Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C@@H:12]([OH:16])[C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(=O)Cc1ccc2c(c1)OCCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)[C@H](O)Cc1ccc2c(c1)OCCO2
Temperature: -35 °C
Reaction time: 4 h

Procedure:
A solution of 12.4 g (23.0 mmol) (1R)—B-chlorodiisopinocampheylborane in 50 mL THF was added dropwise within 30 min to a solution of 4.6 g (20.7 mmol) 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxo-propionic acid and 3.14 mL (23.0 mmol) triethylamine in 150 mL THF cooled to −35° C. and the reaction mixture was kept for 1 h at this temperature and for 4 h at RT. To complete the reaction a solution of 5.0 g (9.3 mmol) (1R)—B-chlorodiisopinocampheylborane in 50 mL THF was added and the reaction mixture was stirred overnight at RT. THF was removed i.vac. and the crude product (2.0 g) was reacted further without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].O.[NH4+].[N:11]#[C:12][S-:13]>Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:12]([NH2:11])=[S:13]
Reactant: Nc1ccccc1Cl
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: NC(=S)Nc1ccccc1Cl
Temperature: 25 °C

Procedure:
2-Chloroaniline (23, 10.52 mL, 100 mmol) was dissolved in conc. HCl (9 mL) followed by H2O (25 mL). The mixture was heated at reflux for 30 minutes then allowed to cool to rom temperature. To this solution was added NH4SCN (7.61 g, 100 mmol) and the mixture was heated at reflux overnight. The reaction was allowed to cool to room temperature and a solid formed. The water layer was decanted off and the solid was dissolved in CH2Cl2 and the organic layer was washed in brine. The organic layer was dried over MgSO4, filtered and evaporated to give a residue, which was purified by flash silica gel chromatography.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:5]([C:7]1[S:11][CH:10]=[N:9][CH:8]=1)=O)[CH2:2][CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>O>[CH2:1]([N:4]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:5]([C:7]1[S:11][CH:10]=[N:9][CH:8]=1)=[S:31])[CH2:2][CH3:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCN(CCOc1ccc(Cl)cc1)C(=O)c1cncs1
Solvent: O
Product: CCCN(CCOc1ccc(Cl)cc1)C(=S)c1cncs1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A mixture of the N-propyl-N-[2-(4-chlorophenoxy)ethyl]thiazole-5-carboxamide (0.9 g, 3 mmol) obtained in Example 2B and Lawesson's Reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide, 1.2g, 3 mmol) was refluxed for 20 hours and then cooled to room temperature. Water (100 ml) was added and the residue was extracted into ether (2×200 ml). The combined organic extract was washed with saturated sodium chloride solution (50 ml) and dried over magnesium sulphate. Evaporation of the solvent left an oil which, after flash chromatography on silica gel using 1:1 ethyl acetate: petroleum ether as the eluant, yielded the desired product as a yellow oil (0.75 g), M+ found: 340
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][N:7]([C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:8]1[CH2:11][CH2:10][CH2:9]1)C>C(OCC)(=O)C.Cl.O>[Cl:21][C:14]1[N:15]=[CH:16][C:17]2[NH:18][C:4](=[O:3])[CH2:5][CH2:6][N:7]([CH:8]3[CH2:11][CH2:10][CH2:9]3)[C:12]=2[N:13]=1
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCN(C2CCC2)c2nc(Cl)ncc2N1
Yield: 66.2 %

Procedure:
A solution of 1.7 g (0.0052 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-propanoic acid ethyl ester (IV-23) in 10 mL of ethyl acetate was added over 1 hour to a suspension of 3.5 g (0.016 mole) of stannous chloride dihydrate in 12 mL of ethyl acetate and 1 mL of hydrochloric acid at ambient temperature. The mixture was stirred for additional hour and then diluted with 30 mL of water, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (80:20-0:100) to give 0.87 g of 2-chloro-9-cyclobutyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-23)
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[C:10]1([CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.[Na+].CC(O)=O>CO>[C:10]1([CH:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][N:1]2[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)C1CCCN(CC(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nipecotic acid (300 mg, 2.38 mmol), diphenylacetaldehyde (1.26 mL, 7.13 mmol), sodium cyanoborohydride (448 mg, 7.13 mmol), and HOAc (204 uL, 3.57 mmol) were dissolved in MeOH (20 mL) and stirred at ambient temperature overnight. The solution was concentrated under reduced pressure, take up in ether and 1N NaOH, extract with ether (3×), acidify the aqueous layer with 1N HCl, and extract with EtOAc (3×). The EtOAc layers were dried (MgSO4) and concentrated to give the title compound without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([Cl:22])[CH:19]=[N:18]2)=[C:13]([Cl:23])[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:25]([O-])C.[Na+].CI>C(O)C>[CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:25])([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([Cl:22])[CH:19]=[N:18]2)=[C:13]([Cl:23])[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reaction time: 4 h

