Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:10]([NH2:12])=[N:11][C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:22]([CH:18]4[O:17][CH2:21][CH2:20][CH2:19]4)=[O:23])[CH2:25][CH2:26]3)=[N:3][C:4]2=[CH:5][C:6]=1[O:15][CH3:16]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: O
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC

Procedure:
The process comprises adding 2-chloro-4-amino-6,7-dimethoxyquinazoline together with 1-(2-tetrahydrofuroyl)piperazine to a polar organic reaction solution comprising a polar organic solvent and water. The water is present in a minimum amount effective to obtain the desired product, Terazosin.HCl dihydrate. As can be seen from the exemplary embodiments, the minimum, effective amount of water can vary, depending on the polar organic solvent selected. In the Examples below, the percent volume of water which satisfactorily yielded the desired product ranged roughly from as little as 5% by volume to as much as 20% by volume and more. Other polar organic solvents may require a larger or smaller portion of water than the range demonstrated by the examples, but the determination thereof is well within the purview of one of ordinary skill in the art. The reaction mixture is then heated. Preferably, to ensure highest yields, the reaction mixture is maintained at reflux temperature for as much as 35-55 hours or until one or the other of the reactants is substantially consumed. The reaction mixture is thereafter allowed to cool, preferably to room temperature, and the crystalline Terazosin.HCl dihydrate is collected by filtration.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:21]>C(Cl)Cl>[Cl:21][CH2:15][C:12]1[CH:11]=[N:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:14][N:13]=1
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2cnc(CCl)cn2)cc1
Reaction time: 6 h

Procedure:
0.20 g (0.79 mmol) of the above prepared [5-(4-trifluoromethyl-phenyl)-pyrazin-2-yl]-methanol was dissolved in 8 ml of CH2Cl2 and treated dropwise at 0° C. with 0.11 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 1 h, at RT for 18 h and 6 h at 30° C. Evaporation of the solvents and dissolution in ether and heptane with consecutive evaporation afforded 0.21 g of pure title compound as light brown solid.
Reaction SMILES: C[Li].C[Si](Cl)(C)C.[C:8]1(=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])/[CH2:9][CH2:10][C:11]2[C:16]/1=[CH:15][CH:14]=[CH:13][CH:12]=2.[CH2:23]1C2C(=CC=CC=2)C(CC(OCC)=O)=C1>C(OCC)C.C(Cl)Cl.[Cu](I)I>[CH3:23][C:8]1([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)/C=C1\CCc2ccccc21
Reactant: CCOC(=O)CC1=CCc2ccccc21
Agent: I[Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CC1(C)CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a suspension of copper iodide (1.9 g, 9.9 mmol) in diethyl ether (10 mL) was added methyl lithium (12.4 mL, 19.8 mmol, 1.6M in diethyl ether) at 0° C. and the mixture was stirred for 10 min. The solvent was removed under reduced pressure at 0° C. and then CH2Cl2 (10 mL) was added. The reaction mixture was stirred for 5 minutes at 0° C., and then the solvent was removed again under reduced pressure at 0° C. To the residue was added pre-cooled CH2Cl2 (75 mL), cooled to −78° C., and then added trimethylsilyl chloride (1.3 mL, 9.9 mmol) and a solution of a mixture of (E)-ethyl 2-(2,3-dihydro-1H-inden-1-ylidene)acetate and ethyl 2-(1H-inden-3-yl)acetate (1:1 mixture, 1 g, 4.9 mmol) in CH2Cl2 (10 mL), successively. The resulted mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by addition of a mixture of aqueous saturated NH4Cl and 28% NH4OH (1:1, 50 mL). The mixture was extracted with diethyl ether (3×50 mL) and the combined extracts were washed with water, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Hexanes-EtOAc, 0 to 10%) to give 0.47 g of the title compound. Additionally, 0.17 g of unreacted ethyl 2-(1H-inden-3-yl)acetate was recovered. MS (DCI/NH3) m/z 236 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.O[C:38]1[CH:39]=[C:40]([CH:43]=C[CH:45]=1)[C:41]#[N:42].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:45]=[CH:38][CH:39]=[C:40]([C:41]#[N:42])[CH:43]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: N#Cc1cccc(O)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4cccc(C#N)c4)c(C)c3C)c2cc1OC
Yield: 55.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-hydroxybenzonitrile (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (40 mg, yield 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[C:13]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[CH:20][C:16]=1[C:17](Cl)=[O:18])#[N:14].O>CN(C)C=O>[C:13]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[CH:20][C:16]=1[C:17]([N:8]1[C:9](=[O:10])[C:4]2=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=[C:5]2[C:6]1=[O:7])=[O:18])#[N:14]
Reactant: O=C1NC(=O)c2cc(Cl)ccc21
Reactant: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)N1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of 4-chlorophthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-cyano-5-(2,4-dichlorophenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-cyano-5-(2,4-dichlorophenoxy)benzoyl]-4-chlorophthalimide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24](=[O:26])[CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=[O:36])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl>[C:24]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)[C:27](=[O:36])/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(N(C(=O)/C=C/c3ccccc3)C3CCN(Cc4ccccc4)CC3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (250 mg, 0.72 mmol) in CH2Cl2 (10 mL) was added cinnamoyl chloride (160 mg, 0.93 mmol) and triethylamine (TEA, 0.30 mL, 2.2 mmol). The mixture was stirred at 25° C. for 16 h. After concentration, the residue was purified by preparative TLC (PTLC, 20% EtOAc/CH2Cl2) to provide 290 mg (85%) of the desired product. 1H NMR (500 MHz, CDCl3): 8.05 (s, 1H), 7.62 (d, J=15.5 Hz, 1H), 7.32-7.20 (m, 10H), 7.17 (d, J=7.9 Hz, 1H), 6.74 (dd, J=6.8, 1.5 Hz, 1H), 6.15 (d, J=15.5 Hz, 1H), 4.80-4.69 (m, 1H), 4.20-4.09 (m, 3H), 3.51-3.45 (m, 1H), 3.31-3.20 (m, 2H), 2.95-2.82 (m, 2H), 2.23 (s, 3H), 2.19-2.08 (m, 2H), 1.91-1.71 (m, 2H). MS: exact mass calculated for C31H33N3O2, 479.26; m/z found, 480.3 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][CH:4]=[CH:5][CH2:6]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]([C:31]#[CH:32])([CH3:30])([CH3:29])[CH3:28]>[Cu]I.[Pd](Cl)Cl.O1CCCC1>[ClH:3].[CH3:28][C:27]([CH3:30])([CH3:29])[C:31]#[C:32]/[CH:4]=[CH:5]/[CH2:6][NH:2][CH3:1]
Reactant: CN
Reactant: C#CC(C)(C)C
Reactant: ClC=CCCl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNC/C=C/C#CC(C)(C)C
Product: Cl
Yield: 70 %

