Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([N:29]1[CH:34]=[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:32](=[O:54])[CH:31]=[C:30]1[CH2:55]O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[BrH:1].[CH2:22]([N:29]1[CH:34]=[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:32](=[O:54])[CH:31]=[C:30]1[CH2:55][Br:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrBr
Reactant: CCCCCCCCCCCCCCCCCCOc1cn(Cc2ccccc2)c(CO)cc1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Br
Product: CCCCCCCCCCCCCCCCCCOc1cn(Cc2ccccc2)c(CBr)cc1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5.1 mL (0.1 mole) Bromine are added dropwise at ambient temperature, while stirring, to a solution of 26.5 g (0.1 mole) triphenylphosphine in 600 mL anhydrous toluene, a white crystalline precipitate thereby being formed. After further stirring for 20 minutes at ambient temperature, 48.17 g (0.1 mole) 1-benzyl-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone are added thereto in portions. Thereafter, the reaction mixture is stirred for 2 hours at 70° C., cooled and the precipitated product is filtered off, washed with toluene, dried and recrystallized from propan-2-ol, pale beige crystals being obtained; m.p. 92°-95° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.C(N(CC)CC)C.[Cl:13][CH:14]([Cl:31])[C:15]([NH:17][CH:18]1[C:29](=[O:30])[N:20]2[C:21]([C:26]([OH:28])=[O:27])=[C:22]([CH3:25])[CH2:23][S:24][C@H:19]12)=[O:16]>C(Cl)(Cl)Cl>[CH3:1][Si:2]([O:28][C:26]([C:21]1[N:20]2[C:29](=[O:30])[CH:18]([NH:17][C:15](=[O:16])[CH:14]([Cl:31])[Cl:13])[C@H:19]2[S:24][CH2:23][C:22]=1[CH3:25])=[O:27])([CH3:5])[CH3:4]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
Trimethylchlorosilane(0.5 ml) and triethylamine (0.17 ml) were added to a solution of 7-dichloroacetamido-3-methyl-3-cephem-4-carboxylic acid(325 mg) in chloroform (12 ml). The reaction mixture was stirred at 10°C. overnight to afford a chloroform solution of 7-dichloroacetamido-3-methyl-3-cephem-4-carboxylic acid trimethylsilyl ester. The resulting solution was added dropwise at -50°C. to a mixture prepared from phosphorus pentachloride(220 mg), quinoline(0.15 ml) and chloroform (15 ml). The reaction mixture was stirred at -50°C. for 3 hours and diluted with dry tetrahydrofuran(20 ml). To this solution was added a methanol solution of lithium methoxide prepared from lithium(150 mg) and methanol(15 ml) a -78°C. The mixture was stirred at -78°C. for 30 minutes and treated with acetic acid(1.5 ml). The solution was poured into water and extracted with chloroform. The extracts were washed with water, dried(Na2SO4) and evaporated under reduced pressure. The residue was dissolved in a small amount of chloroform, to which was added excess hexane to precipitate the desired substance. This process was repeated three times to give 240 mg of 7β-(2'-chloro-1'-methoxyethylidenimino)-7α-methoxy-3-methyl-3-cephem-4-carboxylic acid. NMR(CDCl3) δ ppm: 2.05(3H, singlet), 3.03 and 3.43(2H, AB-quartet, J=18 Hz), 3.40(3H, singlet), 3.75(3H, singlet), 4.18 and 4.53(2H, AB-quartet, J=12 Hz), 5.00(1H, singlet).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=O.Cl.[C:26]1([C@:32]2([OH:53])[CH2:40][CH2:39][C:38]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:37]3[C@H:33]2[CH2:34][NH:35][CH2:36]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl>[C:26]1([C@:32]2([OH:53])[CH2:40][CH2:39][C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C@@H:37]3[C@H:33]2[CH2:34][NH:35][CH:36]3[C:22](=[O:24])[CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O[C@@]1(c2ccccc2)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)C1NC[C@@H]2[C@H]1C(c1ccccc1)(c1ccccc1)CC[C@@]2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