Procedure:
7.38 g (20 mmoles) of 3-chloro-4-(4-chloropyrazol-1-yl)phenylmalonic acid diethyl ester are dissolved in 20 ml of absolute ethanol; a solution of sodium ethanolate in ethanol (consisting of 470 mg of sodium in 20 ml of ethanol) is added; stirring is effected at 40° C. for half an hour and 2.84 g (20 mmoles) of methyl iodide are added. Boiling under reflux is effected for 4 hours; again, 2.84 g of methyl iodide are added, followed by heating for a further 2 hours, concentration, and taking up with diethyl ether. The ethereal phase is washed with sodium hydrogen sulphite solution and water, dried and concentrated. Methyl-[3-chloro-4-(4-chloropyrazol-1-yl) phenyl] malonic acid diethyl ester is obtained.
Reaction SMILES: P([O-])([O-])([O-])=O.[CH3:6][N:7]1[C:12]2[S:13][CH:14]=[C:15]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([F:35])[CH:26]=4)[N:24]=3)=[O:18])[C:11]=2[C:10](=[O:36])[N:9]([CH3:37])[C:8]1=[O:38].[P:39]([O:51][CH2:52]I)([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[H-].[Na+]>CN(C=O)C>[P:39]([O:51][CH2:52][N:24]1[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[C:27]([F:35])[CH:26]=2)=[CH:22][S:21][C:20]1=[N:19][C:17](=[O:18])[CH2:16][C:15]1[C:11]2[C:10](=[O:36])[N:9]([CH3:37])[C:8](=[O:38])[N:7]([CH3:6])[C:12]=2[S:13][CH:14]=1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:40]
Reactant: Cn1c(=O)c2c(CC(=O)Nc3nc(-c4ccc(C(F)(F)F)c(F)c4)cs3)csc2n(C)c1=O
Reactant: CC(C)(C)OP(=O)(OCI)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(CC(=O)N=c3scc(-c4ccc(C(F)(F)F)c(F)c4)n3COP(=O)(OC(C)(C)C)OC(C)(C)C)csc2n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure as described in method A for the preparation of phosphate derivatives by coupling reaction of 2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide (500 mg, 1.004 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (Intermediate 2) (1.22 g, 3.514 mmol) in the presence of sodium hydride (60% dispersion in mineral oil, 60.24 mg, 1.506 mmol) in dry DMF (5 ml) to yield 150 mg of pure product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 1.49 (s, 18H), 3.34 (s, 3H), 3.57 (s, 3H), 4.43 (s, 2H), 6.36-6.44 (m, 2H), 6.79 (s, 1H), 7.33 (s, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.71-7.81 (m, 2H); ESI (m/z): 721 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]2=[O:26])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:27]I.[H-].[Na+].O>CN(C)C=O>[F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[N:17]([CH3:27])[C:16]2=[O:26])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: C#CCn1c(=O)oc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCn1c(=O)oc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 22.2 %

