Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[CH2:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19].O>CC(C)=O>[CH:17]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[CH2:10])=[CH:18][CH3:19]
Reactant: C=CCBr
Reactant: C=CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCc1ccccc1OC=CC
Yield: 98.7 %

Procedure:
200 g of 3-(2-hydroxyphenyl)propene, 226 g of potassium carbonate and 180 g of allyl bromide were stirred in 490 ml of acetone at reflux temperature for hours and then cooled. One liter of water was added and the resultant layers were separated. The aqueous layer extracted with two volumes of diethyl ether, dried and stripped of solvent to give 256 g of 3-(2-propenyloxyphenyl)propene which was subsequently rearranged as described in Examples 55 and 56 to the 2,6-di-propenylphenol intermediate. 52.2 g of said intermediate was dissolved in 500 ml of THF and chilled to -5° C. 300 ml of one molar borane was added over 15 minutes (maximum temperature not exceeding 18° C.), after which the mixture was stirred for 36 hours and chilled to 0° C. 80 ml of water was added over a 5 minute period, after which 120 ml of 5N sodium hydroxide was added all at once. When the temperature of the reaction mixture reached 1° C., 81 ml of 30% hydrogen peroxide was added over a 25 minute period and the mixture stirred for one hour and then concentrated. An additional 500 ml of water and 250 ml of ethyl acetate were added which, following workup, gave about 54 g of the desired 2,6-di(3-hydroxypropyl)phenol intermediate, m.p. 176-187° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]([CH2:34][CH2:35][CH3:36])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31]CC)=[O:30])=[CH:24][CH:23]=2)=[S:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1>O.CO>[C:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[S:20])[C@@H:18]([NH:17][S:14]([C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=2)(=[O:16])=[O:15])[CH2:34][CH2:35][CH3:36])=[CH:23][CH:24]=1)([OH:31])=[O:30]
Reactant: CCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A solution of K2CO3 (3.2 g) in water (40 ml) was added to a solution of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (3.75 g) in methanol (80 ml), and the whole was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure. It was repeated 3 times in order to remove methanol completely that a small amount of purified water was added to the residue, and then the product was concentrated under reduced pressure. The residue was dissolved in purified water and washed with ethyl acetate. The aqueous layer was acidified with 1N HCl, and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution, and dried over Na2SO4. Then, the solvent was evaporated under reduced pressure, and the resulting crude product was recrystallized from acetonitrile to obtain (S)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanamide (2.84 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C@H:15]([C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18])[C:5]2=[CH:4][CH:3]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(N(CC)CC)C.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[S:53]1[CH:57]=[N:56][N:55]=[C:54]1[NH2:58].Cl>C(#N)C.CCO>[Cl:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C@H:15]([C:16]([CH3:21])([CH3:20])[C:17]([NH:58][C:54]4[S:53][CH:57]=[N:56][N:55]=4)=[O:18])[C:5]2=[CH:4][CH:3]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC(C)(C(=O)O)[C@H]1c2ccccc2Oc2nc(Cl)ccc21
Reactant: Nc1nncs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC#N
Product: CC(C)(C(=O)Nc1nncs1)[C@H]1c2ccccc2Oc2nc(Cl)ccc21
Temperature: 80 °C
Yield: 78.6 %

