Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])(C(C)(C)C)(C)C.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:27][C:25]1[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3ccn(C)n3)c2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30.9 %

Procedure:
A solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.30 g, 0.74 mmol), 3-fluoro-4-methoxyphenylboronic acid (255 mg, 1.5 mmol), copper (II) acetate (0.202 g, 1.11 mmol), triethylamine (0.517 mL, 3.71 mmol) and freshly activated 4 Å molecular sieves (1 g) in DCM (40 mL) was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered through celite, washed with DCM (2×10 mL), the DCM removed in vacuo. The residue was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate, the organic layer washed with brine, dried (MgSO4) and concentrated in vacuo. 3.5M Hydrochloric acid (0.5 mL) was added to a solution of the residual oil dissolved in methanol (5 mL) and stirred at RT for 20 minutes, then the solution neutralised with saturated sodium bicarbonate. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica, eluting with ethyl acetate, to give the desired compound (95 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:14]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:12][CH:11]3O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[C:43]([O:50][CH3:51])(=[O:49])[CH2:44][C:45]([O:47][CH3:48])=[O:46]>C1COCC1>[CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:14]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:12][CH:11]3[CH:44]([C:43]([O:50][CH3:51])=[O:49])[C:45]([O:47][CH3:48])=[O:46]
Reactant: COC(=O)CC(=O)OC
Reactant: CSc1nccc2c1cc1n2CCC1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C1CCn2c1cc1c(SC)nccc12

Procedure:
To a suspension of 1-(methylthio)-7,8-dihydro-6H-pyrido[3,4-b]pyrrolizin-8-ol (0.54 g, 2.1 mmol) in THF (10 mL) at −78° C. were added 1M NaHMDS in THF (2.35 mL, 2.4 mmol) and diphenyl chlorophosphate (0.53 mL, 2.6 mmol). After a period of 30 min. dimethyl malonate (0.73 mL, 6.4 mmol) and 1M NaHMDS in THF (6.8 mL, 6.8 mmol) were added. The reaction mixture was brought to 0° C. and then to room temperature. The mixture was then partitioned between ETOAc and NH4Cl. The organic phase was dried over MgSO4, filtered and evaporated. The title compound was purified by flash chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]3)[N:9]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C>[F:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:13]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[N:11]=[C:10]([NH:20][CH:21]4[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]4)[N:9]=3)=[CH:4][CH:3]=2)=[O:41])=[CH:35][CH:34]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)C1
Agent: CN(C)c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)nc(N3CCOCC3)n2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (100 mg, 0.23 mmol), 4-fluorophenylisocyanate (63 mg, 0.46 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; Yield 40 mg (30%); (M+H) 565.6
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C-:19]#[N:20].[Na+].[I-].[K+]>[Cu](I)I.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Cc1cccc(Br)c1)NC(=O)OC(C)(C)C
Reactant: [C-]#N
Agent: I[Cu]I
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(Cc1cccc(C#N)c1)NC(=O)OC(C)(C)C
Temperature: 130 °C

Procedure:
To a sealed pressure tube was added [2-(3-bromo-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (1.23 g, 3.9 mmol), sodium cyanide (250 mg, 5.1 mmol), potassium iodide (130 mg, 0.8 mmol), N-N′-dimethylethylenediamine (0.41 mL, 3.9 mmol), and toluene (6 mL). This suspension was then sparged with nitrogen prior to adding copper iodide (150 mg, 0.8 mmol). Reaction mixture heated to 130° C. for 16 h while stirring. Reaction partitioned between ethyl acetate and 30% aqueous ammonia. Organic washed with saturated ammonium chloride, then dried over magnesium sulfate. Reaction reduced to an oil under vacuum and isolated as a white solid after purification on silica. M+1=261.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17][CH3:18])[N:6]([CH2:19][CH2:20][CH2:21]Cl)[C:5]=2[CH:4]=1.[OH:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17][CH3:18])[N:6]([CH2:19][CH2:20][CH2:21][N:29]3[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]3)[C:5]=2[CH:4]=1
Reactant: OCCC1CCNCC1
Reactant: COc1ccc2c(c1)N(CCCCl)c1cccc(SC)c1S2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)N(CCCN1CCC(CCO)CC1)c1cccc(SC)c1S2
Temperature: 120 °C
Reaction time: 6 h
Yield: 71.7 %

