Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH:20]=[CH2:21])[C@H:10]([CH2:22][OH:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@@H:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:11]([CH:20]=[CH2:21])[C@H:10]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C[C@H]1[C@H](CO)C[C@H](C(=O)OC(C)(C)C)N1Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C[C@H]1[C@H](CO[Si](C)(C)C(C)(C)C)C[C@H](C(=O)OC(C)(C)C)N1Cc1ccccc1

Procedure:
A solution of (±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-(hydroxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (3.6 g, 11.4 mmole), tert-butyldimethylsilyl chloride (3.7 g, 24.5 mmole) and imidazole (2.8 g, 41.2 mmole) in 60 mL of DMF was stirred at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexanes to provide the title compound, as a colorless oil (yield: 3.5 g, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:18][CH2:17][C:11]3[N:12]=[CH:13][NH:14][C:15](=O)[C:10]=3[CH2:9]2)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:21])=O.ClCCCl.CN(C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:21][C:15]1[C:10]2[CH2:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH2:18][CH2:17][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(N2CCc3nc[nH]c(=O)c3C2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)c1ccccc1
Product: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1

Procedure:
Into a 250 ml round bottom flask was combined 5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidin-4(3H)-one (0.250 g, 0.00103 mol), phosphoryl chloride (0.8 mL, 0.008 mol), and 1,2-dichloroethane (10 mL, 0.1 mol). N,N-Dimethylaniline (0.01 g, 0.0001 mol) was added dropwise and the mixture was heated at reflux for 2 hours. The mixture was reduced in vacuo to yield a dark brown oil. The oil was taken up in methylene chloride (50 ml) and poured over ice. The mixture was carefully neutralized using sat sodium bicarbonate. The layers were separated and the organic was dried over sodium sulfate and reduced in vacuo. The mixture was purified by flash chromatography on silica gel using methylene chloride:methanol (0-10%). The combined pure fractions were reduced in vacuo to yield a bright yellow solid. (0.141 g, 52.4%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:15]2OCC[O:16]2)[CH:11]=[CH:12][C:13]=1[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>S(=O)(=O)(O)O.C(OCC)C>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[F:14])[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2OCCO2)cc1Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccc(F)c(Cc2ccccc2)c1
Reaction time: 16 h

Procedure:
A mixture of 2-(3-benzyl-4-fluorophenyl)-1,3-dioxolane (0.7 g) acetone (10 cm3), water (1 cm3) and concentrated sulphuric acid (5 drops) was stirred for 16 hours. The reaction mixture was poured into diethyl ether and the organic layer washed with sodium bicarbonate solution, water and brine, then dried over anhydrous magnesium sulphate. Evaporation of the solvents under reduced pressure gave 3-benzyl-4-fluorobenzaldehdye (0.59 g), which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl)=[N:2]1.[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:7]([NH:6][C:3]4[N:4]=[CH:5][NH:1][N:2]=4)=[O:14])[CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1nc[nH]n1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc[nH]n1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl 1H-1,2,4-triazol-3-ylcarbamate (265 mg, 0.609 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (300 mg, 1.22 mmol) and diisopropylethylamine (0.106 ml, 1.22 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 8 hours. Water was poured into the reaction mixture. A crystal formed was collected by filtration and recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (61.8 mg, 28.5%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.Cl.[NH:42]([C:44]1[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[N:48][CH:49]=1)[NH2:43].NN>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:42]([C:44]3[CH:49]=[N:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[N:43]=[C:17]([OH:19])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(NN)cn1
Reactant: O=C(O)C#Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: NN
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(-n2nc(O)cc2-c2ccc(OCc3ccccc3)cc2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(4-benzyloxyphenyl)propiolic acid (1 g) and 1-hydroxybenzotriazole hydrate (643 mg) in N-methylpyrrolidone (10 ml) was added WSCD-HCl (912 mg) and the mixture was stirred at room temperature for 10 min. In another flask, diisopropylethylamine (2.31 g) was added to a suspension of 5-hydrazino-2-methoxypyridine dihydrochloride (1.26 g) in N-methylpyrrolidone (4 ml) and stirred at room temperature until all 5-hydrazino-2-methoxypyridine dihydrochloride was dissolved. Thus obtained hydrazine solution was added to the reaction flask and the mixture was stirred at room temperature for 1.5 hrs.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([Zn][C:33]#[N:34])#N.Cl[C:36]1[N:41]=[CH:40][C:39]([OH:42])=[CH:38][C:37]=1[CH3:43]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:42][C:39]1[CH:38]=[C:37]([CH3:43])[C:36]([C:33]#[N:34])=[N:41][CH:40]=1
Reactant: Cc1cc(O)cnc1Cl
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(O)cnc1C#N
Temperature: 110 °C
Reaction time: 21 h
Yield: 36.2 %