Procedure:
To a soln. of (S)-2-(2-chloro-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanoic acid (30b, 10 g, 32.9 mmol) in acetonitrile (200 ml) was added triethylamine (22.94 ml, 165 mmol), O-(7-AZABENZOTRIAZOL-1-YL)-N,N,N′,N′-TETRAMETHYLURONIUM PF6 (HATU) (16.27 g, 42.8 mmol) and 1,3,4-thiadiazol-2-amine (9.99 g, 99 mmol). The resulted mixture was heated at 80° C. for 12 h. The reaction mixture was then concentrated in vacuum and the residue was partitioned between EtOAc and 1N HCl. The obtained organic layer was washed with saturated NaHCO3, brine, then dried (Na2SO4) and concentrated to give a solid. The solid was dissolved in EtOH (400 mL) with gentle warming. Added 1N HCl (˜200 mL) portionwise. The solid was collected and washed with water, dried on vacuum pump overnight to give 10 g (79%) of (S)-2-(2-chloro-5H-chromeno[2,3-b]pyridin-5-yl)-2-methyl-N-(1,3,4-thiadiazol-2-yl)propanamide (53a). MS (E+) m/z: 387 (M+H); LC retention time: 3.12 min.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.S(O)(O)(=O)=O.[NH2:25][CH2:26][C:27]#[N:28].C([O-])(=O)C.[Na+]>COCCOC>[C:26]([CH2:27][N:28]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])#[N:25]
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: N#CCN
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)n1CC#N

Procedure:
10.4 g (0.04 mol) of 6-phthalimido-2,5-hexanedione, 6.2 g (0.04 mol) of aminoacetonitrile sulphate and 6.8 g (0.08 mol) of sodium acetate are stirred in 200 ml of ethylene glycol dimethyl ether at 80° C. for 16 hours and the mixture is worked up as in Example 27.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH2:16]([NH2:19])[CH2:17][CH3:18]>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:19][CH2:16][CH2:17][CH3:18]
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Reactant: CCCN
Solvent: CCO
Product: CCCNCCOc1cc(F)cc(S(C)(=O)=O)c1
Temperature: 120 °C
Yield: 87.3 %

Procedure:
A mixture of 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (2.65 g, 8.9 mmol) and propan-1-amine (5.24 ml, 63.7 mmol) in ethanol (32 ml) was divided into 3 aliquots which were each heated under microwave radiation at 120° C. for 30 min. The reaction mixtures were cooled to room temperature, filtrated and pooled before the volatiles were evaporated. Purification by flash column chromatography (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (2.14 g, 87%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 191° C. MS m/z (relative intensity, 70 eV) 275 (M+, 2), 246 (32), 73 (5), 72 (bp), 56 (11).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:13])[C:9]([F:12])([F:11])[CH3:10])(C)(C)C.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[F:11][C:9]([F:12])([CH3:10])[C@H:8]([NH2:7])[CH3:13]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(C)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)C(C)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a round-bottomed flask, ((R)-2,2-difluoro-1-methyl-propyl)-carbamic acid tert-butyl ester (148 mg, 0.71 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1.6 ml, 20.8 mmol) was slowly added. The reaction mixture was stirred at room temperature for 1.5 h then concentrated to give (R)-2,2-difluoro-1-methyl-propylamine trifluoroacetate as a light brown oil which was used without further purification.
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].[Cl:19][C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1[C:28](=[CH:34]N(C)C)[C:29](OCC)=[O:30]>>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1[C:28]1[CH:34]=[N:2][N:1]([C:3]2[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:8])=[CH:5][N:4]=2)[C:29]=1[OH:30]
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1Cl
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)c(Cl)c1

Procedure:
The title compound was prepared in a manner similar to Example 188 using 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide and ethyl 2-(2-chloro-4-cyanophenyl)-3-(dimethylamino)acrylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.39 (m, 4H) 1.68 (d, J=12.9 Hz, 2H) 3.20-3.37 (m, 6H) 3.63 (s, 1H) 3.92 (dd, J=11.2, 2.7 Hz, 2H) 7.90 (d, J=8.1 Hz, 1H) 8.15 (s, 1H) 8.49 (d, J=3.8 Hz, 2H) 8.73-8.87 (m, 1H) 8.98 (s, 1H). MS m/z [M+H]+ 438.4.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:5])[CH3:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:1][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: C1=COCCC1
Reactant: CC(=O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)COC1CCCCO1
Yield: 80.8 %