Procedure:
A mixture of 2-methoxy-6-methylthio-10-(3-chloropropyl)phenothiazine (9.2 g.), 4-hydroxyethylpiperidine (3.2 g.) and sodium bicarbonate (8.4 g.) in dimethylformamide (90 cc.) is heated at 120°C., with stirring, for 6 hours. The solvent is then evaporated under reduced pressure (0.1 mm.Hg) at 60°C. The residue is taken up in chloroform (80 cc.) and distilled water (80 cc.) and purification of the product is effected by making the medium acidic and then reprecipitating the base by the procedure mentioned in Example 1. 2-Methoxy-6-methylthio-10-[3-(4-hydroxyethylpiperidino)propyl]-phenothiazine (7.9 g.) in the crude state, in the form of an amorphous beige powder, is thus obtained. This powder is taken up in boiling acetonitrile (15 cc.). After cooling of the solution for 7 hours at a temperature of about 20°C., the crystals which have formed are filtered off, washed with acetonitrile (10 cc.) and with diethyl ether (60 cc.) and then dried at 45°C. under reduced pressure (0.05 mm.Hg) for 17 hours. 2-Methoxy-6-methylthio-10-[3-(4-hydroxyethylpiperidino)propyl]-phenothiazine (7.37 g.), melting at 101°-103°C., is obtained.
Reaction SMILES: [O:1]1[C@@H:6]2[CH2:7][N:8](C(OCC3C=CC=CC=3)=O)[CH2:9][C@H:5]2[O:4][CH2:3][CH2:2]1>C1COCC1.[Pd]>[O:1]1[C@@H:6]2[CH2:7][NH:8][CH2:9][C@H:5]2[O:4][CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)N1C[C@H]2OCCO[C@@H]2C1
Agent: [Pd]
Solvent: C1CCOC1
Product: C1CO[C@@H]2CNC[C@H]2O1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of (4aR,7aR)-benzyl tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrole-6(3H)-carboxylate (140.0 mg, 0.53 mmol) and 10% Pd/C (0.56 mg, 0.053 mmol) in THF (6 mL) was stirred for 5.0 h at 50° C. The resulted mixture was filtered. The filtrate was concentrated in vacuo and the residue was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:10](OC(=O)C)(=[O:12])[CH3:11].C(O)(=O)C>O>[C:10]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1N
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To 25 ml of 2,6-xylidine (0.20 mole) was added slowly a mixture of 25 ml of acetic anhydride (0.26 mole) and 25 ml of acetic acid (0.44 mole) under stirring at room temperature. The mixture was stirred for 30 minutes at room temperature and, then, diluted with water. The crystalline precipitate was collected by filtration to give 30.1 g (91%) of the title compound (m.p. 182°-184° C.; colorless needles).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH2:26])[CH:21]1[O:25][CH2:24][CH2:23][CH2:22]1>>[O:25]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:20][NH:26][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCCO1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Product: O=C(Nc1nc2cccc(NCC3CCCO3)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and tetrahydrofurfurylamine (1.0 mL) as a white powder (32 mg, 52%). HPLC, Rt: 2.34 min. (purity 91.7%). LC/MS, M+(ESI): 339.0, M−(ESI): 338.1.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([NH2:44])=[O:43]>C1COCC1>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([CH2:41][C:42]([NH2:44])=[O:43])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: NC(=O)CBr
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) in THF (3 mL) was added potassium carbonate (174 mg, 1.26 mmol) and 2-bromoacetamide (63 mg, 0.46 mmol) and the reaction mixture was stirred at RT for 18 hours. The volatiles were evaporated in vacuo and the residue partitioned between DCM and an aqueous saturated sodium bicarbonate solution. The organic layer was washed with water followed by brine, dried (MgSO4), concentrated in vacuo and the residue purified by flash chromatography (SiO2, 0-5% MeOH in DCM) to give 319 isolated as a cream solid after freeze drying from methanol and water (40 mg, 22%). LCMS: RT=3.03 min, [M+H]+=425. 1H NMR δ (ppm) (DMSO-d6): 8.26 (1 H, d, J=8.18 Hz), 8.05 (1 H, s), 7.20 (1 H, dd, J=8.24, 1.83 Hz), 7.08 (1 H, s), 7.00 (2 H, d, J=1.87 Hz), 5.83-5.73 (1H, m), 4.34-4.28 (2 H, m), 3.69-3.62 (2 H, m), 3.63-3.52 (1 H, m), 3.41-3.35 (2 H, m), 3.21-3.14 (2 H, m), 2.99 (2 H, s), 1.50 (6 H, d, J=6.59 Hz)
Reaction SMILES: [C:1]1(=O)[NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[NH:9]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C1CCCCCCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C1CCCCNCCC1
Reaction time: 5 h
Yield: 90 %

