Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:3].C[Si](C)(C)[N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]>C1(C)C=CC=CC=1>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[O:3])=[CH:6][CH:7]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: C[Si](C)(C)N1CCCC1=O
Solvent: Cc1ccccc1
Product: COc1ccc(OC(=O)N2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of 4-methoxyphenyl chloroformate (3.73 g, 20.2 mmol) in anhydrous toluene (10 ml) was added a solution of 1-trimethylsilyl-2-pyrrolidinone (3.46 g, 22.0 mmol) in anhydrous toluene (10 ml). The mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated under reduced pressure to dryness to give a solid material. Recrystallization from ethanol afforded 3.45 g of colorless prisms. Yield 73.4%
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](O)([C:16]1[S:20][N:19]=[CH:18][CH:17]=1)[CH2:11][CH2:10][CH2:9]2>C1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16]1[S:20][N:19]=[CH:18][CH:17]=1)=[CH:11][CH2:10][CH2:9]2
Reactant: OC1(c2ccns2)CCCc2cc(Cl)ccc21
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Clc1ccc2c(c1)CCC=C2c1ccns1
Reaction time: 1.5 h

Procedure:
0.072 ml of thionyl chloride is added at room temperature to a solution of 132 mg of 6-chloro-1-hydroxy-1-(5-isothiazolyl)-1,2,3,4-tetrahydronaphthalene (Example 12) in 0.45 ml of benzene, and the mixture is then stirred at 75° for 1.5 hours. The mixture is concentrated under reduced pressure, 0.156 ml of morpholine is added to the resulting resin, and the mixture is stirred at 75° for 2.5 hours. The black suspension is cooled to 2° and treated with 5N HCl which has likewise been pre-cooled. The pH is then adjusted to 8 with solid NaHCO3 and extraction is carried out with chloroform. The organic phase is separated off, dried over sodium sulfate and concentrated. The crude title compound is purified by column chromatography (SiO2, hexane/ethyl acetate 4:1) and crystallisation from hexane; 1H-NMR (CDCl3): δ(ppm)=2.44 (m,2H), 2.85 (m,2H), 6.37 (t,1H), 7.14 (m, 2H), 7.19 (d,1H), 7.21 (s,1H), 8.49 (d,1H).
Reaction SMILES: C(=O)([O-])O.[Na+].Br[C:7]1[N:11](CC2C=CC(OC)=CC=2)[N:10]=[C:9]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:8]=1[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.Br[C:34]1[C:38]([C:39]2C=CN=CC=2)=C(C2SC(Cl)=CC=2)N(CC2C=CC(OC)=CC=2)N=1.C1(B(O)O)CC1>C(COC)OC.O.C(OCC)(=O)C>[Cl:26][C:23]1[S:22][C:21]([C:9]2[C:8]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)=[C:7]([CH:39]3[CH2:38][CH2:34]3)[NH:11][N:10]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2nc(-c3ccc(Cl)s3)c(-c3ccncc3)c2Br)cc1
Reactant: COc1ccc(Cn2nc(Br)c(-c3ccncc3)c2-c2ccc(Cl)s2)cc1
Agent: O=C([O-])O
Agent: OB(O)C1CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Clc1ccc(-c2n[nH]c(C3CC3)c2-c2ccncc2)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a mixture of sodium hydrogen carbonate (2.0 mmol) and PdCl2dppf:CH2Cl2 1:1 (0.05 eq, 0.03 mmol) under argon, was added a degassed solution of 4-[5-bromo-3-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine and 4-[3-bromo-5-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine (mixture of isomers 2:1, 0.65 mmol) in 10.5 mL dimethoxyethane and 3 mL of water. Cyclopropylboronic acid (1.3 mmol) was then added and the mixture was stirred at 90° C. for 3 h. Further cyclopropylboronic acid was then added (1.3 mmol), and the mixture was stirred overnight at 65° C. After cooling to room temperature, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in 3 mL of trifluoroacetic acid and stirred at 65° C. for 2 h. Water and ethyl acetate were added. And the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with a saturated solution of sodium hydrogen carbonate, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC (Column WATERS Sunfire C18.5 μm 50*150 mm, eluent:water/methanol/0.1% formic acid) to afford 49 mg of 4-[3-(5-chloro-2-thienyl)-5-cyclopropyl-1H-pyrazol-4-yl]pyridine (25% yield).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[CH:3]=1.C([O-])(O)=O.[Na+].[NH2:18][CH2:19][C:20]([OH:22])=[O:21]>CN(C=O)C.O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:18][CH2:19][C:20]([OH:22])=[O:21])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Br)cc1Cl
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CNc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 65 h