Procedure:
A solution of 1-hydroxy-propan-2-one (95%, 78 g, 1.0 mol), 3,4-dihydro-2H-pyrane (95%, 88.5 g, 1.0 mol) and pyridinium p-toluenesulfonate (25.1 g, 0.1 mol) in THF (1.2 l) is stirred at room temperature for 16 hours. The mixture is diluted with ethyl acetate and repeatedly washed with brine. The organic phase is dried, filtered evaporated to afford 1-(tetrahydropyran-2-yloxy)-propan-2-one (127.8 g, 80.8%) as a liquid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[CH3:24][S:25]([O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)[C:10]=1[F:16])(=[O:27])=[O:26]
Reactant: CCN1CCC(c2cccc(O)c2F)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCN1CCC(c2cccc(OS(C)(=O)=O)c2F)CC1
Reaction time: 20 h

Procedure:
To a solution of 3-(1-ethylpiperidin-4-yl)-2-fluorophenol (0.44 g, 1.97 mmol)) in methylene chloride (20 ml) was added triethylamine (4 ml) and methanesulfonyl chloride (0.56 ml, 3.67 mmol). The mixture was stirred for 20 h and water (50 ml) and methylene chloride (50 ml) was added and the phases were separated. The aqueous phase was extracted with methylene chloride (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethyl acetate/methanol, 1:1) gave the title compound: 0.39 g (66%). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 161.5-163.2. MS m/z (relative intensity, 70 eV) 301 (M+, 15), 287 (15), 286 (bp), 222 (23), 207 (38).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)=[N:9][C:8]=2[N:7]([CH3:27])[C:6]1=[O:28].Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([F:37])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[F:37][C:35]1[CH:36]=[C:31]([CH2:30][N:11]2[C:12]3[C:13](=[O:14])[N:5]([CH2:4][CH2:3][CH2:2][OH:1])[C:6](=[O:28])[N:7]([CH3:27])[C:8]=3[N:9]=[C:10]2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:25])([F:26])[F:24])[CH:17]=2)[CH:32]=[N:33][CH:34]=1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2[nH]c(Oc3cccc(OC(F)(F)F)c3)nc21
Reactant: Fc1cncc(CCl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1cncc(F)c1
Temperature: 60 °C
Yield: 45.8 %

Procedure:
To a solution of 1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (60 mg, 0.15 mmol, intermediate 15) in DMF (5 mL) was added 3-(chloromethyl)-5-fluoropyridine (80 mg, 0.55 mmol), potassium carbonate (0.55 g, 0.6 mmol), and TBAI (2 mg, 0.02 mmol). The reaction was heated at 60° C. for 2 h. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to give 7-((5-fluoropyridin-3-yl)methyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (35 mg, 46% yield) as white solid. LCMS retention time 2.577 min; LCMS MH+ 510.
Reaction SMILES: CC1C2NC(=O)OC=2C=CC=1.[Cl-:12].[Cl-].[Cl-].[Al+3].Cl[C:17]1[C:22]([CH3:23])=[C:21]([C:24]([C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:20]=[CH:19][N:18]=1>>[Cl:12][C:19]1[CH:20]=[C:21]([C:24]([C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[C:22]([CH3:23])=[CH:17][N:18]=1
Reactant: [Cl-]
Reactant: Cc1c(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)ccnc1Cl
Agent: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Product: Cc1cnc(Cl)cc1C(=O)c1cc(C)c2[nH]c(=O)oc2c1
Temperature: 125 °C

