Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[C:8]([CH3:20])[CH:7]=1>FC(F)(F)C(O)=O>[CH3:22][N:2]([CH3:1])[C:3](=[O:21])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([CH3:20])[CH:7]=1
Reactant: Cc1cc(OCC(=O)N(C)C)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC(=O)N(C)C)ccc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.1 %

Procedure:
To a 200 mL round bottomed flask with a stirring bar and a drying tube was added N,N-dimethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-methyphenoxyacetamide (1.00 g, 3.24 mmol) and trifluoroacetic acid (20 mL). This solution was stirred at ambient temperature 48 h. The trifluoroacetic acid was removed in vacuo and the residue was dissolved in 200 mL of EtOAc. This solution was washed with NaHCO3 solution and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave 0.493 g (73% yield) of N,N-dimethyl 4-amino-3-methylphenoxyacetamide as white crystals. 1H NMR (CDCl3): d 2.15 (s, 3H), 2.97 (s, 3H), 3.08 (s, 3H), 3.27 (br s, 2H), 4.59 (s, 2H), 6.71 (m, 3H). ##STR52## N,N-Dimethyl-2-(4-amino-3-methylphenoxy)ethylamine (5-4)
Reaction SMILES: [OH-].[Mg+2:2].[OH-].[NH2:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8]>O>[CH2:5]([NH2:4])[CH2:6][S:7]([O-:10])(=[O:9])=[O:8].[CH2:5]([NH2:4])[CH2:6][S:7]([O-:10])(=[O:9])=[O:8].[Mg+2:2]
Reactant: NCCS(=O)(=O)O
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Product: NCCS(=O)(=O)[O-]

Procedure:
A mixture of magnesium hydroxide (9.50 g, 8.62 mmol) and taurine (2.16 g, 17.2 mmol) in 20 ml water was refluxed for 7 hours, then evaporated under vacuum to remove most of the water. The paste was diluted with 10 ml ethanol, and after two hours the solid was collected by filtration and dried. Magnesium taurate was obtained as a white powder (about 99% yield). Magnesium taurate could also be obtained as a white powder by lyophilization or by further drying of the paste remaining after evaporation of the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[C:25](O)(=[O:27])[CH3:26].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:25](=[O:27])[CH3:26])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(=O)O
Reactant: Clc1nc(N2CCOCC2)c2nc(CC3CCNCC3)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reaction time: 8 h

Procedure:
4-(2-chloro-6-(piperidin-4-ylmethyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (40 mg) was added to a pre-stirred (15 minutes) solution of acetic acid (5 eq), 1-Hydroxybenzotriazole (HOBt, 1.2 eq.), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.5 eq.), DIPEA (5 eq) in N,N-Dimethylformamide (DMF, 0.9 mL). The reaction was stirred overnight then extracted with Ethyl Acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to give quantitative yield of 1-(4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 25A in analogy to the synthesis of the compound of Example 71A. 5.15 g (96% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:18]1[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1-c1ccncc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 2-bromo-1-tert-butyl-4-nitrobenzene (8.6 g, 33.3 mmol) and toluene (70 mL) in a 150 mL round bottom flask, 4-pyridylboronic acid (4.5 g, 36.6 mmol), Pd(PPh3)4 (3.8 g, 3.3 mmol) and K2CO3 (13.8 g, 99.9 mmol) were added. The solution was stirred for 24 h at 80° C. before cooling to RT. The solution was filtered through a pad of Celite® and purified by silica flash chromatography (30% EtOAc/Hexanes). This afforded the desired compound as a yellow solid. MS (ES+): 257.2 (M+H)+; (ES−): 255.2 (M−H)−. Calc'd for C15H16N2O2: 256.12.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1>C(OCC)(=O)C.C1COCC1.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([C:6]2[S:5][C:4]([NH:16][C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)=[N:3][C:2]=2[CH3:1])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc(Nc2cnccn2)sc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(Nc2cnccn2)sc1-c1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
[4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine (42b) (1.079 g, 3.4 mmol) is dissolved in ethyl acetate/THF (5/1, 240 ml) and stirred at room temperature under an atmosphere of argon. The solution is then treated with 10% Pd/C (1.1 g). The reaction mixture is purged three times with nitrogen and placed under an atmosphere of hydrogen overnight. The mixture is then filtered through celite and the catalyst is washed with THF (200 ml). The solvent is removed in vacuo to leave [5-(3-amino-phenyl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine (0.351 g, 36%). MH+ (ESMS):283.5
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C.O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][O:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:18][CH:17]=2)[CH2:14][CH2:15]1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](c2ccc(CO)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](c2ccc(COS(C)(=O)=O)cc2)CC1
Reaction time: 8 h

