Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH3:15])([O:3][CH2:4][CH3:5])=[O:2].[H-].[Na+].[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28].[NH4+].[Cl-]>CN(C=O)C>[C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:27]([C:20]1[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=1[CH3:18])(=[O:29])=[O:28])[CH:10]=[C:9]2[CH3:15])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc2[nH]cc(C)c2c1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c(C)cn2S(=O)(=O)c1c(C)cc(C)cc1C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of 5-carboethoxy-3-methylindole (601 mg, 2.96 mmol) in DMF, sodium hydride (178 mg, 4.45 mmol) and 2,4,6-trimethylbenzenesulfonyl chloride (971 mg, 4.44 mmol) were added under cooling with ice, followed by stirring for 30 min. The reaction mixture was mixed with a saturated aqueous NH4Cl solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to remove the solvent; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:5) to give the titled compound (1.02 g, 90%). NMR (method a, CDCl3): δ 1.40 (3H, t, J=7.0 Hz), 2.29 (3H, s), 2.32 (3H, s), 2.52 (6H, s), 4.38 (2H, q, J=6.9 Hz), 6.95 (2H, s), 7.35 (1H, s), 7.41 (1H, d, J=8.9 Hz), 7.90 (1H, dd, J=1.4, 8.9 Hz), 8.24 (1H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:23])[CH:13]=1>CC1(C)NC=NC1=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[N:15]=[C:14]([CH3:23])[CH:13]=[C:12]2[O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: OCc1ccccn1
Agent: CC1(C)NC=NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Product: Cc1cc(OCc2ccccn2)c2cccc(O)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To an ice-cooled solution of 2-hydroxymethylpyridine (164 mg) in anhydrous dimethylimidazolinone (2 ml) was added sodium hydride (40% in oil, 100 mg), and the mixture was stirred at the same temperature for 30 minutes. To this mixture were added 4-chloro-8-hydroxy-2-methylquinoline (194 mg) and tetrabutylammonium iodide (185 mg). The mixture was stirred at 100° C. for 8 hours and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water three times, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography (n-hexane-ethyl acetate) followed by trituration with n-hexane to give 8-hydroxy-2-methyl-4-(2-pyridylmethoxy)quinoline (131 mg) as a pale yellow powder.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:21])[NH:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=[CH:10][C:11]=1O)[CH3:2].C(OCC)(=O)C.[ClH:28].C(=O)([O-])[O-].[K+].[K+]>O>[ClH:28].[ClH:28].[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][C:8]1[CH:9]=[CH:10][C:11]2[O:21][C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]=2[CH:7]=1
Reactant: CCNC(=O)Nc1cc(CCc2ccccn2)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCNc1nc2cc(CCc3ccccn3)ccc2o1
Reaction time: 1 h