0.28 g of carbonyldiimidazole is added to a solution of 0.28 g of (2-methoxyphenyl)acetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred at room temperature for 1 hour and a suspension of 0.7 g of (3aS,4S,7aS)-4,7,7-triphenylperhydroisoindol-4-ol hydrochloride in 20 cm3 of dry dichloromethane and then 0.48 cm3 of triethylamine are subsequently added in succession. The reaction mixture is stirred at room temperature for 24 hours, diluted with 100 cm3 of dichloromethane, washed with 100 cm3 of water (twice) and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 16 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting fractions of 20 cm3. Fractions 7 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 16 cm3 of acetonitrile. The crystals are filtered off and dried. 0.3 g of (3aS,4S,7aS)-4,7,7-triphenyl-2-(2-methoxyphenyl)acetylperhydroisoindol-4-ol is obtained in the form of white crystals which melt at 236° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:31][O:32][C:33]1[N:38]=[C:37]([C:39]([NH:41][NH2:42])=O)[CH:36]=[CH:35][CH:34]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:39]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([O:32][CH3:31])[N:38]=3)=[N:41][N:42]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: COc1cccc(C(=O)NN)n1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2nnc3n2CCN(C(=O)c2ccc(Cl)c(F)c2Cl)C3)n1
Reaction time: 18 h
Yield: 78.6 %

Procedure:
4-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(0.25 g, 0.859 mmol) was dissolved in Dichloromethane (DCM) (2.147 ml) and triethyloxonium tetrafluoroborate (0.196 g, 1.031 mmol) was added. The solution was left to stir under an argon atmosphere for 18 hours. 6-(Methyloxy)-2-pyridinecarbohydrazide (I95) (0.172 g, 1.031 mmol) was added and the solution was left to stir under argon for a further 60 minutes. The Dichloromethane was removed under reduced pressure and 1-butanol (2.147 ml) was added and the reaction mixture was left at reflux for 3 hours. LCMS showed the product had formed so the solvent was removed under reduced pressure and the crude material was purified by flash chromatography (Biotage Isolera 4, 25 g cartridge) with a gradient of methanol 0-10% in Dichloromethane. The solvent was removed under reduced pressure to afford 0.285 g of material that was further purified using MDAP. The solvent was removed to afford the purified desired product in 0.108 g.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=1)=[C:5]([CH3:26])[C:6]([N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[N:7]2.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=1)=[C:5]([CH3:26])[C:6]([N:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Temperature: 0 °C

Procedure:
The tert-butyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)-quinolin-2-yl)piperazine-1-carboxylate (32 mg, 0.059 mmol) was dissolved in DCM (1.0 mL) and cooled to 0° C. The trifluoroacetic acid (1.00 mL, 13.0 mmol) was then added and the reaction mixture was allowed to slowly warm to rt over a period of 1 h. The reaction was then cond to dryness. The crude TFA salt was treated with satd sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the filtrate was cond to give 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 7.85 (1H, d, J=2.5 Hz), 7.63 (1H, d, J=2.2 Hz), 7.23 (1H, ddd, J=10.2, 2.5, 1.4 Hz), 6.79 (1H, d, J=12.9 Hz), 6.71 (1H, ddd, J=13.9, 8.8, 2.5 Hz), 6.49 (1H, t, J=2.3 Hz), 3.70-3.83 (4H, m), 3.19-3.32 (4H, m), 3.03-3.12 (4H, m), 2.92-3.03 (4H, m), 2.00 (3H, s). Mass Spectrum (ESI) m/e=441.2 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[H-].