Procedure:
To a stirred solution of 4-bromo-2,5-dichloronitrobenzene (1.000 g, 3.691 mmol) in DMF (10.0 mL) at 65° C. was added dropwise a solution of NaHCO3 (0.316 g, 3.76 mmol) and glycine (0.280 g, 3.73 mmol, Aldrich, used as received) in water (3.8 mL). The resulting suspension was stirred at 65° C. for 65 h. The bright orange suspension was then cooled to r.t., filtered, washed with water (1.0 mL) and dried under vacuum to afford 0.284 g (98%, based on recovered starting material) of pure title compound as an orange powder; m.p. 264°-265° C. (decomposed); 1H NMR (DMSO-d6): 3.451 (d, 2H, J=3.9 Hz), 7.199 (s, 1H), 8.130 (s, 1H), 8.793 (t, 1H, J=3.6 Hz).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[C:6]2[C:7](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:8]=[CH:9][C:10]=1[C:11]([O:13]CC)=[O:12])[CH3:3].[OH-].[K+]>C(O)C>[CH2:2]([O:4][C:5]1[C:6]2[C:7](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])[CH3:3]
Reactant: CCOC(=O)c1cnc2nn(C)cc2c1OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(C(=O)O)cnc2nn(C)cc12

Procedure:
28.5 g. of 4-ethoxy-2 -methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, hydrochloride from Example 2 and 15 g. of potassium hydroxide are refluxed in 100 ml. of ethanol for 10 hours. The solvent is then distilled off and the residue is dissolved in 20 ml. of water. Acetic acid is added and a precipitate of 16 g. of 4-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid; m.p. 222°-225° (DMF); is obtained.
Reaction SMILES: C(OC([CH:11]([NH:21][CH3:22])[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=O)C1C=CC=CC=1>CO.[C].[Pd]>[CH3:22][NH:21][CH2:11][CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CNC(CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
In methanol (70 ml) was dissolved tert-butyl 4-[(benzyloxy)carbonyl]−4-methylaminobutyrate (6.06 g), and to the mixture was added 10% palladium-carbon (580 mg). Under hydrogen atmosphere, the mixture was stirred at room temperature for 3 hours, and 10% palladium-carbon was removed. The solvent was evaporated under reduced pressure to give tert-butyl 4-methylaminobutyrate (3.35 g, 98%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH3:17][O:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)[C:20](O)=[O:21]>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:14]=[CH:13][N:12]([C:20](=[O:21])[CH:19]([O:18][CH3:17])[C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:27][CH:28]=3)[N:11]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2cc[nH]n2)cc(OC)c1Br
Reactant: COC(C(=O)O)c1ccc(N2CCOCC2)cc1
Product: COc1cc(-c2ccn(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)n2)cc(OC)c1Br
Yield: 22 %

Procedure:
1-(3-(4-Bromo-3,5-dimethoxyphenyl)-1H-pyrazol-1-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was synthesized from 3-(4-bromo-3,5-dimethoxyphenyl)-1H-pyrazole (prepared according to Journal of Org. Chem., 2003, 68, 5381) and 2-methoxy-2-(4-morpholinophenyl)acetic acid using the analogous procedure as for Example 51 to give 1-(3-(4-bromo-3,5-dimethoxyphenyl)-1H-pyrazol-1-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone as a solid (0.065 g, 22% yield). MS: m/z 516.1 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1>>[OH:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][NH:33][C:28]2[N:27]=[C:26]([C:22]3[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=3)[CH2:19][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:31]=[CH:30][N:29]=2)=[CH:37][CH:38]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)C1CCNCC1

