, 0.232 mol, 1 eq) in anhydrous dimethylformamide (250 mL) was added in portions with stirring and under an atmosphere of argon a dispersion in oil of sodium hydride (11.2 g, 0.28 mol, 1.2 eq) in oil. The mixture was stirred for 45 min and then (chloromethyl)cyclopropane (26 mL, 0.28 mol, 1.2 eq) in anhydrous THF (30 mL) was added. The mixture was stirred for 12 h and then treated with water (100 mL) and extracted with ether (3×200 mL). Ether fractions were washed with water (2×100 mL), dried over sodium sulfate and evaporated. The residue was subjected to chromatography (chloroform/ethylacetate 10:1) on silica to afford title compound (50 g, 0.195 mol, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: Fc1cccc(CBr)c1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-fluoro-4-[4-(furan-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (81) and 3-fluorobenzyl bromide according to General Procedure B. Yield 421 mg (49%), MP 121° C.; 1H-NMR (DMSO-d6): δ 1.27 (t, J=7.2 Hz, 3H), 3.15 (m, 4H), 3.92 (m, 4H), 4.29 (q, J=7.2 Hz, 2H), 5.53 (s, 2H), 6.65 (dd, J=1.6, 3.2, Hz, 1H), 7.05 (m, 4H), 7.33 (m, 1H), 7.87 (d, J=1.6 Hz, 1H), 8.18 (dd, J=2.8, 8.8 Hz, 1H), 8.73 (d, J=2.8 Hz, 1H); EIMS: 523 (M+1). Anal. (C27H24F2N4O5) C, H, N.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH:16](O)[C:15]2[CH:19]=[C:20]([S:22]([NH2:25])(=[O:24])=[O:23])[S:21][C:14]=2[S:13]1(=[O:27])=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:28]([N:30](CC)CC)[CH3:29].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N)C>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH:16]([NH:30][CH2:28][CH3:29])[C:15]2[CH:19]=[C:20]([S:22]([NH2:25])(=[O:24])=[O:23])[S:21][C:14]=2[S:13]1(=[O:27])=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCN1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Reactant: CCN(CC)CC
Agent: CCN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCNC1CN(CCCO[Si](C)(C)C(C)(C)C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of the product of Step D (1.4 g , 3 mmol) and triethylamine (1.7 mL, 12 mmol) in THF (10 mL) at -20° C. was added p-toluenesulfonyl chloride (1.2 g, 6 mmol) and the reaction mixture was stirred at 0° C. for 5 hr. The reaction mixture was cooled to -78° C. at which point ethylamine (10 mL) was added; this mixture was allowed to warm to reflux temperature for 2 hr and then maintained at room temperature for 40 hr. After removing the solvent the crude product was diluted with ethyl acetate (150 mL), washed with water (2×50 mL) and brine (2×50 mL), dried (MgSO4), and evaporated to a syrup which was purified by column chromatography [silica; CH3OH/CH2Cl2 (20:1)] to give 900 mg (64%) as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4](Br)[C:5](=O)[CH2:6][O:7][CH3:8].[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[CH3:1][O:2][C:3]([C:4]1[S:14][C:13]([NH2:15])=[N:12][C:5]=1[CH2:6][O:7][CH3:8])=[O:11]
Reactant: NC(N)=S
Reactant: COCC(=O)C(Br)C(=O)OC
Solvent: CCO
Product: COCc1nc(N)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of the crude product (about 30 mmol) obtained in Step 1 and thiourea (2.28 g) in ethanol (60 ml) was heated under reflux overnight. After cooling to room temperature, the reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. Then, suitable amounts of isopropanol, chloroform, ethyl acetate and diisopropyl ether were added, and the mixture was stirred at room temperature for 30 min. The precipitated crystals were collected by filtration and dried to give the title compound (3.27 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])(=O)=O>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]([C:16]1[CH:17]=[C:18]([OH:23])[C:19]([OH:22])=[CH:20][C:21]=1[Cl:27])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)CN(C(=O)OCc1ccccc1)c1ccc(O)c(O)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CN(C(=O)OCc1ccccc1)c1cc(O)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Benzyloxycarbonyl 3,4-dihydroxyphenylglycine (0.79 g, 2.5 mmole) in acetic acid (10 ml) was treated with sulphuryl chloride (0.2 ml), stirred at room temperature for two hours then diluted with ethyl acetate (50 ml), washed with water (2×3 ml) and brine (20 ml), dried and evaporated to a gum which was crystallized from chloroform, 0.36 g, 41%, mp 141°-143°.