Procedure:
1.53 g (10.0 mmol) 3-methyl-1-oxy-isonicotinic acid were stirred with 9.32 mL (100 mmol) phosphorus oxychloride and boiled for 4 h. The reaction mixture was evaporated to dryness i. vac. and coevaporated twice with toluene. The crude product thus obtained (which was present in admixture with 2-chloro-3-methyl-isonicotinic acid chloride) was combined with 1.49 g (10.0 mmol) 4-methyl-3H-benzoxazol-2-one and 5.33 g (40.0 mmol) aluminium trichloride and heated to 125° C. for 1.5 h with stirring. Then the mixture was mixed with ice water and the precipitated grease was separated from the solvent by decanting. The residue was triturated with MeOH. The precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried i. vac. The product thus obtained, which was present in admixture with 6-(2-chloro-3-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one, was reacted further without further purification.
Reaction SMILES: ClC([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)=O.[C-:9]1(C(Cl)=O)[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:17].C(O)CCCCCO.N#N.[Cl-].[NH+]1C=CC=CC=1>C1C=CC=CC=1.N1C=CC=CC=1>[CH-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:17]
Reactant: O=C(Cl)[c-]1cccc1
Agent: [Fe+2]
Agent: N#N
Agent: OCCCCCCO
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: c1cc[cH-]c1
Yield: 88 %

Procedure:
A scheme for the synthesis of 1,1′-di(chlorocarbonyl) ferrocene is shown in FIG. 7. To the solution of 4.0 g (0.013 mole) 1,1′-di(chlorocarbonyl) ferrocene in dry benzene (95 ml), 1.82 g (0.0154 mole) 1,6-hexanediol and pyridine (1.1 ml) was added. The mixture was stirred at 70–75° C. under an inert atmosphere (N2 gas) for 4 hours. The pyridinium chloride salt, being insoluble in benzene was precipitated from the reaction phase. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was extracted with CH2Cl2 and washed with water. The organic layer was dried (Na2SO4) and evaporated to give 4.3 g (88%) of ferrocene containing hydroxyl terminated prepolymer, FcOH. 1H NMR of this compound showed an average molecular weight of −3600. 1H NMR δ: 4.83 (s, 4H), 4.40 (s, 4H), 4.24 (t, 4H), 3.68 (t, 0.43H), 1.78 (m, 4H), 1.52 (m, 4H). IR (cm−1, neat): 1722.9 (C═O), 2940.4 (CH aliphatic), 3486.7 (OH). The 1H NMR spectra were obtained with a BRUKER AMX-360 NMR spectrometer (Bruker, Billerica, Mass.) in CDCl3. The IR spectra were recorded on a NICOLET system 550 (Magna series) FTIR spectrometer (Thermo Nicolet, Madison, Wis.). A scheme for the synthesis of the ferrocene-containing hydroxyl terminated (FCOH) prepolymer is shown in FIG. 8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH:31][C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:34]5[CH2:35][CH2:36][C@H:32]([OH:31])[CH2:33]5)=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: O[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)N5CC[C@H](O)C5)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), (S)-(−)-3-hydroxylpyrrolidine (0.113 g, 1.3 mmol), DIEA (0.2 mL, 1.15 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to obtain a crude yellow solid, which was washed with methanol to obtain a purified product (0.22 g) in 44.9% yield.
Reaction SMILES: [Cl:1][C:2]1[C:6](C(O)=O)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1>[Cu]=O>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=C(O)c1cn(-c2cccnc2)nc1Cl
Agent: O=[Cu]
Product: Clc1ccn(-c2cccnc2)n1

Procedure:
decarboxylating 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (4) with copper oxide in a polar aprotic solvent at a temperature of about 80° C. to about 180° C. to provide 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=[O:4])[CH2:2][CH3:3].[C:13]1([CH3:30])[CH:18]=[CH:17][C:16](S(OCCCCCCC)(=O)=O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH:9][CH2:30][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:4])[CH2:2][CH3:3]
Reactant: CCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCCCCCCNc1cccc(NC(=O)CC)c1