Procedure:
By using 104 ml (3.02 mol) of 40% methylamine aqueous solution instead of n-propylamine, 85 ml of tetrahydrofuran, 9.10 ml (98.8 mmol) of 1,3-dichloropropene (E/Z=9/1), 950 mg (5 mmol) of copper (I) iodide, 355 mg (2 mmol) of palladium chloride, 1.05 g (4 mmol) of triphenylphosphine and 15.0 ml (0.121 mol) of tert-butylacetylene, the treatment was conducted in the same manner as in Example 1 to obtain 12.9 g (yield: 70%) of the above identified compound as off-white crystalline powder.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][N:6]([CH3:28])[C:7]1[N:27]=[C:10]2[CH:11]=[CH:12][C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][C:19]=3[C:24](O)=[O:25])=[O:17])=[CH:14][N:9]2[N:8]=1>>[CH3:5][N:6]([CH3:28])[C:7]1[N:27]=[C:10]2[CH:11]=[CH:12][C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][C:19]=3[C:24]([N:1]3[CH2:4][CH2:3][CH2:2]3)=[O:25])=[O:17])=[CH:14][N:9]2[N:8]=1
Reactant: C1CNC1
Reactant: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1
Product: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)cn2n1

Procedure:
Using azetidine and 5-(2-dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Brown solid (93 mg, 42%). MS: m/z=369 (M+H+). Ames test negative.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH3+:14])=[CH:8][CH:7]=1)=[O:5].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1.O>[CH2:19]([O:18][C:16]([NH:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:7][CH:8]=1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(CC[NH3+])cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
2-(4-(Methoxycarbonyl)phenyl)ethanaminium chloride (3 g, 13.9 mmol) was dissolved in the mixed solution of tetrahydrofuran (30 mL) and water (30 mL), and then benzyl chloroformate (2.37 g, 13.9 mmol) was dropped into it. To the mixture, sodium bicarbonate (2.9 g, 34.7 mmol) was added and the mixture was stirred at room temperature for 1.5 h. Then the mixture was poured into ethyl acetate (50 mL×3) and the organic layer was washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate and condensed to get methyl 4-(2-(benzyloxycarbonylamino)ethyl)benzoate (3.3 g, yield 77%). LC-MS (ESI) m/z: 314 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.ClCCCl.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>N1C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]4[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)sc2c1
Yield: 98.8 %

Procedure:
Prepared as described in the Amide Coupling section using 1,2-dichloroethane 2-(4-aminophenyl)-6-methylbenzothiazole (2.5 g, 10.4 mmol) and 4-nitrobenzoyl chloride (2.12 g, 11.4 mmol) in dry pyridine (30 ml) to give the title compound (4.0 g, 99%) as small tan-coloured needles after recrystallisation from DMF/water.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([CH:11]=1)[CH:9]=[O:10]>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([CH:9]([OH:10])[CH3:1])[CH:11]=1
Reactant: [Li]C
Reactant: O=Cc1cc(Br)ccc1Cl
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)ccc1Cl
Reaction time: 15 h
Yield: 89.3 %