Procedure:
A resealable vessel was charged with Pd2dba3 (0.893 g, 0.975 mmol, Strem), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.858 g, 2.090 mmol, Strem), dicyanozinc (1.636 g, 13.93 mmol), and 6-chloro-5-methylpyridin-3-ol (2.00 g, 13.93 mmol, step 3 intermediate 34). The solids were taken up in DMF (45 mL) and the reaction mixture was purged with Argon. The vessel was sealed and heated in a 110° C. oil bath. After 21 h, the reaction was filtered through Celite and the filter cake was rinsed with 5% MeOH-DCM. The filtrate was concentrated and the residue was purified by silica gel chromatography, eluting with 40% to 50% EtOAc-hexane to afford the title compound (676 mg, 32%). MS m/z=135 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:17]([OH:19])=O)=[N:12][CH:13]=[CH:14][C:15]=1[Cl:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([C:24]1[CH:25]=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=1)([CH3:23])([CH3:22])[CH3:21].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH2:31][C:26]1[CH:25]=[C:24]([C:20]([CH3:22])([CH3:21])[CH3:23])[CH:29]=[CH:28][C:27]=1[NH:30][C:17](=[O:19])[C:11]1[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])=[C:15]([Cl:16])[CH:14]=[CH:13][N:12]=1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1c(Cl)ccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2nccc(Cl)c2CO[Si](C)(C)C(C)(C)C)c(N)c1
Temperature: 19 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
A mixture of 160e (20 g, 66 mmol), 4-(tert-butyl)benzene-1,2-diamine 160f (10.8 g, 66 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (30 g, 79 mmol) and diisopropylethylamine (17 g, 132 mmol) in N,N-dimethylformamide (1000 mL) was stirred at 19° C. for 12 h. See FIG. 5. TLC (petroleum ether:ethyl acetate=1:1) showed that the starting material was completely consumed. The mixture was diluted with water (1000 mL) and extracted with EtOAc (1000 mL×2). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate=1:1) to afford N-(2-amino-4-(tert-butyl)phenyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloropicolinamide 160g (20 g, 67%) as a yellow solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=1)[C:29]([C:42](O)=[O:43])=[CH:28]2.[NH2:45][CH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49]>C(Cl)Cl.O>[OH:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][NH:45][C:42]([C:29]1[N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=2)[C:31]2[C:27]([CH:28]=1)=[CH:26][C:25]([Cl:24])=[CH:33][CH:32]=2)=[O:43]
Reactant: Cc1cccc(Cn2c(C(=O)O)cc3cc(Cl)ccc32)c1
Reactant: CC(C)(CN)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(Cn2c(C(=O)NCC(C)(C)CO)cc3cc(Cl)ccc32)c1
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (0.14 g, 0.57 mmol) and 1-hydroxybenzotriazole hydrate (HOBT) (0.1 μg, 0.59 mmol) were added to a solution of 5-chloro-1-(3-methylbenzyl)-1H-indole-2-carboxylic acid (0.20 g, 0.67 mmol) in DCM (10 ml). After stirring for 10 min, 3-amino-2,2-dimethylpropan-1-ol (0.083 g, 0.80 mmol) was added. After stirring for 17.5 h, water (10 ml) was added, the layers separated, the organic phase washed with water (3×15 ml) and dried with magnesium sulfate. Purification was achieved by silica chromatography using DCM:methanol (3:1) as eluent. Crystallisation of the crude product afforded 5-chloro-1-(3-methylbenzyl)-1H-indole-2-carboxylic acid (3-hydroxy-2,2-dimethylpropyl)amide as a white solid (0.100 g, 43%).
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[C:26]([CH3:33])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]2[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:32]2)=[C:26]([CH3:33])[CH:25]=1
Reactant: Cc1cc(Cl)ccc1N=C=S
Reactant: CC(C)C[C@H](N)CO
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc(Cl)ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Chloro-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-Chloro-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-chloro-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:49])[C@@H:24]([NH:25][C:26](=[O:48])[C:27]([C:31]4[N:32]=[C:33]([NH:37]C(OCC5C=CC=CC=5)=O)[S:34][C:35]=4[Cl:36])=[N:28][O:29][CH3:30])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1>[NH2:37][C:33]1[S:34][C:35]([Cl:36])=[C:31]([C:27](=[N:28][O:29][CH3:30])[C:26]([NH:25][C@@H:24]2[C:23](=[O:49])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[CH:18][CH2:19][S:20][C@H:21]23)=[O:48])[N:32]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12)c1nc(NC(=O)OCc2ccccc2)sc1Cl
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(N)sc1Cl
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
To a solution of 7β-[2-(2-carbobenzoxyamino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (216 mg) in anisole (5 ml) is added aluminium chloride (400 mg) under ice-cooling, and the mixture is stirred for 90 minutes at 10° C. The reaction mixture is adjusted to pH 8-9 with 5% aqueous sodium hydrogen carbonate solution, and filtered to remove separated solid. The filtrate is washed with ethyl acetate, acidified with 10% hydrochloric acid to pH 2 and extracted with methyl ethyl ketone. The extract solution is washed with saline, dried over sodium sulfate and concentrated. The obtained residue is solidified with ether, collected by filtration, and washed with ether to give 7β-[2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (93 mg). Yield: 74%.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[C:5]([O:11][CH3:12])[CH:4]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])=[C:5]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc(CBr)ccc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc(CBr)ccc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of (4-bromomethyl-2-methoxy-phenyl)-methanol (1.1 g, 4.76 mmol) in dichloromethane (15 mL) is added imidazole (0.861 g, 5.71 mmol) and tert-butylchlorodimethylsilane (0.971 g, 12.98 mmol) at 0° C. The reaction mixture is allowed to warm to room temperature and stirred for one hour. The reaction mixture is quenched with water and concentrated. The residue is diluted with DCM, washed with water (15 mL) and brine (15 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (1.1 g, 66.9%). 1H NMR (400 MHz, CDCl3) δ 7.43-7.41 (d, J=8 Hz, 1H), 7.00-6.98 (d, J=8 Hz, 1H), 6.94 (s, 1H), 4.73 (s, 2H), 4.50 (s, 2H), 3.83 (s, 3H), 0.95 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][NH:13]C(OC(C)(C)C)=O)[O:6]1)=[O:4].[ClH:21].COC(C1OC(CCCN)=CC=1)=O>>[ClH:21].[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][NH2:13])[O:6]1)=[O:4]
Reactant: COC(=O)C1CCC(CCCNC(=O)OC(C)(C)C)O1
Agent: COC(=O)c1ccc(CCCN)o1
Agent: Cl
Product: COC(=O)C1CCC(CCCN)O1