[Na+].CS([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]2[CH2:35][C@@H:34]([C:36]3[CH:47]=[CH:46][C:39]4[O:40][C:41]([CH3:45])([CH3:44])[O:42][CH2:43][C:38]=4[CH:37]=3)[O:33][C:32]2=[O:48])=[CH:25][CH:24]=1)(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:44][C:41]1([CH3:45])[O:40][C:39]2[CH:46]=[CH:47][C:36]([C@H:34]3[O:33][C:32](=[O:48])[N:31]([CH2:30][CH2:29][C:26]4[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][O:19][CH2:11][C:8]5[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=5)=[CH:24][CH:25]=4)[CH2:35]3)=[CH:37][C:38]=2[CH2:43][O:42]1
Reactant: CC(C)Oc1ccc(CO)cc1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOS(C)(=O)=O)cc4)C(=O)O3)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(COCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)cc1
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
A solution of (4-isopropoxyphenyl)methanol (93 mg) in DMF (2 ml) was treated with sodium hydride (27 mg) under nitrogen and stirred for 0.5 h. To this was added the 2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethyl methanesulfonate (357 mg) {Example 15 i)} and the resulting solution was stirred for 18 h under nitrogen. The solution was then diluted in EtOAc, washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (Biotage, 40 g) eluting with 40-60° C. petroleum ether-EtOAc (2:1) to give the title compound (156 mg). LCMS RT=3.76 min.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:33])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:19]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:15]=2)[N:10]=[C:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]([CH3:37])=O.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[C:1]([NH:5][C:6](=[O:33])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH:35]([CH3:37])[CH3:34])[CH2:21][CH2:20]3)[CH:15]=2)[N:10]=[C:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCCNCC3)cc2c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCCN(c2ccc3nc(-c4cccc(Cl)c4)n(CC(=O)NC(C)(C)C)c(=O)c3c2)CC1
Yield: 47 %

Procedure:
N-tert-Butyl-2-[2-(3-chlorophenyl)-4-oxo-6-perhydro-1,4-diazepin-1-yl-4H-quinazolin-3-yl]acetamide (EXAMPLE 1a) (17 mg, 0.03 mmol), anhydrous acetone (30 μL), sodium cyanoborohydride (3 mg, 0.03 mmol) and glacial acetic acid (12 μL, 0.21 mmol) in anhydrous THF (0.15 mL) was heated in a microwave at 130° C. for 10 minutes. The resulting mixture was purified by preparative TLC on silica gel with DCM:MeOH:NH4OH (40:2:1, v/v) as eluent to give N-tert-butyl-2-[2-(3-chlorophenyl)-6-(4-isopropylperhydro-1,4-diazepin-1-yl)-4-oxo-4H-quinazolin-3-yl]acetamide (EXAMPLE 5a) (7.1 mg, 0.014 mmol, 47%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[NH2:25][CH2:26][CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:24][C:12]1[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:25][CH2:26][CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:23])=[CH:19][CH:20]=2)=[CH:14][C:9]([NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCNS(C)(=O)=O)cc1
Yield: 90.1 %

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (30 mg, 0.093 mmol), N-(2-aminoethyl)methylsulphonamide (12.9 mg, 0.093 mmol), HATU (35.5 mg, 0.093 mmol), HOBT (12.6 mg, 0.093 mmol) and DIPEA (481 μl, 0.28 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum gave N-[6-methyl-4′-({[2-(methylsulphonylamino)ethyl]amino}carbonyl)-1,1′-biphenyl-3-yl]-3-furamide (37 mg, 90%). NMR; δH [2H6]—DMSO 9.91,(1H, s), 8.59,(1H, t), 8.35,(1H, s), 7.92,(2H, d), 7.78,(1H, t), 7.66,(1H, dd), 7.59,(1H, d), 7.45,(2H, d), 7.27,(1H, d), 7.17,(1H, t), 6.98,(1H, m), 3.40,(2H, q), 3.13,(2H, q), 2.91,(3H, s), 2.19,(3H, s). LCMS: retention time 2.82 min, MH+442.