Procedure:
Methyl lithium (11.6 mL, 16.3 mmol, 1.4M in ether) was added to a cooled −78° C. solution of 5-bromo-2-chloro-benzaldehyde (2.75 g, 12.5 mmol) dissolved in THF (40 mL). The reaction mixture was stirred for 15 hours and then quenched with saturated NH4Cl and extracted with EtOAc. The organic extracts were washed with 1N HCl, brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a solid (2.63 g, 91%). 1H NMR (400 MHz, CDCl3): δ 6.32 (d, J=6.3 Hz, 3H), 2.00 (d, J=3.8 Hz, 1H), 5.24 (m, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.33 (dd, J=8.6, 2.5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:12]([CH3:24])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C@@H:8]([CH3:11])[CH:9]=O)([CH3:4])[CH3:3].[CH3:27][NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(O)(=O)C.CCOC(C)=O>[CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:12]([CH3:24])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C@@H:8]([CH3:11])[CH2:9][NH:28][CH3:27])([CH3:4])[CH3:3]
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=O)cc1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)COCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
A solution of 2,4-dideoxy-3-O-[(1,1-dimethylethyl)dimethylsilyl]-5-O-[(4-methoxyphenyl) methyl]-2,4-dimethyl-L-arabinose (2.8 g, 7.37 mmol) in THF (10 mL) is added slowly to a stirred solution of methylamine (14.7 mL, 29.5 mmol) in THF at room temperature. After being stirred at room temperature for 20 min, sodium triacetoxyborohydride (2.3 g, 11.05 mmol), followed by acetic acid (10 drops) are added at room temperature. After being stirred at room temperature overnight, the reaction mixture is diluted with EtOAc (100 mL), and washed with saturated NaHCO3 (2×30 mL), H2O (50 mL), brine (50 mL) and dried over Na2SO4. After removal of the solvent in vacuo, the residue is chromatographed on silica gel with MeOH/CH2Cl2 (1/99) to give the desired compound (1.54 g, 52.9%) as a pale viscous oil.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:10]([O:17][CH:18]1[CH2:21][C:20]2([CH2:25][C:24]([C:26]3[CH:31]=[N:30][C:29]4[NH:32][N:33]=[CH:34][C:28]=4[C:27]=3[NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:23][O:22]2)[CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O.O>[CH2:10]([O:17][CH:18]1[CH2:21][C:20]2([CH2:25][C:24]([C:26]3[CH:31]=[N:30][C:29]4[N:32]([CH2:1][CH3:2])[N:33]=[CH:34][C:28]=4[C:27]=3[NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:23][O:22]2)[CH2:19]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(COC2CC3(CC(c4cnc5[nH]ncc5c4NC4CCOCC4)=NO3)C2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCOCC3)c(C3=NOC4(C3)CC(OCc3ccccc3)C4)cnc21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Ethyl iodide (0.227 gm, 1.45 mmol) and potassium carbonate (0.2 gm, 1.45 mmol) were added to the solution of 5-[2-(benzyloxy)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.21 gm, 0.48 mmol) (step b) in dimethylformamide and the reaction mixture was stirred at 60° C. for about 5 hours. It was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified over silica gel column.
Reaction SMILES: [CH3:1][C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:3][CH:4]=[O:5].[OH-:14].[Na+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:3][C:4]([OH:14])=[O:5]
Reactant: CC(C=Cc1ccccc1)=CC=O
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C=Cc1ccccc1)=CC(=O)O
Reaction time: 5 h
Yield: 14.7 %