Procedure:
Intermediate 30 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 482. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.4 (d, 1H), δ 8.2 (s, 1H) 8.0 (d, 1H) 7.6 (d, 1H), 7.5 (t, 1H), 7.1 (m, 3H), 6.8 (d, 2H), 4.5 (s, 2H), 3.6 (t, 2H), δ 3.0 (s, 3H), 2.9 (m, 5H), δ 2.8 (t, 2H), 2.0 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH:8]([CH3:13])[NH:7]2.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>O>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[CH2:9][CH:8]([CH3:13])[N:7]3[CH:24]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17](=[O:16])[C:5]([C:6]=23)=[CH:4][CH:3]=1
Reactant: CC1CN(C)c2c(Cl)cccc2N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O
Product: CCOC(=O)c1cn2c3c(c(Cl)ccc3c1=O)N(C)CC2C

Procedure:
A mixture of 0.0765 mole (15 g) of 8-chloro-1,3-dimethyl-1,2,3,4-tetrahydroquinoxaline and 0.0765 mole (16.5 g) of diethyl ethoxymethylenemalonate is heated under a nitrogen atmosphere at 145° to 150° C. for about 75 minutes. The solution is cooled, 70 g of polyphosphoric acid are added and the mixture is heated under nitrogen at 110° to 120° C. for 45 minutes. The hot solution is poured into water with stirring and a white solid precipitates. The product is recrystallized from ethanol to provide ethyl 10-chloro-2,3-dihydro-1,3-dimethyl-7-oxo-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylate, m.p. 259°-261° C. Analyis: Calculated for C16H17ClN2O3 : %C, 60.0, %H, 5.35; %H, 8.75; Found: %C, 60.0; %H, 5.3; %N, 8.9.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7]([CH2:10][CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[OH:44][C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[C:60]3[C:55](=[CH:56][C:57]([O:61][CH2:62][O:63][CH3:64])=[CH:58][CH:59]=3)[S:54][CH2:53][C:52]2([C:66]2[CH:71]=[CH:70][C:69]([O:72][CH2:73][O:74][CH3:75])=[CH:68][CH:67]=2)[CH3:65])=[CH:47][CH:46]=1>O.C1C=CC=CC=1.CN(C)C=O>[CH3:64][O:63][CH2:62][O:61][C:57]1[CH:56]=[C:55]2[C:60]([CH:51]([C:48]3[CH:47]=[CH:46][C:45]([O:44][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7]([CH2:10][CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:8])=[CH:50][CH:49]=3)[C:52]([C:66]3[CH:71]=[CH:70][C:69]([O:72][CH2:73][O:74][CH3:75])=[CH:68][CH:67]=3)([CH3:65])[CH2:53][S:54]2)=[CH:59][CH:58]=1
Reactant: O=S(=O)(CCCCCCl)CCCC(F)(F)C(F)(F)F
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(O)cc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
5-(5-Chloropentylsulfonyl)-1,1,1,2,2-pentafluoropentane (27 mg, 0.082 mmol), potassium carbonate (34 mg, 0.25 mmol) and 18-crown-6 (21 mg, 0.08 mmol) were added to benzene-dimethylformamide (1:1) solution (2 ml) of (3RS,4RS)-4-(4-hydroxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methylthiochroman (37 mg, 0.082 mmol) and then stirred for 8 hours at 100° C. under argon atmosphere. After adding water, the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The crude product thus obtained was purified using silica gel plate (ethyl acetate:hexane=1:2) to obtain 41 mg (yield: 67%) of the title compound.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:18]3[N:19]=[CH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:10]2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Yield: 43.6 %

Procedure:
7-bromo-2-isoquinolin-3-yl-chromen-4-one oxime was prepared using the method D, (step 2) illustrated in example 1C. 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (150 mg, 0.35 mmol) was treated with a 1M solution of titanium tetrachloride (1.1 ml, 1.1 mmol) in dichloromethane (7.5 ml) to yield 7-bromo-2-isoquinolin-3-yl-chromen-4-one oxime (56 mg, 37%) as a beige solid after recrystallization in hot chloroform. The product was isolated as a 90/10 mixture of Z/E oxime isomers.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:4]2([CH:6]([C:7]([O:9]CC)=[O:8])[CH2:5]2)[CH2:3]1.C1(C(OCC)=O)C2(CCCCC2)C1>>[CH3:1][C:2]1([CH3:17])[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:4]2([CH:6]([C:7]([OH:9])=[O:8])[CH2:5]2)[CH2:3]1
Reactant: CCOC(=O)C1CC12CC(C)(C)CC(C)(C)C2
Agent: CCOC(=O)C1CC12CCCCC2
Product: CC1(C)CC(C)(C)CC2(CC2C(=O)O)C1