Reaction SMILES: Cl.[CH3:2][O:3][C@@H:4]([C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)[C@@H:5]([CH3:17])[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([NH:40][C:41]([CH3:66])([C:43]([NH:45][C@H:46]([C:50]([N:52]([C@@H:54]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:55]([O:60][CH3:61])[CH2:56][C:57](O)=[O:58])[CH3:53])=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44])[CH3:42])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([NH:40][C:41]([CH3:66])([C:43]([NH:45][C@H:46]([C:50]([N:52]([C@@H:54]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:55]([O:60][CH3:61])[CH2:56][C:57]([N:19]3[CH2:20][CH2:21][CH2:22][C@H:18]3[C@H:4]([O:3][CH3:2])[C@@H:5]([CH3:17])[C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:58])[CH3:53])=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44])[CH3:42])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)NCCc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 18 h
Yield: 19.5 %

Procedure:
To a solution of #24 (104 mg, 0.256 mmol, 1 eq.) in dichloromethane (10 mL, 0.094 M) were added #32 (156 mg, 0.256 mmol, 0.9 eq.), diisopropylethylamine (135 μL, 0.768 mmol, 3 eq.) and HATU (120 mg, 0.307 mmol, 1.2 eq.). After stirring for 18 hours, the mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (10 mL), washed with 1 M aqueous hydrochloric acid solution (2×5 mL) and with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was diluted with dichloromethane and filtered. The filtrate was concentrated under reduced pressure onto silica and purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to give #55 (44 mg, 19%) as a white solid. LC-MS: m/z 884.5 [M+2H+], retention time=1.04 minutes.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Cl[CH2:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1>C(#N)C.CN(C)C=O>[CH2:1]([NH:5][CH2:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CCCCN
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCNCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
Butylamine (30 mL, 300 mmol) was dissolved in 150 mL of acetonitrile at room temperature. 2-Chloromethylbenzimidazole (5 g, 30 mmol) dissolved in 50 mL dimethylformamide was added dropwise. After stirring 3 hours at room temperature, the solvent was removed in vacuo. The residue was dissolved in 100 mL ethyl acetate and washed 2×100 mL H2O followed by 1×100 mL brine. The organic layer was dried over MgSO4, filtered, and then concentrated. The residue was purified by silica gel chromatography eluting first with ethyl acetate then with 10/2/1 ethyl acetate/methanol/triethylamine to yield 2.6 g 2-butylaminomethylbenzimidazole.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]3[N:17]=[CH:18][CH:19]=[C:20]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:15]3=[N:14][C:13]=2[CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[CH:8][CH:7]=1)[C:3]([O-:5])=O.ClC(Cl)(Cl)[C:41]([N:43]=C=O)=[O:42].O>ClCCl.C(O)C>[O:24]1[CH2:23][CH2:22][N:21]([C:20]2[C:15]3[N:16]([C:12]([C:9]4[CH:10]=[CH:11][C:6]([CH:2]5[O:1][C:41](=[O:42])[NH:43][C:3]5=[O:5])=[CH:7][CH:8]=4)=[C:13]([CH2:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[N:14]=3)[N:17]=[CH:18][CH:19]=2)[CH2:26][CH2:25]1
Reactant: O=C([O-])C(O)c1ccc(-c2c(CCc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: O=C1NC(=O)C(c2ccc(-c3c(CCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cc2)O1
Temperature: 25 °C

Procedure:
A solution of compound 50c (0.15 g, 0.29 mmol) and 2,2,2-trichloroacetyl isocyanate (81 mg, 0.43 mmol) in dichloromethane (10 mL) was stirred at rt for 30 min and concentrated in vacuo. The residue obtained was dissolved in ethanol (10 mL), and TEA (87 mg, 0.86 mmol) was added. The reaction mixture was heated at reflux for 2 h and allowed to cool to rt. Water (10 mL) was added. The solids formed were collected by filtration and washed with Et2O (2×20 mL) to obtain the title compound 70 as a yellow solid. 1H-NMR (300 MHz, DMSO-d6+D2O) δ (ppm): 8.17 (d, J=8.4 Hz, 1H), 8.00 (d, J=5.4 Hz, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.70 (t, J=7.8 Hz, 1H), 7.54-7.48 (m, 3H), 7.37-7.31 (m, 3H), 6.27 (d, J=5.7 Hz, 1H), 5.27 (s, 1H), 3.90-3.73 (m, 4H), 3.68-3.56 (m, 4H), 3.34-3.28 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C30H26N6O4: 535.2 (M+H). Found: 535.2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[O:14]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][CH:4]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCC(=O)c1ccc(Sc2ccccc2)cc1
Temperature: 110 °C
Yield: 75.5 %

Procedure:
4-(4-Fluoro-phenyl)-4-oxo-butyric acid (10.0 g, 51 mmol), thiophenol (5.2 g, 51 mmol) and powdered potassium carbonate (13.8 g, 100 mmol) were added to 25 mL of dimethyl sulfoxide (DMSO). The reaction mixture was heated to 110° C. for 2 hours, then cooled and diluted by addition of 250 mL water. The aqueous mixture was extracted three times with 100 mL of EtOAc, and the combined organic layers were dried (MgSO4), and evaporated under reduced pressure to yield 11 g (38.5 mmol, 75.5%) of 4-oxo-4-(4-phenylsulfanyl-phenyl)-butyric acid as a crude solid. MS: 287 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[CH2:3][CH2:2]1.[OH:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH:21]3[NH:28][CH3:29])[CH2:19]1)[CH2:25]2>>[OH:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH:21]3[N:28]([CH3:29])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([O:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:9]=3)[CH2:19]1)[CH2:25]2
Reactant: CNC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)c1cccc(OC2CCOCC2)c1
Product: CN(C(=O)c1cccc(OC2CCOCC2)c1)C1C2CC3CC1CC(O)(C3)C2

Procedure:
Prepared from 3-(tetrahydro-pyran-4-yloxy)-benzoic acid and 1-hydroxy-4-methylaminoadamantane. LC-MS (m/z): 387 (M+2).
