Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N:23]3[CH2:24][CH2:25][O:20][CH2:21][CH2:22]3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(N2CCOCC2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(N2CCOCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-morpholinobenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.72 min.; [M+H]+: 411.21 g/mol.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([S:31](=[O:36])(=[O:35])[N:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:37]([O:39]C)=[O:38])=[CH:20][C:19]=3[CH:41]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:26]=[CH:27][C:28]([S:31](=[O:35])(=[O:36])[N:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:37]([OH:39])=[O:38])=[CH:20][C:19]=3[CH:41]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(S(=O)(=O)N(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc(S(=O)(=O)N(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
In methanol (50 ml) and THF (50 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34 g). To the solution was added 1N sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature at 60° C. for 1 hour, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.33 g) as yellow crystals.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:7][C:8]1[C:13]([CH2:14]Br)=[CH:12][CH:11]=[CH:10][N:9]=1.O>CN(C)C=O>[Br:7][C:8]1[C:13]([CH2:14][O:4][CH:1]([CH3:3])[CH3:2])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: CC(C)O
Reactant: BrCc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OCc1cccnc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of isopropyl alcohol (7.31 mL, 95.65 mmol) in dimethylformamide (50 mL) at 0° C. is added sodium hydride (3.63 g, 90.87 mmol) and the mixture is stirred at room temperature for 30 minutes (this reaction is run using a shield as special protection). Then, 2-bromo-3-bromomethyl-pyridine (6 g, 23.91 mmol) in 10 mL of dimethylformamide is added via syringe and the mixture is stirred at room temperature for 1 h. Water is added and the mixture is extracted with ethyl acetate, washed with brine and water, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude material is purified by normal phase Isco chromatography using ethyl acetate and hexane as eluent (gradient of 5 to 25% of ethyl acetate) to yield 3.67 g of the title compound. MS (m/z): 230, 232 (M+1, M+3)
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C@H:17]1[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]1=[O:28])[CH2:12][CH2:11][CH2:10]2>CCOC(C)=O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C@H:17]1[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:26][CH:27]=3)[C:18]1=[O:28])[CH2:12][CH2:11][CH2:10]2
Reactant: O=S(=O)(O)Cl
Reactant: O=C1[C@@H](N2CCCc3cc(Cl)ccc32)CCN1c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1[C@@H](N2CCCc3cc(Cl)ccc32)CCN1c1ccc(S(=O)(=O)Cl)cc1
Temperature: 50 °C
Yield: 61 %

Procedure:
Prepared using general procedure 62: To chlorosulfonic acid (15 mL, 220 mmol) at 0° C. under N2 was added (S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-1-phenylpyrrolidin-2-one (2.43 g, 7.4 mmol) in portions. The reaction mixture was heated to 50° C. for 15 min. and, after cooling to RT, carefully poured onto ice-water (500 mL). EtOAc (150 mL) was added, the phases were separated, and the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic extracts were dried over MgSO4 and concentrated. Purification via silica gel chromatography using 50-80% EtOAc in hexane gave 4-((S)-3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-benzene-1-sulfonyl chloride as an off-white solid (1.92 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ 7.66 (dd, J=2.1, 6.8 Hz, 2H), 7.61 (dd, J=2.1, 6.8 Hz, 2H), 6.99 (d, J=9.0 Hz, 2H), 6.77 (d, J=8.7 Hz, 1H), 5.01-4.96 (m, 1H), 3.85-3.81 (m, 2H), 3.17 (t, J=5.6 Hz, 2H), 2.70 (t, J=6.4 Hz, 2H), 2.42-2.32 (m, 1H), 2.15-2.08 (m, 1H), 1.92-1.79 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=425.1; tR=4.03 min