Procedure:
A mixture of 2-[2-{3-(3-ethylureido)-4-hydroxyphenyl}ethyl]pyridine (3.3 g) and polyphosphate ester (30 g) was stirred at 110° to 115° C. for one hour. To a reaction mixture was added a mixture of ethyl acetate and water and the resultant mixture was acidified to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 8.0 with aqueous 20% potassium carbonate and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel. The fraction eluted with a mixture of chloroform and methanol (19:1 V/V) was collected and the solvent was evaporated in vacuo. The oily residue was crystallized from 15% hydrogen chloride-ethanol and tetrahydrofuran to give 5-[2-(2-pyridyl)ethyl]-2-ethylaminobenzoxazole dihydrochloride (0.97 g).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:25]=[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[CH:16]=2)=[O:14])=[N:8][CH:7]=1>>[CH2:27]([O:26][C:24]1[C:18]2[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=2[CH:16]=[C:15]([C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:34])=[O:4])=[CH:7][N:8]=2)=[O:14])[CH:25]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCc3ccccc3)c3c(c2)OC(C)(C)C3)nc1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)Cc2c(OCc3ccccc3)cc(C(=O)Nc3ccc(C(=O)O)cn3)cc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
NaOH (110 uL, 0.1 mmol, 3N aqueous solution) was added to a solution of 6-[(4-benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbonyl)-amino]-nicotinic acid methyl ester (77c) (48 mg, 0.11 mol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and purified by reverse phase chromatograph to give a white solid (10 mg, 22% yield). 1H NMR (400 MHz, CD3OD) δ 8.93 (s, 1 H) 8.31-8.41 (m, 1 H) 8.21-8.31 (m, 1 H) 7.47-7.54 (m, 2 H) 7.42 (t, J=7.33 Hz, 1 H) 7.35 (t, J=7.07 Hz, 1 H) 7.23 (s, 1 H) 7.00 (s, 1 H) 5.24 (s, 2 H) 3.06 (s, 2 H) 1.51 (s, 6 H); LCMS for C24H22N2O5 m/z 419.00 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:30])[N:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][CH2:19][CH2:20][CH2:21][OH:22])([CH3:14])([CH3:13])[CH3:12]>ClCCl>[CH2:23]([N:17]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:30])[CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N(CCCCO)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(CCCC=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
A commercially available 2 M solution of oxalyl chloride in DCM solution (13.8 mL of 27.6 mmol), obtained from Aldrich Chemical Co., was diluted with anhydrous dichloromethane (50 mL). The solution was cooled to −78° C., and a solution of dimethyl sulfoxide “DMSO” (4.45 ml 62 mmol) in DCM (10 ml) was added over a 45 min period. After the addition was completed a solution of benzyl-(4-hydroxy-butyl)-carbamic acid tert butyl ester (6.9 g, 25 mmol) in DCM (20 mL) was added was added over a 30 min period resulting in a thick white suspension. The reaction mixture was stirred for an additional 15 min followed by the addition of triethylamine TEA (24 mL) over a 30 min period. The cooling bath was removed and stirring was continued for 1 h. The reaction mixture was quenched with water (200 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 mL). The organic layer was washed with water, brine, and dried over Na2SO4. The crude yellow oil was purified by chromatography using a 8:2 ethyl acetate-hexane mixture as eluent to afford N-benzyl-N-(t-butoxycarbonyl)-4-amino-1-butanal (4.41 g, 63%) as a colorless, viscous oil. 1H NMR δ 9.74 (s, 1H); 7.24-7.36 (m, 5H); 4.41 (bs, 2H); 3.18 (bs, 2H); 2.42 (bs, 2H); 1.66 (bs, 2H); 1.50 (bs, 9H). ELSD/MS: m/z 278 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:23][C:24]([O:26]C)=[O:25])([CH:6]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2].Cl>C(O)(=O)C>[CH2:1]([O:3][P:4]([CH2:23][C:24]([OH:26])=[O:25])([CH:6]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: CCCCCC(=O)CC(CCc1ccccc1)P(=O)(CC(=O)OC)OCC
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCC(=O)CC(CCc1ccccc1)P(=O)(CC(=O)O)OCC
Temperature: 25 °C
Reaction time: 46 h

Procedure:
A solution of the product from part (b) (1.5 g., 3.79 mmole) in glacial acetic acid (5 ml.) is treated with concentrated hydrochloric acid (2.5 ml.) and stirred at room temperature for 46 hours. The mixture is poured onto an ice-water mixture and extracted with ethyl acetate. The ethyl acetate extract is washed with water, saturated sodium chloride solution, dried over Na2SO4 and evaporated. The residue is purified by flash chromatography on silica gel (75 g.) eluting with acetic acid/methanol/dichloromethane (0.5:2.0:100) to give 130 mg. of recovered starting material and 1.2 g. of [ethoxy[3-oxo-1-(2-phenylethyl)octyl]phosphinyl]acetic acid as a colorless glass, Rf (acetic acid/methanol/dichloromethane 0.5:5:100) 0.32.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([CH3:6])[CH:4]=O.[C:7]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH3:6][C:3]1[CH:2]=[N:1][C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:4]=1
Reactant: CC(C=O)=CN
Reactant: O=C1CCCCC1
Product: Cc1cnc2c(c1)CCCC2
Yield: 30 %

Procedure:
The title compound was prepared from commercially available 3-amino-2-methylacrolein and cyclohexanone according to the method of Breitmaier and Bayer (Tet. Letts, 1970, 38, 3291-4) and isolated as a pale yellow oil b.p. 120°/15 mm. (30% yield).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.CC(C)=[O:19].O>[B-](F)(F)(F)F.[Ag+].CO>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[C:5](=[O:7])[CH2:6][CH:2]([OH:19])[CH:3]=1)([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Reactant: CC(C)=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 1.5 h