Procedure:
15.4 g of trans-N-tert.butoxycarbonyl-N-methyl-4-(4-hydroxymethylphenyl)cyclohexylamine in 120 ml of methylene chloride are mixed at O° C. with 4.5 ml of methanesulphonic acid chloride and then 8.1 ml of triethylamine in 20 ml of methylene chloride are slowly added dropwise. After stirring overnight, water is added, the organic phase is washed with water, dried and concentrated by evaporation. After recrystallisation from diisopropylether at low temperature, 12.1 g of the title compound are obtained, melting point 138°-139° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH:13]([CH3:18])[C:14]([NH:16][CH3:17])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH:13]([CH3:18])[CH2:14][NH:16][CH3:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CNC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: CNCC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C

Procedure:
In this example, 13.3 g (0.0392 mole) of α-[4-(4-trifluoromethylphenoxy)-phenoxy]-N-methylpropionamide was added portionwise to a stirred slurry containing 1.5 g (0.0392 mole) of lithium aluminum hydride. The resulting mixture was refluxed for 18 hours and then chilled to about 0° C. Then 1.6 ml of water, 1.6 ml of aqueous 15% by weight sodium hydroxide, and 4.8 ml of water were successively added to the chilled mixture and the resulting mixture was stirred until a white precipitate formed. Magnesium sulfate was then added to the mixture to absorb water and then the mixture was filtered. The filter cake was washed thoroughly with ethyl ether. The combined filtrate and ethyl ether washings was evaporated under vacuum affording an oil which crystallized upon standing. Infrared spectrographic examination showed incomplete reduction and accordingly the solid was dissolved in 300 ml of ethyl ether and then 1.5 g of lithium aluminum hydride was added portionwise to this solution. The resulting mixture was refluxed for 18 hours and then chilled to about 0° C. while water (1.5 ml), aqueous (15% by weight), sodium hydroxide (1.5 ml) and water (4.5 ml) were successively added. The mixture was then stirred until a white precipitate separated out. Magnesium sulfate was added and the mixture then filtered and the filter cake washed with methylene chloride. The combined filtrate and washing was evaporated under vacuum affording the title compound as an oil. Complete reduction was confirmed by infrared spectrography and n.m.r. analysis.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])[CH2:13][N:14]([C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])[C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[N+:41]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[O:34][CH2:33][C:12](=[O:11])[CH2:13][N:14]([C@@H:25]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:26])[C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:43])=[O:42]
Reactant: C[C@H](c1ccccc1)N(CC(O)COc1ccccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N(CC(=O)COc1ccccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (13.0 mL, 150 mmol) in dichloromethane (300 mL) at −78° C. was treated dropwise with DMSO (14.6 mL, 205 mmol), stirred for 10 minutes, treated with the product from Example 1C (46 g, 100 mmol) in dichloromethane (50 mL), stirred for 30 minutes, treated with triethylamine (55 mL, 400 mmol), warmed to 0° C. over 30 minutes, quenched with 10% NaHCO3, and extracted with diethyl ether. The organic layer was washed with 10% NaHSO4, 10% NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was filtered through a plug of silica gel with 7:3 hexane/ethyl acetate to provide the title compound. 1H NMR (300 MHz, CDCl3) δ1.52 (d, 3H), 4.00 (d, 1H), 4.22 (d, 1H), 4.30 (d, 0.5H), 4.45 (d, 0.5H), 4.57 (d, 0.5H), 4.71 (d, 0.5H), 5.05-5.30 (m, 2H), 5.51 (q, 0.5H), 5.68 (q, 0.5H), 6.62 (d, 0.5H), 6.92 (d, 0.5H), 7.05 (t, 1H), 7.20-7.42 (m, 10H), 7.50 (t, 1H), 7.88 (d, 1H).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1.[ClH:44]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:44][C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cl
Reactant: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