Procedure:
The title compound was prepared from 5-(3-tert-butoxycarbonylaminopropyl)-tetrahydrofuran-2-carboxylic acid methyl ester following the procedure described in Step C for Preparation 2a.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[NH2:31])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].C(=O)([O-])[O-].[K+].[K+].C1C(=O)N([O:45][C:46]([CH2:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=2)=O)C(=O)C1>O.CS(C)=O>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[NH:31][C:46](=[O:45])[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=1)([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](N)[C@H]1O
Reactant: O=C(CCc1ccc(O)cc1)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](NC(=O)CCc2ccc(O)cc2)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
3'-Amino-3'-deoxyadenosine 5'-triphosphate (6 mg, 11 mmol) and potassium carbonate (7.2 mg, 55 mmol.) were dissolved in 0.8 ml of water. 3-(4-Hydroxyphenyl) propionic acid N-hydroxysuccinimide ester (27 mg, 0.1 mmol) in 0.4 ml of DMSO was added at room temperature, and the mixture was stirred for 24 hours at room temperature. The product was purified by the procedure described for 3'-acetylamino-3'-deoxyadenosine 5'-triphosphate (above); t=14 min (4.3 mg obtained, 41% yield). UV: lmax =259 nm. High resolution MS for C19H24N6O14P3 : calcd. 653.0563, found 653.0596 (MH3-).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].N1C=CC=CC=1.CO>C(Cl)Cl>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:24]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(Cl)c1ccccc1F
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccccc1F
Reaction time: 0.5 h

Procedure:
2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine (1.52 g, 5.84 mmol) was dissolved in DCM (30 mL). To this solution was transferred a solution of 2-fluorobenzoyl chloride in DCM (2 mL), followed by pyridine (7.5 mL). The solution was stirred at r.t. for 2 h when TLC (10% MeOH in DCM) and LC/MS showed that the reaction was complete. The reaction was quenched with polymer bounded diethylenetriamine (4 mmol/g, 1.5 g) and the suspension was stirred for 30 min. Then, 10 mL of DCM was added to the suspension and the suspension was filtered through a Celite pad, rinsed with DCM and 10% MeOH in DCM. The crude product was purified on a silica gel column eluted with 2%, 5% and 7.5% MeOH in DCM to obtain the title compound as a yellow solid, 1.79 g (80%). LCMS: RT=1.53 minutes, MS: 382 (M+H).
Reaction SMILES: BrC1C=C[C:5]([N:8]=C=S)=CC=1.[NH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[OH:20].CCN=C=NCCCN(C)C>C1COCC1>[CH3:18][C:16]1[CH:15]=[C:14]([CH3:19])[C:13]2[O:20][C:5]([NH2:8])=[N:11][C:12]=2[CH:17]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Cc1cc(C)c(O)c(N)c1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: Cc1cc(C)c2oc(N)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 177.5 %