Procedure:
Caprylolactam (Fluka, N.Y., #21631) (25 g, 117 mmoles) is combined with lithium aluminum hydride (10.5 g) in ether and reduced with stirring for 5 hr. The reaction mixture is filtered and evaporated with ether. The product is octahydroazonin (90% yield).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=O)[CH2:3][CH2:2]1.[CH3:14][N:15]([CH3:33])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1>>[CH3:14][N:15]([CH3:33])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][CH:25]=2)[C:11]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:1][CH2:2][CH2:3]2)=[O:13])=[CH:20][CH:21]=1
Reactant: O=C(O)C1CCOc2ccccc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3ccccc32)cc1
Yield: 24.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using chroman-4-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.63 g) as starting materials, N-[(4-dimethylaminophenyl) methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.25 g) was obtained. melting point: 110-112° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][F:6].[Mg].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>>[F:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: OCCCCCCCCCCCCBr
Reactant: FCCCCBr
Agent: [Mg]
Product: OCCCCCCCCCCCCCCCCF

Procedure:
A general procedure for the preparation of terminal fluorinated alkoxyalkyl esters of acyclic nucleoside phosphonates is illustrated in Scheme 7, below. Fluoroalkoxyalkyl esters of acyclic nucleoside phosphonates such as 3-(16-fluorohexadecyloxy)propyl cidofovir (16-F-HDP-CDV) 49 and 3-(16-fluorohexadecyloxy)propyl (S)-HPMPA 50 (16-F-HDP-(S)-HPMPA) can be prepared using this process. Briefly, with reference to Scheme 7, the Grignard reagent prepared from 1-bromo-4-fluorobutane and magnesium is reacted with 12-bromododecanol 44 to obtain 16-fluorohexadecanol 45. Reaction of 45 with methanesulfonyl chloride followed by reaction with 1,3-propanediol provides 16-fluorohexadecyloxy-1-propanol 46. Coupling of 46 with cyclic cidofovir or cyclic (S)-HPMPA as described generally in Example 2 (step a), provides the cyclic esters (47 and 48, respectively) which can then be converted to the desired compounds (49 and 50, respectively) using the general method set forth in Example 2 (step b).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[H-].[Na+].[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>N1C=CC=CC=1.CN(C=O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:16]=2)=[CH:7][C:5]=1[NH:6][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])c(N)c2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])c(NC(=O)c3ccc(OC)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.3 %

Procedure:
A suspension of 102 (599 mg, 2.20 mmol), NaH 60% (141 mg, 3.52 mmol) and 4-methoxybenzoyl chloride (450 mg, 2.64 mmol) in pyridine (5 ml) and DMF (12 ml) was stirred at room temperature during 48 h. The solid was filtered out and rinsed with MeOH to give 584 mg (82%) of the title compound 103 as a yellow solid. 1H NMR: (400 MHz, DMSO) δ (ppm): 10.72 (s, 1H), 8.13-8.08 (m, 3H), 7.96 (d, J=8.8 Hz, 2H), 7.90 (d, J=8.6 Hz, 2H), 7.74 (dd, J=8.6, 2.2 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:13]=[N:12][NH:11][C:10]=2[NH2:14])[CH:4]=1.[CH3:15][O-].[Na+].IC>>[CH3:15][N:12]1[CH:13]=[C:9]([C:5]2[CH:4]=[C:3]([S:2][CH3:1])[N:8]=[CH:7][N:6]=2)[C:10]([NH2:14])=[N:11]1
Reactant: C[O-]
Reactant: CSc1cc(-c2cn[nH]c2N)ncn1
Agent: [Na+]
Solvent: CI
Product: CSc1cc(-c2cn(C)nc2N)ncn1
Reaction time: 0.5 h