Procedure:
To a solution of 1-[6-fluoro-3-propargyl-2(3H)benzoxazolon-5-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (2.0 g) in dimethylformamide (10 g), methyl iodide (0.5 g) and sodium hydride (0.4 g) were added, and the resultant mixture was heated at 40° to 50° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography to give 1-[6-fluoro-3-propargyl-2(3H) -benzoxazolon-5-yl]-3-methyl -4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (0.3 g ).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][N:14]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C1COCC1>[CH2:27]([N:14]([CH2:13][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:15][CH2:16][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccccc1NC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1NCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a stirred slurry of 11 g of lithium aluminum hydride in 250 ml anhydrous THF under nitrogen was added dropwise a solution of 43.6 g of 2-[bis(phenylmethyl)amino]-N-(2-methoxyphenyl)acetamide in 500 ml anhydrous tetrahydrofuran and stirred overnight at room temperature. After cooling to 0°, the mixture was treated cautiously in succession with 50 ml of water. The granular precipitate was separated by filtration and washed several times with methylene chloride. The filtrate was evaporated to dryness, the residue dissolved in either and the organic phase extracted with 3 N hydrochloric acid. the water phase was made alkaline with 3 N sodium hydroxide and the base extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate and evaporated at reduced pressure. The crude syrup (36.9 g) was chromatographed on silica gel column packed in methylene chloride. Elution with methylene chloride provided N,N-dibenzyl-N'-(2-methoxyphenyl)ethylenediamine (22.8 g) in the form of an oil.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][CH:16]=[C:4]2[CH2:3]1.[Cl:17]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1Cc2cncn2-c2ccccc2C1=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)ncn2-c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5 g (23.5 mmol) of 4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 30 ml of dimethylformamide are treated with 3.20 g (23.5 mmol) of N-chlorosuccinimide and stirred at room temperature for 1.5 hours and at 60° for 10 minutes. The clear brown solution is poured into about 200 ml of water and extracted three times with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on a silica gel column and subsequent recrystallization from ethyl acetate there is obtained 3-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 193°-194°.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C=O)C.[H-].[Na+].I[CH2:45][CH2:46][CH3:47]>O>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:45][CH2:46][CH3:47])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COCCOCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1ccc(-c2ccc3cc(OCOCCOC)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1

Procedure:
3 g (6.1 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid and 100 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. 200 mg (6.7 mmol) of sodium hydride (80% in oil) were added portionwise and stirring was carried out until gas evolution had ceased. 500 μl (6.1 mmol) of iodopropane were then added and the reaction mixture was stirred for one hour. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2.[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][NH:43][C:44]1[S:45][CH:46]=[CH:47][N:48]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][N:43]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)[S:23]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[CH:22][C:13]=2[CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:18]=1)(=[O:24])=[O:25]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)cccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4)cccc3c2)c(OC)c1
Reaction time: 0.5 h

Procedure:
A round-bottom flask was charged with perfluorophenyl 5-(pyrrolidin-2-yl)naphthalene-2-sulfonate 2,2,2-trifluoroacetate (0.234 g, 0.420 mmol), N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.126 g, 0.504 mmol), and THF (4.20 ml) to give a clear solution. The flask was cooled in an dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (0.924 ml, 0.924 mmol) was added dropwise over 30 seconds. The reaction was stirred for 30 minutes, then the cooling bath was removed and the reaction was stirred for 30 minutes. The mixture was diluted with saturated aq. ammonium chloride solution, then extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g, 0 to 10% MeOH/DCM) to give N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide as a white foam. (ESI) 510.2 (M+H)+.
Reaction SMILES: [S:1](=[O:32])(=[O:31])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9]C(C)(C)[O:11]2)[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([S:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)[NH2:2]>FC(F)(F)C(O)=O.O>[S:1](=[O:32])(=[O:31])([O:3][CH2:4][C@H:5]1[CH2:6][C@@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([S:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]=3[CH:17]=[CH:16]2)[C@H:8]([OH:9])[C@@H:12]1[OH:11])[NH2:2]
Reactant: CC1(C)O[C@@H]2[C@@H](COS(N)(=O)=O)C[C@@H](n3ccc4c(Sc5ccccc5)ncnc43)[C@@H]2O1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)OC[C@H]1C[C@@H](n2ccc3c(Sc4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Yield: 0.1 %

Procedure:
{(3aR,4R,6R,6aS)-2,2-Dimethyl-6-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methyl sulfamate (14.4 mg, 30.2 mmol) was stirred in 1.00 mL of 90% trifluoroacetic acid in water for 3 h at rt. The solvent was then removed in vacuo and the resulting oil was purified by silica gel chromatography eluting with a gradient of 60 to 100% EtOAc in hexanes to afford the title compound (7.50 mg, 57%). 1H NMR (400 MHz, CD3OD, δ): 8.45 (s, 1H), 7.66-7.36 (m, 2H), 7.51-7.41 (m, 4H), 5.92 (d, J=3.8 Hz, 1H), 5.13-5.06 (m, 1H), 4.58-4.55 (dd, J=3.8, 9.0 Hz, 1H), 4.42-4.37 (dd, J=8.0, 9.8 Hz, 1H), 4.18-4.14 (m, 2H), 2.92-2.82 (m, 1H), 2.24-2.08 (m, 2H) ppm. LC/MS: Rt=1.38 min, ES+ 437 (FA standard).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([CH:23]=2)[CH2:21][CH2:20][S:19]3)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([CH:23]=2)[CH2:21][CH2:20][S:19]3=[O:32])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(-c2cn3c(n2)S(=O)CC3)cc(C(C)(C)C)c1O
Yield: 77.5 %