Procedure:
A mixture of 1-bromo-4-isothiocyanatobenzene (63.92 g, 0.298 mol) and THF (1200 mL) was treated with 2-amino-4,6-dimethylphenol (41.8 g, 0.304 mol), stirred at room temperature for 3 hours, treated with EDCI (68.46 g, 0.358 mol), warmed to 40° C. for 16 hours, cooled to room temperature, and filtered. The filtrate was concentrated at 50° C. to a final volume of about 300 mL, treated with acetonitrile (800 mL), concentrated to a volume of about 200 mL, treated with acetonitrile (800 mL), and again concentrated to a volume of about 200 mL. The mixture was treated with acetonitrile (800 mL), cooled to room temperature, and filtered. The filter cake was washed with acetonitrile (100 mL) and dried to constant weight in a vacuum oven at 45° C. over 24 hours to provide 85.8 g (85%) of 5,7-dimethyl-1,3-benzoxazol-2-amine. A mixture of 5,7-dimethyl-1,3-benzoxazol-2-amine (76.4 g, 0.230 mol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (73.9 g, 0.292 mol), potassium acetate (71.5 g, 0.730 mol), and DMF (760 mL) was cycled three times through vacuum degassing and nitrogen purging, treated with Pd(dppf)Cl2.CH2Cl2 (19.9 g, 0.024 mol), sealed, cycled three times through vacuum degassing and N2 purging, heated to 80° C. for 5 hours, and distilled on high vacuum (0.2 mm Hg) at 40° C. to 80° C. to remove DMF. The residue was treated with CH2Cl2 (1300 mL), stirred for 10 minutes, and filtered. The filter cake was washed with CH2Cl2 (300 mL) and the filtrate was concentrated to a volume of about 800 mL. The solution was treated with SiO2 (509 g), stirred for 10 minutes, poured onto a bed of SiO2 (790 g) in a 4 L coarse glass fritted funnel. The SiO2 was washed with 16 L of 15% ethyl acetate and the solution was concentarated at 50° C. The concentrate was treated with heptane (800 mL), concentrated, treated with heptane (900 mL), stirred at 50° C. for 30 minutes, cooled to room temperature over 2 hours, and filtered. The filter cake was washed with 100 mL heptane and dried to constant weight in a vacuum oven at 45° C. over 24 hours to provide 68.3 g (77%) of the desired product. The final product was determined to be 98.2% potency (vs. analytical standard) by HPLC. Rt=6.5 min. HPLC conditions: Zorbax SB-C8 Rapid Resolution (4.6 mm×75 mm, 3.5 um); flow 1.5 mL/min; 5:95 to 95:5 acetonitrile:water (0.1% H3PO4) over 7 minutes.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].CCOCC>O1CCCC1.CN(C)C=O.O>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:20]([CH2:21][CH3:22])[CH2:18][CH3:19])=[O:9])=[CH:10][CH:11]=1
Reactant: CCNCC
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccc(CBr)cc1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
4-Bromomethylbenzoic acid (50 g, 233 mmol) is dissolved in 500 mL of tetrahydrofuran containing a few drops if N,N-dimethylformamide at room temperature under nitrogen and treated dropwise over 1 hour with oxalyl chloride (268 mmol, 34.0 g, 23.4 mL). After the addition, the reaction mixture is stirred for 0.5 hour, at which point the solvent is removed in vacuo. The solid residue is dissolved in 200 mL of tetrahydrofuran and poured into a rapidly stirring solution of diethylamine (536 mmol, 39.2 g, 55.7 mL) in 400 mL of water. After the mixture cools to room temperature, 100 mL of ether are added and the two phases are separated. The organic phase is dried over magnesium sulfate and concentrated in vacuo affording 54.01 g (200 mmol, 86% yield) of the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Na+].[CH2:17]([OH:20])[CH:18]=[CH2:19].Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.Cl[Pd]Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:19][CH2:18][CH:17]=[O:20])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1Cl
Reactant: C=CCO
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=CCCc1ccc(Cl)c(C(=O)O)c1

Procedure:
2-Chloro-5-iodobenzoic acid (5.0 g), tetrabutylammonium chloride (5.0 g), sodium hydrogencarbonate (5.3 g) and allyl alcohol (1.6 ml) were combined in N,N-dimethylformamide (50 ml) and PdCl2 (0.6 g) was added under nitrogen. After 24 h ethyl acetate and 2M hydrochloric acid were added to the crude reaction mixture and the precipitated Pd filtered off. The organic phase was separated and washed thrice with 2M hydrochloric acid then once with brine and dried over magnesium sulfate, filtered and evaporate. Purification by chromatography on silica (eluting ethyl acetate: acetic acid/19:1) gave the subtitled product as an oil (2.77 g).