Procedure:
To a stirred solution of 10.6 g. (ca. 34 mmoles) of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 100 ml. of acetone and 65 ml. of water is added 8.80 g. (45.2 mmoles) of silver fluoborate during 2 minutes. The temperature is maintained at 25°-30° C. by external cooling. The mixture is stirred for 90 minutes, filtered, saturated with sodium chloride, and extracted with ether. The extract is extracted with half saturated sodium bicarbonate solutions. The basic solutions is reacidified with dilute hydrochloric acid, saturated with sodium chloride, and extracted with ether. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by partition chromatography on Celite to give an oil; λmax.MeOH =233 mμ. (7360); νmax.=3380 (hydroxyl groups), 1710 (carbonyl groups), and 1632 cm-1 (olefin group).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14]C)[CH:9]=2)[CH:7]=1.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]#[C:17][Si:18]([CH3:19])([CH3:21])[CH3:20])=[C:6]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)[CH:7]=1
Reactant: COc1cc(-c2cc(Cl)ccc2C#C[Si](C)(C)C)ccn1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: C[Si](C)(C)C#Cc1ccc(Cl)cc1-c1cc[nH]c(=O)c1

Procedure:
550 mg (purity 41%, 0.71 mmol) of 4-{5-chloro-2-[(trimethylsilyl)ethynyl]phenyl}-2-methoxypyridine and 20 eq. of pyridinium hydrochloride were reacted according to General Method 3A. The reaction mixture was concentrated under reduced pressure and water was added to the residue. After addition of ethyl acetate and phase separation, the organic phase was washed once with water, dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, cyclohexane/ethyl acetate and dichloromethane/methanol mixtures). Yield: 141 mg (purity 91%, 59% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][OH:21])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:22][CH3:23])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(NC(C)C)(C)C.[Cl:68][C:69]1[CH:70]=[C:71]([CH:75]=[CH:76][CH:77]=1)[C:72](O)=[O:73]>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:68][C:69]1[CH:70]=[C:71]([CH:75]=[CH:76][CH:77]=1)[C:72]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][OH:21])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:22][CH3:23])=[CH:4][CH:3]=1)=[O:73]
Reactant: CCn1cnc2c(Nc3ccc(N)cc3)nc(NCCO)nc21
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCn1cnc2c(Nc3ccc(NC(=O)c4cccc(Cl)c4)cc3)nc(NCCO)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
62 mg (0.2 mmol) of 6-(4-amino-phenyl-amino)-9-ethyl-2-(2-hydroxy-ethyl-amino)-9H-purine (prepared according to Example 108), 0.18 g (0.4 mmol) of (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), 54 mg (0.4 mmol) of 1-hydroxybenzotriazole (HOBT) and 68 μl of diisopropylamine are stirred in 6 ml of dimethylacetamide at RT for 5 min and then treated with 63 mg (0.4 mmol) of 3-chlorobenzoic acid. After the reaction mixture has been stirred at RT for 30 min, it is diluted with ethyl acetate and washed with water. The crude product is purified by chromatography over silica gel (mobile phase: methylene chloride:methanol=9:1). 6-(4-[3-Chloro-benzoyl-amino]-phenyl-amino)-9-ethyl-2-(2-hydroxy-ethyl-amino)-9H-purine is obtained; FAB-MS: (M+H)+=452; Rf=0.45 (methylene chloride:methanol=9:1).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(=O)C)=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:26]>C(O)(C)C.O>[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:26]
Reactant: CC(=O)Nc1ccc(Nc2nccc(-c3cnc(C)n3C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1ncc(-c2ccnc(Nc3ccc(N)cc3)n2)n1C
Yield: 69 %