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9]([OH:34])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>CN(C)C1C=CN=CC=1.ClCCl>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:35]([C:7]([CH2:5][CH3:6])([CH:9]([O:34][C:44](=[O:46])[CH3:45])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)(CC)C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CN(C)c1ccncc1
Agent: O=[PH](O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)(CC)C(OC(C)=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A stirred solution of diethyl 3-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 24), triethylamine (0.22 g) and 4-dimethylaminopyridine (0.03 g) in dry dichloromethane (10 ml) was treated dropwise with acetic anhydride (0.28 g), whilst maintaining the temperature below 5° C. The mixture was allowed to warm to room temperature, stirred for a further two hours, diluted with dichloromethane, washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (19:1) as eluant, to give diethyl 3-acetoxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.86 g, m.p. 100-102° C.). NMR (CDCl3): δ 1.3(6H,t), 1.65-1.9(2H,m), 2.1(3H,s), 2.2-2.35(2H,m), 4.05(4H,m), 5.9(1H,t), 7.1(6H,m), 7.3(9H,m), 7.9(1H,s). M/S: M+ 547.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][CH:19]=[N:20][C:13]=3[N:12]=[C:11]2[C@H:21]([N:23]([CH:38]2[CH2:43][CH2:42][N:41]([CH:44]([CH3:46])[CH3:45])[CH2:40][CH2:39]2)[C:24](=[O:37])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH3:22])=[CH:6][CH:5]=1)[CH3:2]>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][NH:20][C:13]=3[N:12]=[C:11]2[C@H:21]([N:23]([CH:38]2[CH2:43][CH2:42][N:41]([CH:44]([CH3:45])[CH3:46])[CH2:40][CH2:39]2)[C:24](=[O:37])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([F:35])([F:34])[F:36])[CH:27]=2)[CH3:22])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-n2c([C@@H](C)N(C(=O)Cc3ccc(F)c(C(F)(F)F)c3)C3CCN(C(C)C)CC3)nc3ncccc3c2=O)cc1
Solvent: CO
Product: CCOc1ccc(-n2c([C@@H](C)N(C(=O)Cc3ccc(F)c(C(F)(F)F)c3)C3CCN(C(C)C)CC3)nc3c(c2=O)CCCN3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
F2 (665 mg, 1.09 mmol) was dissolved in methanol and degassed with nitrogen for 5 min. Palladium (10% wt. on C, 665 mg) was added, then the reaction was placed under hydrogen atmosphere with a balloon. The reaction stirred overnight at room temperature, then it was filtered through Celite, and concentrated in vacuo. Purified by reverse-phase HPLC to yield 280 mg of a colorless solid, 5. MS (MH+): 644.5. 1H NMR (400 MHz; CDCl3; T=298 K): δ 7.10 (m, 7H), 5.08 (broad s, 1H), 4.70 (dd, 1H, J=11.2, 5.0 Hz), 4.01 (quint, 2H, 6.8 Hz), 3.67 (broad s, 1H), 3.42 (s, 3H), 3.14 (broad s, 3H), 2.67 (broad m, 3H), 2.55 (t, 3H, J=6.2 Hz), 2.29 (broad s, 2H), 1.90 (dd, 3H, J=5.6, 2.5 Hz), 1.39 (t, 6H, J=6.9 Hz), 1.25 (d, 6H, 6.4 Hz) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12](Cl)=[CH:11][C:10]=2[CH3:16])=[CH:5][CH:4]=1)#[N:2].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[NH:18][NH2:19]>C(O)CCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH:19][NH:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][C:10]=2[CH3:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)NN
Reactant: Cc1cc(Cl)nnc1-c1ccc(C#N)cc1
Solvent: CCCCO
Product: CCOC(=O)NNc1cc(C)c(-c2ccc(C#N)cc2)nn1
Temperature: 25 °C

Procedure:
A mixture of 2.29 g. of 6-(p-cyanophenyl)-5-methyl-3-chloropyridazine and 2.18 g. of ethyl carbazate in 50 ml. of n-butyl alcohol is prepared. This solution is stirred and heated at reflux temperature for 4 hours. The reaction mixture is cooled to room temperature and the solvent removed on a rotating evaporator. Water is added to the residue and the resulting solid filtered, washed with water, ether and dried. The product is recrystallized from ethanol, m.p. 189°-191° C.