Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[C:17](O)(=[O:19])C>C=O>[CH2:1]([N:5]1[C:9]([CH2:17][OH:19])=[C:8]([CH3:10])[N:7]=[C:6]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCn1cc(C)nc1-c1ccccc1
Agent: C=O
Product: CCCCn1c(-c2ccccc2)nc(C)c1CO

Procedure:
A solution of 112 (1 g) in acetic acid (10 mL) and 40% aqueous formaldehyde (2 mL) is refluxed for 14 h. The reaction is then concentrated and dried by repeated reconcentration with toluene. The residue is purified by column chromatography (10% MeOH/CHCl3). The fractions are assayed by GC and those fractions uncontaminated by the isomeric hydroxymethylimidazole combined. Concentration of the combined fractions provides compound 113 (320 mg) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.4-7.6 (m, 6H), 4.61 (s, 2H, CH2OH), 4.02 (t, J=7 Hz, 2H, NCH2), 2.22 (s, 3H, Me), 1.63 (m, 2H), 1.25 (m, 2H), 0.81 (t, J=7 Hz, 3H). Preparation of 1-(1-Butyl)-2-phenyl-4-methyl-5(N-[3,4-methylenedioxyphenyl-]-N-phenylmethyl)aminomethylimidazole
Reaction SMILES: C[O-].[Na+].[C:4]([Si:8]([CH3:40])([CH3:39])[O:9][CH2:10][C@H:11]([CH2:22][N:23]1[CH:28]=[CH:27][C:26](=[O:29])[N:25](C(=O)C2C=CC=CC=2)[C:24]1=[O:38])[C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13])([CH3:7])([CH3:6])[CH3:5].[Cl-].C([NH+](CC)CC)C>CO>[C:4]([Si:8]([CH3:39])([CH3:40])[O:9][CH2:10][C@H:11]([CH2:22][N:23]1[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]1=[O:38])[C@H:12]([O:14][Si:15]([C:18]([CH3:20])([CH3:21])[CH3:19])([CH3:17])[CH3:16])[CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1ccc(=O)n(C(=O)c2ccccc2)c1=O
Agent: CC[NH+](CC)CC
Agent: C[O-]
Agent: [Cl-]
Solvent: CO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1ccc(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
Sodium methoxide, 25% in MeOH (6 ml) was added to asolution of 41 (8.7 g, 15.9 mmol) in 300 ml of MeOH. The reaction was stirred at 50° C. for 3 hrs, then treated with 5.3 g of solid triethylammonium chloride and concentrated. The obtained residue was partitioned between water and ethyl acetate. The organicphase was washed with saturated NaCl and dried over Na2SO4. Concentration of the extract gave an oil. The oil was chromatographed on silica eluting with 20 to 30% ethyl acetate in hexane to afford a crude product, which was re-crystallized from hexane (˜30 ml) at −20° C. to yield 5.4 g (76%) of 42 as white crystals. 1H NMR (DMSO-d6): δ 11.18 (s, 1H), 7.49 (d, J=7.5 Hz, 1H), 5.51 (d, J=7.5 Hz, 1H), 3.99 (m, 1H), 3.75 (m, 1H), 3.55 (m, 3H), 2.03 (m, 1H), 1.12 (d, J=6 Hz, 3H), 0.84 (s, 18H), 0.02 (s, 6H), 0.00 (s, 6H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)=[O:6].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH2:18]1[CH2:19][O:20][CH:4]([CH2:3][CH2:2][Cl:1])[CH:5]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[O:6]1
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C1CCc2cc(C3OCCOC3CCCl)ccc2N1