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 52B for the product from Example 1A. 1H NMR (DMSO-d6, 300 MHz) δ 1.34-1.43 (m, 3H), 1.11-1.19 (m, 4H), 0.95 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.87 (m, 1H), 0.85 (s, 3H), 0.82 (dd, J=4.0, 7.9 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 19.3, 24.9, 25.7, 30.7, 30.9, 31.2, 31.5, 32.0, 32.4, 40.1, 48.7, 51.9, 173.2.
Reaction SMILES: [P:1]([O:33]CC1C=CC=CC=1)([O:25]CC1C=CC=CC=1)([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[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH2:23])=[O:22])[C:16]2=[O:24])[O:6]1)=[O:2]>FC(F)(F)C(O)=O>[P:1]([OH:33])([OH:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]([OH:11])[C@@H:8]([OH:9])[C@H:7]([N:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH2:23])=[O:22])[C:16]2=[O:24])[O:6]1)=[O:2]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COP(=O)(OCc1ccccc1)OCc1ccccc1)O[C@H]2n1ccnc(C(N)=O)c1=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nccn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c1=O
Temperature: 0 °C
Yield: 40.7 %

Procedure:
In 3 mL of 90% aqueous solution of trifluoroacetic acid was dissolved 60 mg of {(3aR,4R,6R,6aR)-6-[3-(aminocarbonyl)-2-oxo-1(2H)-pyrazinyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl dibenzyl phosphate at an ice-cooled temperature. After stirring the solution thus obtained at the same temperature as above for 30 minutes and further at room temperature for 2 hours, the solvent was removed under reduced pressure. Diethyl ether was added to the residue thus obtained, and the solid product was collected by filtration and washed with methanol. Thus, 15 mg of {(2R,3S,4R,5R)-5-[3-(aminocarbonyl)-2-oxo-1(2H)-pyrazinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl dihydrogen phosphate was obtained as a light red-colored solid product.
Reaction SMILES: [CH2:1]([C:5]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH3:24])[CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].N.O1CCCC1>[Ni].CO>[CH2:1]([C:5]1[C:14]([CH2:15][NH2:16])=[C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH3:24])[CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc2nc(CC(C)C)c(C#N)c(-c3ccccc3)c2c1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2nc(CC(C)C)c(CN)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.5 %

Procedure:
To a mixture of 2-isobutyl-6-methoxy-4-phenylquinoline-3-carbonitrile (1.00 g, 3.16 mmol), 25% aqueous ammonia (4 ml), tetrahydrofuran (30 ml) and methanol (50 ml) was added Raney-nickel (1 ml) and the mixture was stirred under a hydrogen atmosphere at 0.5 MPa, room temperature for 6 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized from n-hexane-ethyl acetate to give the title compound (0.44 g, yield 44%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>>[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: Cc1noc(N)c1Br
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1noc(NS(=O)(=O)c2ccc(C(C)C)cc2)c1Br
Yield: 77 %