First, 18 mg of isoamyl nitrite was added dropwise to a mixture of 0.16 g of methyl 2-[3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]propionate, 63 mg of copper (I) chloride, 129 mg of copper (II) chloride, and 1.5 ml of acetonitrile at 0° C., and the mixture was stirred for 1 hour and further stirred at room temperature for 1 hour. The reaction mixture was poured into a mixture of 1N hydrochloric acid and ice, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of methyl 2-[3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]propionate (compound b-6) as a mixture of diastereoisomers.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:5][NH:6][CH2:7][CH2:8][C:9]=2[N:10]=1.Br[CH2:12][B-:13]([F:16])([F:15])[F:14].[K+:17]>O1CCCC1>[CH3:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([CH2:12][B-:13]([F:16])([F:15])[F:14])[CH2:7][CH2:8][C:9]=2[N:10]=1.[K+:17]
Reactant: Cc1nc2c(s1)CNCC2
Reactant: F[B-](F)(F)CBr
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc2c(s1)CN(C[B-](F)(F)F)CC2
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (3.00 g), potassium bromomethyltrifluoroborate (3.91 g), KHCO3 (1.95 g), KI (0.32 g), and tetrahydrofuran (25 mL) is stirred at reflux temperature for 4 h. After cooling to room temperature, the solvent is evaporated and the residue is suspended in acetone. The insoluble salts are separated by filtration and the filtrate is treated with diethyl ether. The precipitate is separated by filtration and dried to give the title compound (alternatively, the crude product is purified by chromatography on silica gel using dichloromethane and methanol as eluent). Mass spectrum (ESI−): m/z=235 [M]−.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[CH:26][CH:25]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-diphenylaminophenyl boronic acid (2.57 g, 8.9 mmol), 4-bromo-iodobenzene (5.03 g, 17.8 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and K2CO3 (3.0 g, 22 mmol) in dioxane/water (80 mL/15 mL) was degassed and heated at about 80° C. for about 20 hours. The whole was mixed with water/dichloromethane, the organic phase was collected and washed with brine, dried over Na2SO4, loaded on silica gel, and purified by flash column (hexanes to hexanes/dichloromethane 30:1). The desired fraction was collected, and concentrated to give a white solid (Compound 12), which was filtered and washed with methanol (2.70 g, in 76% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:6]([C:3]2[CH:4]=[CH:5][NH:1][CH:2]=2)=[O:8])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)[CH3:10]
Reactant: O=C(O)c1cc[nH]c1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(NC(=O)c2cc[nH]c2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from pyrrole-3-carboxylic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 10.82 (s, 1H), 8.88 (d, J=9.3, 1H), 8.65 (s, 1H), 7.70 (d, J=3.0, 1H), 7.54-7.52 (m, 1H), 7.28-7.24 (m, 1H), 6.87-6.85 (m, 1H), 6.71-6.69 (m, 1H), 4.08 (q, J=6.9, 2H), 1.45 (t, J=6.9, 3H).
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12]>C(OCC)C>[CH2:1]([NH:6][C:11]([NH:10][CH2:9][CH2:8][Cl:7])=[O:12])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CN
Reactant: O=C=NCCCl
Solvent: CCOCC
Product: CC(C)(C)CNC(=O)NCCCl
Temperature: 5 °C

Procedure:
Neopentylamine (8.7 g, 0.1 mol) was dissolved in 50 ml of anhydrous diethyl ether and cooled to 5° C. 2-Chloroethyl isocyanate (10.5 g, 0.1 mol) dissolved in an additional 50 ml of ether was added over 30 minutes while maintaining a temperature of less than 10° C. Stirring continued for an additional hour, and the cold mixture was filtered and washed with chilled ether. The compound was dried in a desiccator over sodium hydroxide overnight giving 15.4 g (80%) as a white powder, MP (melting point) 90°-1° C. (decomposes). Elemental analysis showed the following:
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:37])([CH3:36])[C:34]#[N:35])=[CH:29][CH:28]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:34]([C:33]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]4[N:10]([CH:25]=[C:7]([NH:6][C:4]([CH:1]5[CH2:3][CH2:2]5)=[O:5])[N:8]=4)[N:11]=3)[CH:17]=2)=[CH:32][CH:31]=1)([CH3:37])[CH3:36])#[N:35]
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C#N)c1ccc(NC(=O)c2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)cc1
Yield: 56.2 %