Procedure:
10 Grams (39.7 mM) of 6-(4-chlorobutyryl)-3,4-dihydrocarbostyril was dissolved in 300 ml of benzene, then to this solution was added 7.4 g (120 mM) of ethylene glycol and 300 mg of p-toluenesulfonic acid, and the whole mixture was refluxed by heating under dehydrating in Dean-Stark extractor for 6 hours. The reaction mixture was cooled and neutralized with an aqueous solution saturated with sodium hydrogen carbonate, then extracted with chloroform. The chloroform extract was washed with water then dried with anhydrous magnesium sulfate, then concentrated by removing the solvent by evaporation. The residue thus obtained was purified by means of a silica-gel column chromatography (eluent: chloroform:methanol=40:1) to yield 10.5 g of 6-(1-ethylenedioxy-4-chlorobutyl)-3,4-dihydrocarbostyril.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]1[CH2:16][CH2:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)[CH:20]=1.C(N(CC)C(C)C)(C)C.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>C(Cl)Cl>[CH:39]1([C:42]([N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)[CH:20]=2)[CH2:17][CH2:16][N:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=3)[C:2]2=[O:1])=[O:43])[CH2:41][CH2:40]1
Reactant: COC(=O)c1ccc2ccn(CCNc3cccc(-n4cccn4)c3)c(=O)c2c1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2ccn(CCN(C(=O)C3CC3)c3cccc(-n4cccn4)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of methyl 1-oxo-2-(2-{[3-(1H-pyrazol-1-yl)phenyl]amino}ethyl)-1,2-dihydroisoquinoline-7-carboxylate (77 mg, 0.20 mmol) dissolved in methylene chloride (1.5 mL) was added N,N-diisopropylethylamine (69 μL, 0.4 mmol) and cyclopropanecarbonyl chloride (27 μL, 0.30 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was then concentrated to dryness and the residue was purified by flash silica gel chromatography (30% to 100% EtOAc/hexanes) to afford methyl 2-(2-{(cyclopropylcarbonyl)[3-(1H-pyrazol-1-yl)phenyl]amino}ethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (77 mg, 85%). LC-MS: (FA) ES+ 457.
Reaction SMILES: [Cl:1]C1C=C(CO)C=C(Cl)N=1.N1C=CC=CC=1.[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23])([O-:19])=[O:18].S(Cl)(Cl)=O>ClCCl>[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([Cl:1])=[O:23])([O-:19])=[O:18]
Reactant: OCc1cc(Cl)nc(Cl)c1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
1.4 g of 2,6-dichloro-4-pyridinemethanol were dissolved into 5 ml of pyridine, and the solution was cooled by ice. To this, 1.5 g of 2-nitrobenzoyl chloride, which was prepared from 2-nitrobenzoic acid and thionyl chloride, were added dropwise. After the reacted solution was stirred for 2 hours, dichloromethane was added. The organic phase was washed with water, and was dried by adding sodium sulfate. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography to obtain 1.4 g of (2,6-dichloro-4-pyridinyl)methyl 2-nitrobenzoate ester (Compound No. 69).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[CH3:26]O>>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([O:14][CH3:26])=[O:13])=[CH:6][CH:5]=1
Reactant: CO
Reactant: Nc1ccc(CC(C(=O)O)c2cn(C3CCCCC3)cn2)cn1
Agent: Cl
Product: COC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3 ml of an HCl-saturated ether solution were added to a solution of 50.0 mg (0.16 mmol) of the compound from example 1i in 8 ml of methanol and stirred at room temperature for 6 h. The solution was then concentrated to dryness, and the resulting residue was dried under high vacuum. 51 mg of the title compound resulted as bishydrochloride in the form of an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:13][CH:14](O)[CH3:15].OS(O)(=O)=O.[OH-].[Na+].CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>C(OC(=O)C)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH:14]([CH3:15])[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Reactant: CC(C)O
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)/C=C/c1cccc(Br)c1
Yield: 91.7 %

Procedure:
To a solution of (E)-3-(3-bromophenyl)acrylic acid (7.5 g, 32.4 mmol) in propan-2-ol (50 mL, 832 mmol) was added dropwise H2SO4 (0.431 mL, 8.09 mmol). The reaction was heated to reflux for 18 h then it was concentrated in vacuo providing a brown liquid which was redissolved in 50 mL ethylacetate. 1N NaOH was added dropwise until the aqueous mixture reached pH10. The organic layer was collected and washed with aqueous sodium bicarbonate (sat), brine, dried over magnesium sulfate, filtered and concentrated providing (E)-isopropyl 3-(3-bromophenyl)acrylate (8.4202 g, 29.7 mmol, 92% yield) as a yellow liquid. 1H NMR (500 MHz, DMSO) δ 7.98 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.67-7.55 (m, 2H), 7.37 (t, J=7.9 Hz, 1H), 6.70 (d, J=16.0 Hz, 1H), 5.02 (dt, J=12.5, 6.2 Hz, 1H), 1.26 (d, J=6.3 Hz, 6H). Mass spec.: 270.88 (MH)+.
Reaction SMILES: [Cl:1][C@H:2]1[CH2:15][C@@H:14]([O:16]C2CCCCO2)[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:33]C2CCCCO2)[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C(O)C.C(Cl)Cl>[Cl:1][C@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)=CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)=CCC(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](Cl)C[C@H]1O
Temperature: 25 °C
Reaction time: 120 h
Yield: 42 %