Procedure:
4-iso-Pro pyl-N-(4-bromo-3-methyl-5-isoxazolyl) benzenesulfonamide was prepared in the same manner as described in Example 30 from 5-amino-4-bromo-3-methylisoxazole and 4-iso-propylbenzenesulfonyl chloride in 77% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 130-133° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[Li].O>CO>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(Cc2ccccc2)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 1-benzyl-1H-pyrazole-4-carboxylate (1.05 g, 3.56 mmol) was dissolved in MeOH (20 ml). Water (10 ml) and LiOH.H2O (0.299 g, 7.11 mmol) were added and the suspension was stirred for 3 h at rt. The reaction mixture was evaporated in vacuum to remove the MeOH. The water phase was washed with AcOEt, then treated with 1N HCl until pH3, and extracted with AcOEt. The organic phase was dried over MgSO4 and evaporated in vacuum to give the title compound which was used in the next step without any further purification. HPLC/MS (Method A) RtA=1.3 min, MS [M+H]+=203.1.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Cl[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:60])=[C:44]([CH:59]=1)[O:45][CH2:46][CH2:47][O:48][Si:49]([CH:56]([CH3:58])[CH3:57])([CH:53]([CH3:55])[CH3:54])[CH:50]([CH3:52])[CH3:51]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:3][CH:2]2[O:1][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([CH3:60])=[C:44]([O:45][CH2:46][CH2:47][O:48][Si:49]([CH:53]([CH3:55])[CH3:54])([CH:56]([CH3:58])[CH3:57])[CH:50]([CH3:51])[CH3:52])[CH:59]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: Cc1ccc(CCl)cc1OCCO[Si](C(C)C)(C(C)C)C(C)C
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc(C)c(OCCO[Si](C(C)C)(C(C)C)C(C)C)c2)cc1

Procedure:
Analogously to Method D, 0.700 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 10f) and [2-(5-chloromethyl-2-methylphenoxy)ethoxy]triisopropylsilane are reacted. The title compound is obtained as a colourless oil. Rf=0.41 (1:2 EtOAc-heptane); Rt=7.94.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27]C)=[O:26])[CH:19]=3)[NH:14]2)=[CH:9][CH:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>CO.O>[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[C:22]([CH3:23])([CH3:24])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=3)[NH:14]2)=[CH:11][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C(C)C)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C(=O)Nc1ccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc1
Yield: 92 %

Procedure:
To a mixture of methyl 2-(4-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (46 mg, 0.12 mmol) in methanol (3 mL) and water (1.5 mL) was added a solution of sodium hydroxide (82 mg, 2.06 mmol.) in water (1.5 mL). The resultant mixture was heated to reflux until the completion of the reaction (monitored by thin layer chromatography). Methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 2-(4-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, 40 mg, 92% yield; MS (ESI+APCI) M+1=367.6.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Cl[CH2:10][CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: OCCCl
Reactant: Oc1ccccc1O
Product: OCCOc1ccccc1O

Procedure:
reaction of catechol with 2-chloroethanol to obtain 2-(2-hydroxyethoxy)phenol of formula: ##STR41## b) reaction of the 2-(2-hydroxyethoxy)phenol obtained in a) with 1,2-dibromoethane to obtain 1,2-bis[2-(2-hydroxyethoxy)phenoxy]ethane and
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]([S:17]([CH3:20])(=[O:19])=[O:18])[C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)#[N:2].[Br:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:28])=[N:26][CH:27]=1.C(N(CC)CC)C>C(O)C.Cl.C(#N)C.[Pt](=O)=O>[Br:21][C:22]1[C:23]([NH:2][CH2:1][CH2:3][CH2:4][CH2:5][N:6]([S:17]([CH3:20])(=[O:19])=[O:18])[C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=2)=[N:24][C:25]([Cl:28])=[N:26][CH:27]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(=O)Nc1cccc(N(CCCC#N)S(C)(=O)=O)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC#N
Product: CC(=O)Nc1cccc(N(CCCCNc2nc(Cl)ncc2Br)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
460 mg (1.56 mmol) of N-{3-[(3-cyano-propyl)-methanesulfonyl-amino]-phenyl}-acetamide in 25 ml of ethanol and 0.5 ml of concentrated HCl are hydrogenated with use of 60 mg (0.26 mmol) of platinum(IV)oxide for 5 hours at room temperature under normal pressure. The batch is filtered and concentrated by evaporation. The residue that is obtained is mixed with a solution of 355 mg (1.56 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 15 ml of acetonitrile. 0.45 ml of triethylamine is added drop by drop, and it is stirred for 16 hours at room temperature. The batch is concentrated by evaporation, and the residue that is obtained is purified by chromatography (DCM/EtOH 95:5). 330 mg (0.67 mmol, corresponding to 43% of theory) of the product is obtained.