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([CH:8]1[CH2:18][CH:17]2[N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:10]([CH2:11][C:12]3[NH:13][N:14]=[CH:15][C:16]=32)[CH2:9]1)=O)C>C1COCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:19]2[CH:10]3[CH2:9][CH:8]([CH2:6][OH:5])[CH2:18][CH:17]2[C:16]2[C:12]([CH2:11]3)=[N:13][NH:14][CH:15]=2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2Cc3n[nH]cc3C1CC(CO)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Lithium borohydride (17 mg, 0.80 mmol) was added to a solution of 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid ethyl ester (8) (328 mg, 0.80 mmol) in THF (3 mL). The resulting solution was stirred at room temperature for 18 h then heated to 60° C. for 2 h. The reaction was quenched by the addition of water (5 mL) and the resulting mixture was extracted with EtOAc (3×5 mL). The combined organic phases were dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography (eluant hexane/EtOAc, 9/1 to 1/1) and preparative HPLC to give [12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2,5-dien-10-yl]-methanol (10) as a white solid. Retention time (min)=1.242, method [1], MS (ESI) 368.0 (M+H); 1H NMR (CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.58 (s, 1H), 7.38 (d, J=8.2 Hz, 2H), 5.33 (s, 1H), 4.48 (d, J=7.1 Hz, 1H), 3.41 (d, J=2.7 Hz, 2H), 3.08 (dd, J=17.6, 7.7 Hz, 1H), 2.62 (d, J=17.6 Hz, 1H), 1.81-1.54 (m, 5H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][NH:20][N:19]=1.C([BH3-])#N.[Na+]>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][NH:17][C:18]2[C:22]([C:23]([OH:25])=[O:24])=[CH:21][NH:20][N:19]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1n[nH]cc1C(=O)O
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(CNc2n[nH]cc2C(=O)O)cc1OC1CCCC1
Yield: 48 %

Procedure:
The condensation of 3-cyclopentyloxy-4-methoxybenzaldehyde with 3-amino-4-pyrazolecarboxylic acid in the presence of sodium cyanoborohydride produces 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-pyrazolecarboxylic acid in 48% yield. Treatment with excess borane-tetrahydrofuran complex in tetrahydrofuran solution gives 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole (Example 1) in 40% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:26][NH2:27]>>[C:15]1([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:26][NH2:27])[N:7]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: NN
Reactant: Clc1nccc(N2CCC[C@@H]2COc2cccc3ccccc23)n1
Solvent: O
Product: NNc1nccc(N2CCC[C@@H]2COc2cccc3ccccc23)n1
Yield: 88.7 %

Procedure:
480 mg of 2-chloro-4-[(R)-2-(naphthalen-1-yloxymethyl)pyrrolidin1-yl]pyrimidine are warmed at 80° C. for 6 h with 5 g of hydrazine hydrate, giving 420 mg of {4-[(R)-2-(naphthalen-1-yloxymethyl)pyrrolidin1-yl]pyrimidin-2-yl}hydrazine;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:10][C:11](=O)[CH3:12])[CH3:9])[CH:3]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:11]([CH3:12])=[N:10][C:8]([CH3:9])=[C:4]2[CH:3]=1
Reactant: CC(=O)NC(C)c1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1nc(C)n2ccc(Br)cc12

Procedure:
N-(1-(4-bromopyridin-2-yl)ethyl)acetamide (2.28 g, 9.38 mmol) was suspended in anhydrous benzene (20 mL), then phosphorus oxychloride (2.2 mL, 23.6 mmol) was added and the reaction heated to reflux for 3 hours. The crude reaction was then added portion-wise to 1M potassium carbonate solution (60 mL) and stirred until gas evolution ceased. The pH was then adjusted to pH 10 with potassium carbonate. The aqueous layer was extracted with DCM (50 mL×2), the organic were combined, dried over Na2SO4, and concentrated to afford the product, which was used without further purification. LCMS-ESI+: calc'd for C9H10BrN2: 225.1 (M+H+); Found: 225.05 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[CH:6][C:7]1[S:8][C:9]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=1)[CH3:2]>CO.[Pd]>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH2:12][C:9]1[S:8][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])=[CH:11][CH:10]=1)[CH3:18]
Reactant: CCOC(=O)C=Cc1ccc(C=CC(=O)OCC)s1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc(CCC(=O)OCC)s1
Reaction time: 1 h
Yield: 100.5 %

Procedure:
A stirred solution of the intermediate from Step A (6.0 g, 21 mmol) in MeOH (200 mL) was flushed with nitrogen gas and then palladium (600 mg; 10 wt. % (dry basis) on activated carbon) was added. The reaction flask was placed under vacuum and flushed with hydrogen gas (3 cycles). The reaction mixture was stirred for 1 hour and then flushed with nitrogen gas, filtered and the solvent removed under reduced pressure to afford 6.0 g of the title intermediate (99% yield), which was used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7].[Cl-].[Li+].CN(C=O)C.Cl>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(O)c(O)c1
Temperature: 180 °C
Yield: 70.6 %

Procedure:
To a 3-necked 250 mL round bottom flask equipped with a mechanical stirrer and a condenser, 3-methoxy-4-hydroxybenzonitrile (13.4 g, 89.9 mmole), lithium chloride (7.6 g, 179.2 mmole), and N,N′-dimethylformamide (60 mL) were added successively at 25° C., followed by heating in an oil bath at 180° C. for 20 hours. The reaction mixture was allowed to cool to 85° C. Water (285 mL) was then added, and upon cooling to 25° C., treatment with concentrated hydrochloric acid proceed. The resulting mixture was extracted with ethyl acetate (300 mL×2). The extract was concentrated under reduced pressure to give a pale brown solid. Water (430 mL) was added and the mixture was then heated till the mixture became homogeneous. After the reaction mixture was cooled down to approximately 40° C., 3,4-Dihydroxybenzonitrile was precipitated out and the reaction mixture was further cooled to 10° C. so as to ensure complete precipitation. The resulting solid was isolated by filtration and dried under reduced pressure. 3,4-Dihydroxybenzonitrile was obtained as a white solid with a yield of 70.6% and a purity of greater than 99% as indicated by HPLC analysis.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.[C@H:18]12[CH2:24][C@H:21]([NH:22][CH2:23]1)[CH2:20][N:19]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([N:7]2[C:3]([CH2:2][N:22]3[CH2:23][C@@H:18]4[CH2:24][C@H:21]3[CH2:20][N:19]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:4][N:5]=[N:6]2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-n2nnnc2CCl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (500 mg, 1.90 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) in acetonitrile (10 mL) was added 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (377 mg, 1.90 mmol, commercially available, for example from Sigma Aldrich Corporation) and triethylamine (0.796 mL, 5.71 mmol). The mixture was then heated to 120° C. for 20 min in a microwave reactor.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:32][C:25]=3[S:24]4)=[CH:17][CH:16]=2)=[O:13])[CH:7]=1)([CH3:5])[CH3:4].[NH4+].F[C@H:44]1[O:52][C@H:51]([C:53]([O-:55])=[O:54])[C@@H:49]([OH:50])[C@H:47]([OH:48])[C@H:45]1[OH:46]>CS(C)=O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[OH:50][CH:49]1[CH:47]([OH:48])[CH:45]([OH:46])[CH:44]([O:1][CH2:2][C:3]([CH3:4])([C:6]2[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[N:22]=[C:23]5[N:27]([CH:28]=4)[C:26]4[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)=[CH:32][C:25]=4[S:24]5)=[CH:17][CH:16]=3)=[O:13])[CH:7]=2)[CH3:5])[O:52][CH:51]1[C:53]([OH:55])=[O:54]
Reactant: O=C([O-])[C@H]1O[C@H](F)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(C)(CO)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COC1OC(C(=O)O)C(O)C(O)C1O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Alternatively, 3,4,5-trihydroxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid (I-6) is prepared by following an alternative general procedure given in Org. Lett. 2008, 10, 1585. To a stirred mixture of 1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1) (1 equivalent) in a mixture of dimethyl sulfoxide (final volume 12.5-25% v/v) and 50 mM sodium phosphate buffer (pH=7.5) at rt, is added a solution of 1-deoxy-1-fluoro-α-D-glucopyranuronic acid ammonium salt (prepared as described in Org. Lett. 2008, 10, 1585) (1.2 equivalents) in 50 mM sodium phosphate buffer (pH=7.5). To this mixture is added E. coli. E504G β-glucuronylsynthase (final concentration 0.1-0.2 mg/mL) or E. coli. E504A β-glucuronylsynthase (final concentration 0.1-0.2 mg/mL) and the mixture is stirred at rt for 4 days. Lyophilization of the mixture and purification of the residue by preparative reverse-phase HPLC or silica gel flash chromatography affords 3,4,5-trihydroxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid (I-6).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[N:12]([C:25](=[O:27])[CH3:26])[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[N:12]([C:25](=[O:27])[CH3:26])[N:11]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1C)OCO3
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a suspension of 1.91 g (5.37 mmol) of 1-(4-nitrophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (product of Example 27) in 40 ml of methanol about 0.2 g of Raney nickel catalyst and 1.4 ml (28 mmol) of 100% hydrazine hydrate were added, then the reaction mixture was stirred at 20°-25° C. for one hour. The starting nitro derivative was dissolved within 10-20 minutes. After filtering the filtrate was evaporated under reduced pressure, the white crystalline residue was washed with 30 ml of distilled water onto a filter, it was washed with 3×10 ml of distilled water and dried at 100 ° C. to give 1.50 g of a raw product, m.p. 218°-220° C. This raw product was purified by treating with 12 ml of hot isopropanol. After cooling it was filtered at 5° C., washed with 3×1 ml of isopropanol and dried at 100° C. to yield 1.40 g (77.35%) of a white crystalline powder, m.p. 221°-223° C. On the basis of analyses and spectra it was identical to the product of Example 15 obtained by a different process.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](O)(=[O:29])[CH2:24][CH2:25][C:26]([CH3:28])=O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[C:23](=[O:29])[CH2:24][CH2:25][C:26]([CH3:28])=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCC(=O)O