Procedure:
A solution of 144 mg of (5Z,13E)-(8R,9S,11R,12R,15S,16RS)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoic acid in 2 ml of absolute ethanol was combined with 6.4 mg of pyridine p-toluenesulfonate and agitated for 5 days at room temperature under argon. The reaction mixture was then diluted with 100 ml of methylene chloride, washed twice with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to dryness under vacuum. The residue was purified by column chromatography on silica gel with hexane/50-100% ethyl acetate as the eluent, thus obtaining 42.5 mg of the desired carboxylic acid as a highly viscous oil.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:17])([CH3:16])[CH2:10][C:11](=[O:15])[NH:12]2)=[CH:7][CH:6]=1)(=O)C.Cl.N>C(O)C>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:17])([CH3:16])[CH2:10][C:11](=[O:15])[NH:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)CC2(C)C
Agent: Cl
Agent: N
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc(N)ccc21

Procedure:
A suspension of 23.2 g. (0.1 mole) 7-acetamido-1,2,3,4-tetrahydro-4,4-dimethylquinolin-2-one, 200 ml. ethanol and 20 ml. concentrated hydrochloric acid is boiled under reflux until dissolving is complete. pH value is then adjusted with ammonia to 8, the reaction mixture is extracted three times with dichloromethane and the organic phase is dried over anhydrous sodium sulphate and freed from solvent. Yield 13.1 g. (69% of theory); m.p. 161°-163° C.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][N:6]([CH2:37][C:38]([O:40]CC)=[O:39])[C:7](=[O:36])[C:8](=[O:35])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+]>CO>[C:38]([CH2:37][N:6]([C:7](=[O:36])[C:8](=[O:35])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:11][CH:10]=1)[CH2:5][C:4]([OH:43])=[O:3])([OH:40])=[O:39]
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)C(=O)c1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN(CC(=O)O)C(=O)C(=O)c1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1
Yield: 88.5 %

Procedure:
A mixture of 1.3 g (2.17 mmol) of N-(2-ethoxy-2-oxoethyl)-N-[1,2-dioxo-2-[4-[(12-phenoxydodecyl)oxy]phenyl]ethyl]glycine ethyl ester and 1.8 ml (10.8 mmol) of 6N NaOH in 125 ml of methanol was stirred at reflux for 3.5 hours. The reaction mixture was cooled in an ice bath and the precipitated sodium salt was filtered. The sodium salt was suspended in water, acidified with 6N HCl and extracted with ethyl acetate. The dried extract was concentrated to a solid which was triturated with hexane and filtered to give 1.04 g (88% yield, mp 130°-132°) of N-(carboxymethyl)-N-[1,2-dioxo-2-[4-[(12-phenoxydodecyl)oxy]phenyl]ethyl]glycine.
Reaction SMILES: [C:1](Cl)(=O)C.[NH2:5][C@H:6]([C:10]([OH:12])=[O:11])[CH2:7][CH2:8][CH3:9]>CO>[CH3:1][O:11][C:10](=[O:12])[C@H:6]([CH2:7][CH2:8][CH3:9])[NH2:5]
Reactant: CCC[C@H](N)C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: CCC[C@H](N)C(=O)OC

Procedure:
To 20 mL of methanol was slowly added 2.6 mL acetyl chloride. Then 2.0 g (17.1 mmole) of L-norvaline was added. The solution was heated to reflux and monitored by thin-layer chromatography (TLC) until complete. The methanol was stripped off by rotary evaporation and the resulting oil was pumped under high vacuum overnight to give the title compound. NMR(300 MHZ, CD3OD): δ 4.03 (t, Nva-α, 1H), 3.81 (s, COOCH3, 3H), 1.87 (m, CH2CH2CH3, 2H), 1.44 (m, CH2CH2CH3, 2H), 0.98 (t, CH2CH2CH3, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:4]=1.[C:20](#[N:22])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:8][N:7]1[C:3]([CH2:2][C:20]#[N:22])=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[N:6]1
Reactant: CC#N
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CC#N