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[O:14])[C@H:9]([OH:20])[C@@H:8]1[OH:21])([OH:4])([OH:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[P:34]([O:46][CH2:47][C@H:48]1[O:52][C@@H:51]([N:53]2[CH:60]=[CH:59][C:57](=[O:58])[NH:56][C:54]2=[O:55])[C@H:50]([OH:61])[C@@H:49]1[OH:62])([O:37][P:38]([O:41][P:42](O)([OH:44])=[O:43])([OH:40])=[O:39])(=[O:36])[OH:35].C([NH+](CCCC)CCCC)CCC>CN(C=O)C.C(N(CCCC)CCCC)CCC>[OH:4][P:1]([O:5][P:42]([O:41][P:38]([O:37][P:34]([OH:36])([OH:46])=[O:35])([OH:40])=[O:39])([OH:44])=[O:43])(=[O:2])[OH:3].[C@@H:10]1([N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[O:14])[O:11][C@H:7]([CH2:6][OH:5])[C@@H:8]([OH:21])[C@H:9]1[OH:20].[C@@H:51]1([N:53]2[CH:60]=[CH:59][C:57](=[O:58])[NH:56][C:54]2=[O:55])[O:52][C@H:48]([CH2:47][OH:46])[C@@H:49]([OH:62])[C@H:50]1[OH:61]
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: CCCC[NH+](CCCC)CCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: O=P(O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)O
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
Uridine 5′-monophosphate (Sigma, Milwaukee, 3.0 g, 9.26 mmol) was dissolved in dry DMF (10 mL) and tributylamine (Aldrich, 2 mL). The solution was evaporated in vacuo at 40° C. to an oil. The residue was dissolved in dry DMF (Aldrich, 8 mL) to form a solution. Carbonyldiimidazole (Aldrich, 1.65 g, 10.18 mmol) was added to this solution. The reaction was heated at 50° C. for one hour. Uridine 5′-triphosphate (Yamasa, 5.60 g, 10.18 mmol) prepared as the anhydrous tributylammonium salt in DMF (5 mL) and tributylamine (2 mL), as described in Example 3 below, was added to the reaction solution. The mixture was allowed to stir at 50° C. for three days when the solution was evaporated in vacuo to an oil, redissolved in water (5 mL) and purified by column (300×50 mm) chromatography (Sephadex DEAE-A25, 40–120μ, Aldrich, pre-swollen in 1.0 M NaHCO3 and washed with 2 column volumes of deionized H2O (H2O→0.30 M NH4HCO3 gradient). The pure fractions were concentrated in vacuo at 35° C., and H2O added and reevaporated 5 times to obtain diuridine tetraphosphate tetrammonium salt as a white solid (2.37 g, 30% yield): 92.11% pure by HPLC with the same retention time as the standard. In addition, the tetrammonium salt was analyzed by FABMS to give a mass of [C18H25N4O23P4 (M-H+)−: calculated 788.9860] 788.9857, confirming a parent formula of C18H26N4O23P4 for the free acid].