Procedure:
3-Propionylaminoaniline (16.4 parts) was reacted with n-heptyl p-toluenesulfonate (27 parts) at 100° C. for 4 hours in methyl cellosolve (200 parts) in the presence of anhydrous sodium carbonate (5.3 parts) to obtain 3-propionylamino-N-heptylaniline. Thereafter, reaction was further continued at 100° to 110° C. for 4 hours with addition of n-amyl p-toluenesulfonate (24.2 parts) and anhydrous sodium carbonate (5.3 parts) to obtain 3-propionylamino-N-n-heptyl-N-n-pentylaniline (coupling component). In the same manner as in Example 1, 2-cyano-4-nitro-6-chloroaniline was diazotized and coupled with the above coupling component to obtain 45.9 parts of a dye (7).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH2:14][C:15](=[O:20])[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])[CH3:2].CO.Cl>O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(=O)CC4
Agent: Cl
Solvent: O
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Yield: 66.7 %

Procedure:
Stir 13β-ethyl-17β-hydroxy-gon-5(10)-en-3-one (300 mg.) for 2 hours under nitrogen at room temperature with methanol (10 cc.)-11N hydrochloric acid (0.5 cc.)-water (0.3 cc.). Add sodium bicarbonate (2 g.) and ether (50cc.), filter the mixture, evaporate the ether and recrystallize the residue from ethyl acetate-ether to give 13β-ethyl-17β-hydroxy-gon-4-en-3-one (0.2 g.), m.p. 147°-149°; ultraviolet absorption peak at 242 mμ (ε 17,600); infrared absorption peaks at 2.78, 2.90, 6.02, 6.17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N+:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][NH:21][CH2:22]2)([O-:16])=[O:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][CH:25]=[CH:26][C:17]=4[N+:14]([O-:16])=[O:15])[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: O=[N+]([O-])c1cccc2c1CCNC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2c(cccc2[N+](=O)[O-])C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:55]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])(=[O:58])[CH:56]=[CH2:57]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:60]([O:59][C:55](=[O:58])/[CH:56]=[CH:57]/[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1)([CH3:63])([CH3:62])[CH3:61]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccc(/C=C/C(=O)OC(C)(C)C)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 57.5 %

Procedure:
To a solution of 5-(5-bromo-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (1.0 g, 0.0025 mol) and triethylamine (0.38 g, 0.0038 mol) in acetonitrile (2 ml), was added palladium(II) acetate (0.03 g, 0.00013 mol), tri-o-tolylphosphine(0.076 g, 0.00025 mol) and t-butyl acrylate (0.48 g, 0.0038 mol). The mixture was heated under reflux for 4 hours, then cooled and evaporated under vacuum. The residue was suspended in water (30 ml) and extraction with dichloromethane (3 x 20 ml) effected. The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum to give a yellow-green solid. Chromatography on silica gel (12 g), using a methanol in dichloromethane elution gradient (0-2% methanol), followed by crystallisation from ethyl acetate-hexane gave the title compound as a white solid (0.65 g, 58%), m.p. 167-168° C. Found: C,66.47; H,7.00; N,12.31. C25H32N4O4 requires C,66.35; H,7.13; N,12.38%.
Reaction SMILES: [ClH:1].Cl.C(O[NH:11][C:12]1[CH:17]=[C:16]([CH2:18][CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.C[OH:28]>[Pd]>[ClH:1].[ClH:1].[NH2:11][C:12]1[CH:17]=[C:16]([CH2:18][CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[CH:15]=[CH:14][C:13]=1[OH:28]
Reactant: CO
Reactant: CCCN(CCC)CCc1cccc(NOCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Product: CCCN(CCC)CCc1ccc(O)c(N)c1

Procedure:
1.9 g of 2-(benzyloxy-5-(2-dipropylaminoethyl)aniline, dihydrochloride, is hydrogenated in 30 ml of methanol in the presence of 150 mg of palladium/carbon (10% strength). After removing the catalyst by filtration, the mixture is concentrated and recrystallized from isopropanol, thus obtaining 0.88 g of N-[2-(3-amino-4-hydroxyphenyl)ethyl]-N,N-dipropylamine, dihydrochloride, mp 127°-151° C.