Procedure:
In analogy to the procedure described for example 9 b], 5-chloromethyl-1-methyl-3-(4-trifluoromethoxy-phenyl)-1H-pyrazole was reacted with tetrabutylammonium cyanide in acetonitrile to give [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-acetonitrile as yellow solid.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[CH2:34][C@H:33]([CH3:35])[N:32]([C:36]3[S:37][C:38]([C:42]([OH:44])=O)=[C:39]([CH3:41])[N:40]=3)[C:31]2=[O:45])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[CH2:34][C@H:33]([CH3:35])[N:32]([C:36]3[S:37][C:38]([C:42]([NH2:7])=[O:44])=[C:39]([CH3:41])[N:40]=3)[C:31]2=[O:45])=[CH:27][CH:26]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)O
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(N)=O

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with (S)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 197-198° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.37-7.17 (m, 6H), 4.57-4.51 (m, 1H), 4.42 (d, J=5.4 Hz, 2H), 3.60 (dd, J=9.0, 9.0 Hz, 1H), 3.03 (dd, J=9.0, 3.4 Hz, 1H), 2.46 (s, 3H), 1.38 (d, J=6.2 Hz, 3H); MS (ES+) m/z 348.9 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH2:17][NH:18][NH:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=[O:21])[CH:11]=[CH:10]2)[CH2:4][CH3:5])[CH3:2].S(Cl)([Cl:33])=O>CN(C)C=O.C(OCC)C>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH2:17][NH:18][NH:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([Cl:33])=[O:27])=[CH:24][CH:23]=1)=[O:21])[CH:11]=[CH:10]2)[CH2:4][CH3:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCN(CC)Cc1ccc2cc(CNNC(=O)c3ccc(C(=O)O)cc3)ccc2c1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1ccc2cc(CNNC(=O)c3ccc(C(=O)Cl)cc3)ccc2c1
Yield: 99.3 %

Procedure:
A solution of 4-[6-(diethylaminomethyl)naphth-2-ylmethylaminocarbamoyl]benzoic acid (3.1 g, 7.6 mmol) and thionyl chloride (1.1 ml, 15.2 mmol) in dimethylformamide (30 ml) was stirred overnight at room temperature, then the suspension was diluted with diethyl ether and the solid was filtered and dried yielding 3.2 g of crude 4-[6-(diethylaminomethyl)naphth-2-ylmethylaminocarbamoyl]benzoyl chloride. This compound was added as solid to a solution of hydroxylamine hydrochloride (0.6 g, 8.5 mmol) and sodium bicarbonate (1.2 g, 14 mmol) and 1N sodium hydroxide (8.5 ml, 8.5 mmol) in water (30 ml) and THF (40 ml). The mixture was stirred at room temperature for 2 hours, then the mixture was saturated with sodium chloride and the organic phase was separated and the aqueous phase was extracted with THF. The combined organic phases were dried foyer anhydrous sodium sulphate and the solvent was removed under reduced pressure. Crude was dissolved in hot THF (150 ml) and the insoluble material was filtered off. The solution was cooled at room temperature and treated with 1.5 N etheric solution of HCl. The solid product was filtered and dried yielding 1.2 g (yield 38%) of pure 4-[6-(diethylaminomethyl)naphth-2-ylmethylaminocarbamoyl]-benzohydroxamic acid hydrochloride as white solid; m.p.=167-168° C. (dec.)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1.[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>>[C:17]([O:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(OCc1cc2c3ccccc3[nH]c(=O)n2n1)c1ccccc1
Yield: 85 %

Procedure:
A mixture of 3.0 g (0.014 mole) of 2-(hydroxymethyl)-pyrazolo[1,5-c]quinazolin-5(6H)-one and 100 g of benzoic acid is heated at the point of fusion (140°-145°, silicone oil bath) under nitrogen for 18 hours (using a magnetic stirrer for agitation). The melt is poured into a well stirred solution of 1 molar sodium bicarbonate, the insoluble solid filtered, washed with water and dried to give (3.8 g, 85%) of the title compound, m.p. 262°-265°. An analytical sample is prepared by recrystallizing 0.5 g of this material from dioxane-isopropyl ether, m.p. 270°-272°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[O:15].[NH4+].[Cl-]>CN(C=O)C>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH2:13][N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[C:6]([O:8][CH3:9])=[O:7])=[CH:17][CH:18]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: COC(=O)c1ccc[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1CC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.8 %