Procedure:
To the solution of 4-(6-Methylsulfanyl-pyrimidin-4-yl)-2H-pyrazol-3-ylamine (245 mg, 1.18 mmol) is added with NaOMe solution (25 wt % in MeOH, 425 μL, 1.53 mmol) dropwise. The reaction mixture is kept stirring for 30 minutes. Then Iodomethane (110 uL, 1.76 mmol) is added into the reaction mixture drop wise. After stirring overnight at room temperature, the reaction mixture is concentrated, treated with 75 mL ethyl acetate, and washed with water. Filtration removes the undissolved solid. The obtained filtrate is separated, and the collected organic layer is dried over sodium sulfate, and concentrated. The crude product is purified by ISCO chromatography eluting with ethyl acetate in hexanes from 25% to 100% to afford 1-Methyl-4-(6-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazol-3-ylamine: 1H NMR 400 MHz (d6-DMSO) δ 8.73 (s, 1H), 8.27 (s, 1H), 7.44 (s, 1H), 5.81 (s, 1H), 3.65 (s, 3H), 2.53 (s, 3H); MS m/z 222.07 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)[C:5]([NH:7][C@H:8]([C:18]([O:20]C(C)(C)C)=[O:19])[CH2:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[O:6].FC1C=C(C=CC=1N(CCCl)CCCl)C(N[C@H](C(OC(C)(C)C)=O)CCC(OC(C)(C)C)=O)=O>C(O)(C(F)(F)F)=O>[C:5]([NH:7][C@H:8]([C:18]([OH:20])=[O:19])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:6])[C:4]1[CH:3]=[CH:2][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)c(F)c1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N(CCCl)CCCl)c(F)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC[C@H](NC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Compound (16) (0.10 g, 0.16 mmol), (17) (0.08 g, 0.13 mmol), or (18) (0.06 g, 0.11 mmol) was suspended in TFA (4% w/v) and stirred for 40 min at room temperature. The acid was removed under reduced pressure and the remaining oil was diluted with ethyl acetate (1 ml) which was evaporated. This latter step was repeated 5-6 times. Compound (19); yield (0.09 g, 91%) 3-fluoro, 4-[bis-[2-mesyloxy)ethyl]amino]benzoyl-L-glutamic acid, was obtained as a pure product from (16); 1H NMR (Me2 SO-d6)δ1.99 (m, 2H, CH2CH2CO2H), 2.35 (t, 2H, J=7.45 Hz, CH2CH2CO2H), 3.13 (s, 6H, (CH3 SO3)2), 3.72 (t, 4H,J=5.34 Hz, (CH3SO3CH2 CH2)2), 4.31 (t, 4H, J=5.16 Hz, (CH3SO3CH2 CH2)2), 4.39 (m, 1H, CH), 7.16 (dd, 1H, JH-5,H-6 =8.59, JH-5,F =18.03 Hz, H-5), 7.68 (dd, JH-6,H-5 =8.91, JH-2,F =15.29 Hz, H-2, H-6), 8.45 (d, 1H, J=7.69 Hz, NH); 19F NMR (Me2SO-d6) δ-122.54(m); mass spectrum (FAB) m/z (529[M+H+ ],45) 382 (M-glu, 100); Accurate mass expected 529.0961 found +5.4 ppm; Anal: C18H25N2O11FS2 -0.22TFA-0.21EtOAc requires C-40.47, H-4.74, N-4.90, F-5.51, S-11.21, found C-40.87, H-4.76, N-4.75, F-5.85, S-10.98. (The presence of EtOAc and TFA, noted in the elemental analysis was confirmed by NMR). This compound reacted positively with the Epstein spray reagent.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[N:14]=[C:13](Cl)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1>C(Cl)Cl>[Cl:4][C:5]1[N:14]=[C:13]([NH:2][NH2:3])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: NN
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: ClCCl
Solvent: O
Product: NNc1nc(Cl)nc2ccccc12
Reaction time: 8 h