Procedure:
Using 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoic acid (100 mg, 0.30 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (57 mg, 0.36 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (63 mg, 0.33=mol), 4-(dimethylamino)pyridine (54 mg, 0.44 mmol) and pyridine (3.0 mL) as starting materials and in the same manner as in Example 318, the title compound (81 mg, 57%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[C:12]3\[O:13][C:14]4[C:21]([CH2:22][N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=4[C:16]\3=[O:17])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[ClH:37].[NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[C:12]3\[O:13][C:14]4[C:21]([CH2:22][N:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=4[C:16]\3=[O:17])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4cc(N)ccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCNCC4)C3=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(6-amino-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.023 g, 0.047 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-2-[(6-amino-1H-indol-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.010 g, 43%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:25]([O:26]C(=O)C)[C@H:24]([O:30]C(=O)C)[CH2:23][S:22][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)(=O)C.C[O-].[Na+]>>[S:7]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[C@@H:6]1[S:22][CH2:23][C@@H:24]([OH:30])[C@H:25]([OH:26])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(-c3ccc(C#N)cc3)cc2)SC[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1ccc(-c2ccc(S[C@@H]3SC[C@@H](O)[C@H](O)[C@H]3O)cc2)cc1
Yield: 79.5 %

Procedure:
If the procedure described in Preparation V is followed starting from 0.340 g (70.1.10-3 mol) of 4-(4-cyanophenyl)phenyl 2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 14a) and 17 ml of sodium methylate (8% w/v solution of Na in methanol), 0.200 g (yield: 80%) of the expected product is obtained after purification by recrystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH:10]=[O:11])[CH:3]=1.S([CH2:22][N+:23]#[C-:24])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:9][C:6]1[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=[C:4]([C:10]2[O:11][CH:24]=[N:23][CH:22]=2)[N:5]=1
Reactant: O=Cc1cc(Cl)c(Cl)c(Cl)n1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Clc1cc(-c2cnco2)nc(Cl)c1Cl
Temperature: 50 °C
Yield: 85 %

Procedure:
A mixture of 4,5,6-trichloropyridine-2-carbaldehyde (1.66 g, 8 mmol), tosylmethyl isocyanide (1.54 g, 8 mmol) and potassium carbonate (1.09 g, 8 mmol) in methanol (20 mL) was heated at 50° C. for 30 min and then heated at 80° C. for 5 min. The solvent was removed by rotary evaporation and the residue was suspended in water (200 mL) and stirred vigorously. The precipitate was collected by suction filtration, washed with water and air-dried to provide of 2,3,4-trichloro-6-(5-oxazolyl)pyridine (1.7 g, 6.8 mmol), mp 128-130° C.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH2:15]([C:17]([C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([OH:42])=[C:37]([CH3:43])[CH:36]=1)([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]([CH2:32][CH3:33])([OH:31])[CH2:29][CH3:30])=[C:22]([CH3:34])[CH:21]=1)[CH2:18][CH3:19])[CH3:16]>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[CH2:15]([C:17]([C:35]1[CH:36]=[C:37]([CH3:43])[C:38]([OH:42])=[C:39]([CH3:41])[CH:40]=1)([C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([CH2:29][CH3:30])([OH:31])[CH2:32][CH3:33])=[C:22]([CH3:34])[CH:21]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2cc(C)c(O)c(C)c2)cc1C)CC
Agent: COCCO[Al+]OCCOC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(O)c(C)c2)cc1C)CC
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
Sodium bis(2-methoxyethoxy)aluminum hydride (65 wt % solution in toluene, 4.2 mL, 13.98 mmol) was added to a solution of 4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenol (Example 38-(3); 1.83 g, 4.66 mmol) in tetrahydrofuran (20 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred at 0° C. for two hours. Then, ethyl acetate and brine were added to the reaction mixture, which was further diluted with ethyl acetate. Thereafter, celite was added and the mixture was stirred at room temperature for one hour. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 30:70, 40 minutes) to give the target compound as a colorless oil (1.55 g, 84%).