Procedure:
To a chilled solution of methyl 1H-pyrrole-2-carboxylate (1.0 g, 8.0 mmol) in dry DMF (20 mL) was added sodium hydride (60% in mineral oil, 320 mg, 8.0 mmol) portionwise. The mixture was stirred at 0° C. for 1 hour before a solution of 2-bromo-1-(4-hydroxyphenyl)ethanone (780 mg, 3.6 mmol) in DMF (5 mL) was added. The resulting yellow solution was allowed to warm to room temperature. After 2.5 hours the reaction was complete (monitored by LCMS). A saturated aqueous solution of NH4Cl (40 mL) was added and the mixture was extracted with EtOAc (1×20 mL). The organic layer was concentrated in vacuo to yield a residue that was purified by flash chromatography using the (Biotage SP4, 40 g cartridge, 0 to 100% EtOAc gradient in hexane) to give methyl 1-[2-(4-hydroxyphenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate as a white solid (810 mg, yield 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1>ClCCl.CO>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][N:8]1[CH2:7][CH2:6][O:5][C:4]1[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCc2ccccc2C1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N)ccc1OCCN1CCc2ccccc2C1

Procedure:
Prepared analogously to Example 3.1.b. from 1.4 g (2.77 mmol) of 2-[2-(2-methoxy-4-nitrophenoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline (65%). Yield: 1.2 g (94% of theory); C18H22N2O2 (M=298.38); calc.: molecular ion peak (M+H)+: 299; found: molecular ion peak (M+H)+: 299; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Br:6][CH2:7][CH:8]([OH:10])[CH3:9]>C(Cl)(Cl)(Cl)Cl>[Br:6][CH2:7][CH:8]([O:10][P:1]([Cl:5])([Cl:3])=[O:2])[CH3:9]
Reactant: CC(O)CBr
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(CBr)OP(=O)(Cl)Cl
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a solution of 46 g of phosphorous oxychloride in 110 ml of carbon tetrachloride was added with stirring 21 g of 1-bromo-2-propanol. The mixture was stirred overnight, the solvent removed and the residue evaporated twice from toluene at 35° C., then evaporated to dryness giving a dark oil. This oil was distilled on a Kugelrohr at 75° C., 0.3 mm giving 16.3 g of the desired compound as a white oil.
Reaction SMILES: P(N)(=O)([O-])[O-].[NH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[C@:20]([CH3:22])([OH:21])[CH2:19][C@@H:18]([CH2:23][OH:24])[O:17]2)=[C:9]([O:25][CH3:26])[N:8]=1.C([Mg]Cl)(C)(C)C.Cl[C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]=1[O:44][P:45](=[N:47][C@@H:48]([CH3:59])[C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[O:46]>C1COCC1>[NH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[O:17][C@H:18]([CH2:23][O:24][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]=3[O:44][P:45](=[N:47][C@@H:48]([CH3:59])[C:49]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[O:50])=[O:46])[CH2:19][C@:20]2([OH:21])[CH3:22])=[C:9]([O:25][CH3:26])[N:8]=1
Reactant: C[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)OCc1ccccc1
Reactant: COc1nc(N)nc2c1ncn2C1O[C@H](CO)C[C@@]1(C)O
Agent: CC(C)(C)[Mg]Cl
Agent: NP(=O)([O-])[O-]
Solvent: C1CCOC1
Product: COc1nc(N)nc2c1ncn2C1O[C@H](COc2ccc3ccccc3c2O[P+]([O-])=N[C@@H](C)C(=O)OCc2ccccc2)C[C@@]1(C)O
Yield: 58.5 %

Procedure:
Using the general procedure for the synthesis of nucleoside 5′-phosphoramidates (Method A), to a solution of (3R,5S)-2-(2-amino-6-methoxy-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-3-ol 100 mg (0.339 mmol) in 5 mL of THF, was added tert-BuMgCl 0.68 mL (0.68 mmol), followed by (2S)-benzyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate 273 mg (0.68 mmol), in 5 mL of THF. After work up and silica gel column chromatography, 131 mg of (2S)-benzyl 2-((((2S,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate was obtained in a 58% yield, as an off-white solid. MS (ES+) m/e: 663.23 (MH+, 100%); Accurate mass: C32H36N6O8P calculated: 663.2332. found 663.2341.