Reactant: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Solvent: CCCCO
Product: CC1=NN(c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)C(=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
To a suspension of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (2 g) in n-Butanol (40 mL) was added of 0.744 g of levulinic acid. The mixture was heated at reflux. After 3 h, the mixture was cooled at 0° C. and the 4-({4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-hydrazono)-4-methyl-butyric acid (1.92 g, 73%) was recovered by filtration. Mp 218–220° C., 1H NMR DMSO-d6) 12.1 (1H, OHacid), 9.93 (1H, s, NH), 9.48 (1H, s, NH), 8.64 (1H, d, 5 Hz), 8.24 (1H, d, 5 Hz), 8.0 (1H, s), 7.76 (2H, m), 7.46 (1H, d, 5 Hz), 7.38 (1H, dd, 2 Hz, 5 Hz), 7.30 (1H, t, 8 Hz), 6.98 (1H, dd, 1 Hz, 8 Hz), 2.51 (4H, s), 1.92 (3H, s), 13C NMR (DMSO-d6 176.2, 164.6, 161.6, 161.2, 150.5, 150.1, 147.5, 144.0, 134.9, 132.1, 122.97, 120.13, 119.2, 113.7, 111.1, 105.9, 35.33 (CH2), 32.56(CH2), 18.09 (CH3), MS (ES−) 409 (M−1, 100), 819 (2M−1, 30). The 4-({4-[2-(3-Chloro-phenylamino)-pyrimnidin-4-yl]-pyridin-2-yl}-hydrazono)-4-methyl-butyric acid (1.5 g) was dissolved in acetic acid (40 mL). The solution was stirred at 110° C. for 3 h then the solution was poured in a mixture of water and ice (250 mL) and neutralised with a solution saturated of sodium hydrogenocarbonate until pH 7. The mixture was extracted with ethyl acetate (3×100 mL). The organic phase were combined, dried over MgSO4, and concentrated. Flash silica chromatography, eluting with ethyl acetate-tetrahydrofuran (3-1), afforded the title compound as a solid (0.7263 g, 51%). Mp 189–192° C., 1H NMR (DMSO-d6) 10.07(1H, NH), 8.73 (1H, d, 5 Hz), 8.69 (1H, d, 5 Hz), 8.16 (1H, s), 8.06 (2H, m), 7.73 (1H, dd, 3 Hz, 10 Hz), 7.60(1H, d, 5 Hz), 7.31 (1H, t, 8 Hz), 7.03(1H, dd, 3 Hz, 8 Hz), 2.63 (4H, m), 2.07 (3H, s). 13C NMR (DMSO-d6) 165.3, 160.3, 159.6, 159.3, 154.9, 153.9, 149.0, 141.1, 132.5, 129.7, 120.7, 119.2, 117.8, 117.6, 116.7, 108.66, 26.4, 25.3, 22.0. MS (ES+) 393 (MH+, 100), 785 (2 MH+, 60).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([OH:39])([CH3:38])[CH3:37])[CH:35]=1)[C:30](O)=[O:31])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([OH:39])([CH3:38])[CH3:37])[CH:35]=1)[C:30]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:31])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)O)c1
Product: Cc1ccc(NC(=O)c2cc(C(C)(C)C)cc(C(C)(C)O)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
40 mg (0.14 mmol) of the compound of Example 6A and 33 mg (0.14 mmol) of the compound of Example 28A were reacted and worked up analogously to the procedure of Example 33. This gave 31 mg (44% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:23]3[CH2:22][CH2:21][N:20]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=4)[CH2:25][CH2:24]3)[N:10]=2)[CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2cc(Br)ccc2n1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Fc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
Yield: 62.1 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (0.253 g), 1-(4-fluorophenyl)piperazine (Aldrich; 0.186 g), triethylamine (Aldrich; 0.104 g), and ethylene glycol (2 mL) give 0.249 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/hexane; mp 110-112° C.; MS m/z 388, 390; IR (mineral oil) 1511, 1234, 1219, 1448, 1326 cm-1. 1H NMR (CDCl3) δ2.74, 3.16, 3.77, 6.87-6.98, 7.21, 7.48, 7.53, 8.24.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[C:33](Cl)(=[O:35])[CH3:34]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:33]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 28 h
Yield: 71.9 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.450 mmol) produced in Example C12(iv) in pyridine (5 mL) were added acetyl chloride (128 μL, 1.80 mmol) and N,N-dimethylpyridine-4-amine (8.8 mg, 0.0720 mmol), and the mixture was stirred at room temperature for 28 hr. The title compound (157 mg, 72%) was obtained as white crystals by operation in the same manner as in Example C81. The present compound was recrystallized from ethyl acetate and tetrahydrofuran.