Procedure:
Sodium hydroxide (1.2 g, 3.0 mmole) was added to a solution of 4-(1,2-dimethyl-imidazol-5-yl)-2-(4-acetamidoanilino)pyrimidine (Example 164; 1.25 g, 3.88 mmole) in isopropanol (12 mL) and water (0.5 mL) and the mixture heated under reflux for 90 minutes. The mixture was allowed to cool and was partitioned between saturated aqueous sodium hydrogen carbonate solution and EtOAc. The organic layer was separated and the volatiles evaporated. The residue was purified by column chromatography on silica gel eluting with DCM/7M methanolic ammonia (96:4) to give the title compound (0.75 g, 69%) as a brown solid. NMR: 2.33 (s, 3H), 3.85 (s, 3H), 4.75 (brs, 2H), 6.51 (d, 2H), 6.92 (d, 1H), 7.22 (d, 2H), 7.51 (s, 1H), 8.22 (d, 1H), 8.90 (s, 1H); m/z 281.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=1[CH3:15])[CH2:2][CH3:3].[CH3:17][C:18]1[C:23]([CH:24]=O)=[CH:22][N:21]=[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:19]=1.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.C(O)(=O)C>[CH2:1]([O:4][C:5](=[O:16])[NH:6][C:7]1[C:8]([CH3:15])=[CH:9][C:10]([NH:14][CH2:24][C:23]2[C:18]([CH3:17])=[N:19][C:20]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:21][CH:22]=2)=[CH:11][C:12]=1[CH3:13])[CH2:2][CH3:3]
Reactant: CCCOC(=O)Nc1c(C)cc(N)cc1C
Reactant: Cc1nc(-c2ccccc2)ncc1C=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCOC(=O)Nc1c(C)cc(NCc2cnc(-c3ccccc3)nc2C)cc1C
Temperature: 170 °C
Yield: 16.5 %

Procedure:
(4-Amino-2,6-dimethyl-phenyl)-carbamic acid propyl ester (22 mg) and 4-methyl-2-phenyl-5-pyrimidinecarbaldehyde (20 mg) were dissolved in methanol (0.5 mL) and heated to 170° C. for 10 minutes in a sealed microwave process vial. Sodium cyanoborohydride (2 M in methanol, 250 uL) and acetic acid (100 uL) were added and the reaction mixture was heated to 50° C. for 2 hours. Aqueous sodium carbonate (10%, 1 mL) was added, the product was extracted with ethyl acetate (2×1 mL), and the combined organic phases were concentrated in vacuo. The crude product was redissolved in dimethyl sulfoxide (0.5 mL) of which 0.25 mL was subjected to preparative LC-MS purification to furnish 6.6 mg (33% yield) of the title compound as an oil. LC-MS (m/z) 405 (MH+); tR=3.12, (UV, ELSD) 84%, 99%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1.[CH3:19][CH:20]1[O:25][CH:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>C(#N)C>[CH3:26][CH:24]1[CH2:23][N:22]([CH2:2][C:3]2[CH:7]=[CH:6][N:5]([C:8]3[N:18]=[CH:17][CH:16]=[CH:15][C:9]=3[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=2)[CH2:21][CH:20]([CH3:19])[O:25]1
Reactant: CC1CNCC(C)O1
Reactant: CCOC(=O)c1cccnc1-n1ccc(CCl)n1
Solvent: CC#N
Product: CCOC(=O)c1cccnc1-n1ccc(CN2CC(C)OC(C)C2)n1
Yield: 103.3 %