Procedure:
In 10 ml of chloroform was dissolved 1.6 g of 6-(3,5-di-tertbutyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole and after adding thereto 1 g of m-chloroperbenzoic acid, the mixture was stirred for 10 minutes. The reaction mixture was washed with an aqueous 5% sodium hydrogen carbonate solution, dried, and then the solvent was distilled off. The crystals thus formed were recrystallized from ethanol to provide 1.3 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole 1-oxide as the 1/2 ethanol addition product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27](=[O:30])(=[O:29])[CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:32]([N:34]1[N:38]=[N:37][C:36]([CH2:39][N:40]2[C:45]3[CH:46]=[C:47]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[S:48][C:44]=3[C:43](=[O:55])[N:42]([CH:56]3[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]3)[C:41]2=[O:62])=[N:35]1)[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:59]4[CH2:60][CH2:61][CH:56]([N:42]5[C:43](=[O:55])[C:44]6[S:48][C:47]([C:49]7[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=7)=[CH:46][C:45]=6[N:40]([CH2:39][C:36]6[N:37]=[N:38][N:34]([CH2:32][CH3:33])[N:35]=6)[C:41]5=[O:62])[CH2:57][CH2:58]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27](=[O:29])(=[O:30])[CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCS(=O)(=O)C[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCS(=O)(=O)C[C@H]21
Reaction time: 12 h

Procedure:
The title compound is prepared analogously as described for example 1 (however, stirring is performed for 12 h at RT) using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-2,2-dioxido-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (330 mg; compound C4), 1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (365 mg; hydrochloride salt of compound B39), HBTU (322 mg), DIPEA (0.65 ml) and DCM (20 ml). The crude product is purified by flash column chromatography [silica gel, eluant: DCM/MeOH, 19/1 (v/v)] to yield the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.O=S(Cl)Cl.[CH3:17]O>>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: Cc1cc(C(=O)O)c(F)cc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)c(Br)cc1F
Temperature: 80 °C

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylbenzoic acid (i-2a) (1.87 g, 8 mmol) in CH3OH (50 mL) at 0° C. was added SOCl2 (6 mL, 80 mmol) dropwise. Then the mixture was heated to 80° C. for 2 h. The solvent was removed in vacuo and the residue was diluted with EtOAc and washed with H2O, brine, dried over anhydrous Na2SO4, and concentrated. The resulting crude solid was washed with PE to give the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, d), 7.37 (1H, d), 3.92 (3H, s), 2.39 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([CH:10]2[O:14][CH:13]([CH2:15][O:16]C(C3C=CC(OC)=CC=3)(C3C=CC(OC)=CC=3)C3C=CC=CC=3)[CH:12]([OH:40])[CH2:11]2)[CH:3]=1.[Si:41](Cl)([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N1C=CN=C1>CN(C=O)C>[Si:41]([C@@:12]1([OH:40])[C@@H:13]([CH2:15][OH:16])[O:14][C@@H:10]([N:4]2[CH:3]=[C:2]([CH3:1])[C:8](=[O:9])[NH:7][C:5]2=[O:6])[CH2:11]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1ccc(C(OCC2OC(n3cc(C)c(=O)[nH]c3=O)CC2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@@](O)([Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
5′-O-Dimethoxytritylthymidine is silylated with 1 equivalent of t-butyldiphenylsilyl chloride (TBDPSCl) and 2 equivalents of imidazole in DMF solvent at room temperature. The 5′-protecting group is removed by treating with 3% dichloracetic acid in CH2Cl2.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:15]4[CH2:18][CH:17]([OH:19])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([O:24]CC)=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:15]4[CH2:16][CH:17]([OH:19])[CH2:18]4)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(O)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC(O)C3)c(F)cc2c1=O
Yield: 100 %

Procedure:
A solution of 0.4 g (1.10 mmoles) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 2 ml of ethanol and 10 ml of 0.5N sodium hydroxide is left to reflux for 1.5 hours. It is then allowed to cool, diluted with water, adjusted to pH 5 and a precipitate is obtained which is filtered and washed with water. The solid is dried under vacuum yielding 0.37 g (100%) of 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at 286°-288° C.