Procedure:
To a stirred solution of 3-methyl-5-phenyl-2,4-pentadienal (16.5 g) in ethanol (330 mL) was added dropwise a solution of silver nitrate (19.28 g) in water (160 mL) followed by dropwise addition of an aqueous sodium hydroxide (25 g, 80 mL) solution. The resulting mixture was allowed to stir for an additional five hours and then filtered. The solid was washed with ethanol. The combined filtrate was concentrated in vacuum. The residue was dissolved in water (200 mL). The aqueous solution was extracted with ether (300 mL) twice and acidified with 6 N hydrochloric acid (74 mL). The solid formed was filtered and recrystallized from methanol (40 mL) to yield 2.65 g of the desired 3-methyl-5-phenyl-2,4-pentadienoic acid. 1H NMR (acetone-d6, 300 MHz), δ(ppm) 7.60 (d, 2H), 7.35 (m, 3H), 7.06 (m, 2H), 6.02 (broad s, 1H), 2.50 (s, 3H).
Reaction SMILES: CC(OC(=O)[NH:7][C:8]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]([N:25]2[CH2:29][C@@H:28]([CH:30]3[CH2:35][CH2:34][N:33]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:32][CH2:31]3)[CH2:27][C@H:26]2[C:40]2[NH:41][C:42]([C:45]3[CH:50]=[CH:49][C:48]([NH:51][C:52]([O:54][CH3:55])=[O:53])=[CH:47][CH:46]=3)=[CH:43][N:44]=2)=[O:24])[CH2:19][CH2:18]1)=[N:9]C(=O)OC(C)(C)C)(C)C.FC(F)(F)C(O)=O.[Cl:64]CCl>>[ClH:64].[ClH:64].[C:8]([N:17]1[CH2:18][CH2:19][CH:20]([C:23]([N:25]2[CH2:29][C@@H:28]([CH:30]3[CH2:31][CH2:32][N:33]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:34][CH2:35]3)[CH2:27][C@H:26]2[C:40]2[NH:41][C:42]([C:45]3[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:53])[O:54][CH3:55])=[CH:47][CH:46]=3)=[CH:43][N:44]=2)=[O:24])[CH2:21][CH2:22]1)(=[NH:7])[NH2:9]
Reactant: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)C3CCN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC3)[nH]2)cc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)C3CCN(C(=N)N)CC3)[nH]2)cc1
Product: Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of the compound prepared in Example 68 (0.067 g, 0.084 mmol) in dichloromethane (2 mL) at 0° C. was added trifluoroacetic acid (0.09 mL, 1.2 mmol). The reaction was warmed to room temperature and stirred for 4 h whereupon the solvent and excess trifluoroacetic acid was removed in vacuo. The resulting residue was dissolved in methanol (5 mL) and 6 M hydrochloric acid (0.70 mL) was added. The mixture was concentrated to dryness and the process repeated twice. The residue was triturated with methanol and methyl tert-butyl ether, the resulting solids dissolved in water and lyophilized to afford the title compound (0.050 g, 96%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]#N)[C:9]2=[O:17])=[C:4]([CH3:18])[CH:3]=1.S(=O)(=O)(O)[OH:20].[OH-:24].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([OH:20])=[O:24])[C:9]2=[O:17])=[C:4]([CH3:18])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Reactant: Cc1cc(F)ccc1-n1c(C)ccc(C#N)c1=O
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)ccc1-n1c(C)ccc(C(=O)O)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
1-(4-fluoro-2-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (590 mg, 2.9 mmol) was suspended in water (3.0 mL), conc. sulfuric acid (3.0 mL) was slowly added dropwise. The mixture was stirred overnight at 100° C., and allowed to cool to room temperature. The reaction system was basified with aqueous sodium hydroxide solution (8N) and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (1N), and extracted twice with ethyl acetate. The mixed organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Hexane-ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration to give the title compound (480 mg, 75%) as a white solid.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:12].[Na+:13].I[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]>O.C(O)(C)C>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][O:12][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[S:8]([O-:11])(=[O:10])=[O:9].[Na+:13]
Reactant: O=S(=O)(O)c1ccc(O)cc1
Reactant: CC(C)CCI
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)CCOc1ccccc1S(=O)(=O)[O-]

Procedure:
A solution of 4hydroxybenzenesulfonic acid (10.0 grams, 43.1 mmole) and sodium hydroxide (3.3 grams, 83 mmole) in water (40 mL) was mixed with a solution of 1-iodo-3methylbutane (11.3 mL, 86.4 mmole) in isopropanol (60 mL) and the resulting mixture was heated at reflux for 2 days. The isopropanol was removed by evaporation under vaccuum. The titled compound, 10.0 grams (87%), was collected by filtration washing with isopropanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1.[CH2:25]=O.[CH2:27]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>>[OH:1][C:2]1[C:7]([CH2:25][N:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:6][C:5]([C:8]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:9])[CH3:10])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C=O
Reactant: CCCCNCCCC
Product: CCCCN(CCCC)Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Temperature: 160 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
2-[2-Hydroxy-5-tert-octylphenyl]-2H-benzotriazole (30 g, 0.092 mol), paraformaldehyde (3 g, 0.0955 mol) and di-n-butylamine (24.9 g, 0.191 mol) are charged to a pressure reaction at ambient temperature. The reactor is sealed and the temperature raised to 160° C. The reaction mass is held at 160° C. for four hours and then discharged. The reactor is rinsed with toluene. The toluene, amine and water are stripped by rotary evaporation. The crude product is prepared in a 96% yield (40 g). This product is chromatographed on silica gel using a heptane/ethyl acetate gradient as eluent to remove a trace of unreacted starting benzotriazole intermediate. The title compound is a yellow oil whose structure is confirmed by 1Hnmr.