Procedure:
Ethyl 2-(3-(chloromethyl)-1H-pyrazol-1-yl)nicotinate (650 mg, 2.446 mmol), 2,6-dimethylmorpholine (0.482 mL, 3.91 mmol) and K2 CO3 (1082 mg, 7.83 mmol) in acetonitrile (25 mL) were stirred over night at room temperature. The mixture was concentrated, the remaining solid partitioned between 60 mL of water and dichloromethane, the organic layer separated, dried (MgSO4), filtered and concentrated again to yield 870 mg of the title compound as clear oil; ESI-MS [M+H]+: 345.2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:21]([O-])=[O:22].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 41.3 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-n-butyl-3-D-ribofuranosylurea are dissolved in 10 ml of formic acid, and 1.5 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.4 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-ribofuranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[CH:4][C:3]=1[CH:16]([CH3:35])[C:17]([OH:34])([C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][C:28](=[O:31])[N:27]([CH3:32])[C:26]=2[CH:33]=1)[C:18]([F:21])([F:20])[F:19].[C:36]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)([OH:38])=[O:37].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:42]2[CH:43]=[CH:44][C:39]([C:36]([OH:38])=[O:37])=[CH:40][CH:41]=2)=[CH:4][C:3]=1[CH:16]([CH3:35])[C:17]([OH:34])([C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][C:28](=[O:31])[N:27]([CH3:32])[C:26]=2[CH:33]=1)[C:18]([F:19])([F:20])[F:21]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(c1cc(OS(=O)(=O)C(F)(F)F)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(c1cc(-c2ccc(C(=O)O)cc2)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: 80 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
To a suspension of trifluoromethanesulfonic acid 4-chloro-3-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-phenyl ester (100 mg), 4-carboxyphenylboronic acid (48 mg) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]dichloromethane adduct (7.5 mg) in dioxan (0.54 ml) under argon were added water (0.4 ml) and a 2 M aqueous sodium carbonate solution (0.27 ml). The mixture was stirred at 80° C. for 7 h, at 50° C. for 2 days and again at 80° C. for 5 h. The mixture was filtered and to the filtrate was added an aqueous KHSO4 solution. The mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>85:15) to give the title compound (38 mg) as a light brown solid. MS (m/e, ISP neg. ion)=518.2 [M−H+].
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][N:4]=1.[CH3:12][O:13][N:14]=[C:15]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]=O)=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>>[CH3:12][O:13][N:14]=[C:15]1[C:23]2[C:18](=[CH:19][C:20](/[CH:24]=[CH:10]/[C:9]([C:6]3[CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4][CH:5]=3)=[O:11])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CON=C1CCc2cc(C=O)ccc21
Reactant: CSc1ncc(C(C)=O)cn1
Product: CON=C1CCc2cc(/C=C/C(=O)c3cnc(SC)nc3)ccc21
Yield: 28 %

Procedure:
The title compound (2.6 g, 28%) was prepared from the product of Step 1 and the product of Example 1 Step 2 using the method of Example 2 Step 1; MS(ES+) m/e 340 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C>[Si:13]([O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: OCc1cccs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccs1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 110 %

Procedure:
A 100 ml round-bottom flask, equipped with a magnetic stirring bar, septum, and nitrogen inlet, was charged with 500 μl (3.98 mmol, 1.0 equiv) 2-thiophenemethanol and 5 ml DMF (over sieves). This clear solution was cooled down to 0° C. 825 mg (11.95 mmol, 3.0 equiv) imidazole was added in one portion, followed by the addition of 930 mg (5.97 mmol, 1.5 equiv) t-butyldimethylsilyl chloride. The reaction was kept at 0° C. for 5 minutes, warmed up to room temperature to go for half an hour, and then quenched with distilled water. Ethyl acetate was added to dissolve the organics. Layers were separated, and the aqueous layer was extracted with 5×10 ml ethyl acetate. The combined organic portion was washed with 5×20 ml H2O, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on a silica gel column (5 cm×24 cm, 100:1=hexane:ethyl acetate) to afford 1 gram of the title compound: Rf=0.26 (100:1=hexane:ethyl acetate), 1H NMR δ4.87 (s, OCH2), 0.91 (s, tBu), 0.09 (s, CH3).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1(Cl)[NH:10][C:9]([Cl:11])=[CH:8][S:7]1)(=[O:5])=[O:4].[CH:13]([NH2:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH3:1][N:2]([NH:16][CH:13]([CH3:15])[CH3:14])[S:3]([C:6]1[S:7][CH:8]=[C:9]([Cl:11])[N:10]=1)(=[O:5])=[O:4]
Reactant: CC(C)N
Reactant: CNS(=O)(=O)C1(Cl)NC(Cl)=CS1
Solvent: Cc1ccccc1
Product: CC(C)NN(C)S(=O)(=O)c1nc(Cl)cs1

Procedure:
In analogy to Example 5, the N-methyl-2-N-isopropylamino-4-chlorothiazole-sulphonamide was prepared by reacting N-methyl-2,4-dichlorothiazole-sulphomamide from Example 2 with a 65% strength aqueous isopropylamine solution. Following recrystallization from toluene, 89% yield of product of m.p. 135° C. were obtained.