Procedure:
87 g (1.74 moles) of hydrazine hydrate were added dropwise to a suspension of 86.5 g (0.43 mole) of 2,4-dichloroquinazoline in 1500 ml of methylene chloride at room temperature, while cooling with ice and stirring vigorously. After 8 hours at room temperature, the precipitate was filtered off under suction, washed with water and dried. Yield: 78.4 g (92%) of 2-chloro-4-hydrazinoquinazoline, mp.>280° C.
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[N:6]2[N:5]=1)=[O:3].[C:25](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>>[CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[N:6]2[N:5]=1)=[O:3]
Reactant: Cc1ccc(-c2ccc3cnc(S(C)=O)nn23)c(NS(C)(=O)=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc(-c2ccc3cnc(S(C)=O)nn23)c(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-methyl-phenyl]-methanesulfonamide (530 mg, 1.4 mmol) was dissolved in 20 mL of dry and warm DMF. The solution was cooled (ice bath). Potassium carbonate (0.80 g, 5.8 mmol) in N,N-Dimethylformamide (20 mL, 200 mmol) was added followed by methyl iodide (270 uL, 4.4 mmol). After 18 h, the mixture was stirred at room temperature overnight. The mixture was filtered and the solvent was evaporated. The product was purified by flash chromatography (ISCO, EtOAc to EtOAc: MeOH 90:10). The product, N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-methyl-phenyl]-N-methyl-methanesulfonamide, was obtained as a solid (320 mg, 58%). LCMS (E/I+) 379 (M+H).
Reaction SMILES: Cl.Cl.O[C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9][C:8]=2[N:21]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9][C:8]=2[N:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc2c(n1)CCN(Cc1ccccc1)CC2
Agent: Cl
Product: Clc1ccc2c(n1)CCN(Cc1ccccc1)CC2

Procedure:
Prepared by reacting 2-hydroxy-7-benzyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine dihydrochloride with phosphorus oxychloride at 140° C.
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[CH2:10]([NH2:13])[CH:11]=[CH2:12].CC(N=NC(C#N)(C)C)(C#N)C>C(O)CCC>[CH2:1]([P:3]([CH2:12][CH2:11][CH2:10][NH2:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: C=CCN
Reactant: CCCCOP([O-])CC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCO
Product: CCCCOP(=O)(CC)CCCN
Yield: 65.1 %

Procedure:
150 g (1 mol) of butyl ethylphosphonite (produced as in Example 2) and 68.4 g (1.2 mol) of allylamine are initially charged in 200 ml of butanol in a four-neck round-bottom flask equipped with stirrer, reflux condenser, thermometer and nitrogen inlet, and heated. At about 100° C., in the course of 1 h, 98.4 g of a 5% solution of AIBN in butanol are added dropwise, whereafter the solvent is distilled off in vacuo. Chromatographic purification yields 135 g (65% of theory) of butyl ethyl(3-aminopropyl)phosphinate.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C@H:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:14][C:15]1[C:29]([NH:30][C:31]2[C:34](=O)[C:33](=[O:36])[C:32]=2[O:37]C)=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([CH2:19][NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18]>CO>[OH:14][C:15]1[C:29]([NH:30][C:31]2[C:32](=[O:37])[C:33](=[O:36])[C:34]=2[NH:13][C@@H:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([CH2:19][NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18]
Reactant: Cc1ccc([C@H](N)C2(C)COC2)o1
Reactant: COC(=O)CNCC(=O)c1cccc(Nc2c(OC)c(=O)c2=O)c1O
Solvent: CO
Product: COC(=O)CNCC(=O)c1cccc(Nc2c(N[C@@H](c3ccc(C)o3)C3(C)COC3)c(=O)c2=O)c1O
Temperature: 60 °C
Yield: 78 %

Procedure:
A mixture of 371 mg (2.07 mmol, 1.2 eq) of C—(R)-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine (prepared in EXAMPLE 50, steps 1 to 4) and 600 mg (1.7 mmol, 1 eq) of methyl {[2-hydroxy-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzoyl]methylamino}acetate in 24 ml of methanol was heated at 60° C. for 16 hours. The methanol was evaporated off and the residue was chromatographed on silica gel, eluent dichloromethane/ethyl acetate (75/25). The paste obtained was crystallized from diethyl ether and heptane and dried under vacuum at 40° C. 660 mg of methyl {[2-hydroxy-3-(2-{[(R)-(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzoyl]methylamino}acetate were obtained in the form of a pale yellow solid. Yield=76%.