Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26](OC)=O.[H-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]1[O:1][C:2]2[C:3]([C:20](=[O:22])[CH:21]=1)=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=2[C@@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]1[CH2:14][OH:15]
Reactant: COC(=O)c1ccccc1Cl
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO

Procedure:
(+)-trans-1-[2-Hydroxy-3-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)- -4,6-dimethoxyphenyl]-1-ethanone (compound 13), was prepared from (+)-trans-[1-Methyl-3-(2,4,6-trimethoxy-phenyly-pyrrolidin-2-yl]-methanol using the procedures described in examples 6 & 7. Compound 13, (0.7 g, 2.2 mmol) was reacted with methyl 2-chlorobenzoate (1.15 g, 6.75 mmol) in dry DMF (15 mL) in the presence of NaH (50%, 0.54 g, 11.25 mmol), using the procedure described in example 8 to afford the title compound(4).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)=[O:10])=[CH:4][C:3]=1[O:22][CH3:23]>C(O)C.[Pt]=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)=[O:10])=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1cc(CC(=O)N[C@H]2CC[C@@H](C=C(C)C)CC2)ccc1O
Agent: O=[Pt]
Solvent: CCO
Product: COc1cc(CC(=O)N[C@H]2CC[C@@H](CC(C)C)CC2)ccc1O
Reaction time: 3 h

Procedure:
The compound (0.3 g) of Example 95 was dissolved in ethanol (15 ml), platinum oxide (50 mg) was added to the solution, and the mixture was hydrogenated at room temperature. After 3 hours, the catalyst was removed by filtration from the reaction mixture and then the solvent was evaporated under reduced pressure. The residue was crystallized from diisopropyl ether to give 0.21 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:27]=2)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].Cl>O.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:27]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)c1ccc(-c3ccnc(F)c3)cc1N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)NC(=O)c1ccc(-c3ccnc(F)c3)cc1N2
Yield: 79.1 %

Procedure:
A mixture of Example 69B (60 mg, 0.17 mmol) and LiOH (20 mg, 0.85 mmol) in water (5 mL) and THF (5 mL) was heated to reflux until a homogeneous solution formed, adjusted to pH 5 with 10% HCl, and extracted with ethyl acetate several times. The combined extracts were washed with brine, dried (CaCl2), filtered, and concentrated under vacuum to provide 47 mg (80%) of the desired product. MS (DCI) m/e 349 (M)+; 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.42 (s, 1H), 8.36 (d, J=5.3 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.62 (d, J=5.3 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.55 (dd, J=8.4, 1.9 Hz, 1H), 7.45 (s, 1H), 7.24 (d, J=1.6 Hz, 1H), 7.37 (dd, J=8.1, 1.9 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:41][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5ccccc5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (150 mg, 0.32 mmol) and benzylamine (138 mg, 1.3 mmol) was heated at 130° C., with stirring for 2 hours. The residue was purified by chromatography (silica gel, 6 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) and then further purified by prep-HPLC to afford {4-[3-(2-benzylamino-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 30 mg, 18.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:23]3[S:19][C:20](=[O:25])[NH:21][C:22]3=[O:24])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(SCCc2ccc(Cl)cc2)cc1
Product: O=C1NC(=O)C(=Cc2ccc(SCCc3ccc(Cl)cc3)cc2)S1

Procedure:
4-[2-(4-Chlorophenyl)ethylthio]benzaldehyde and thiazolidine-2,4-dione were coupled according to the method of Example 5 to form present title product in similar yield; m.p. 215°-225° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[N:42]1[CH:47]=[C:46](B(O)O)[CH:45]=[N:44][CH:43]=1>>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([C:46]3[CH:47]=[N:42][CH:43]=[N:44][CH:45]=3)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: OB(O)c1cncnc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3cncnc3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Yield: 73.4 %

Procedure:
A similar procedure as described in Example 12, step 8 was used, starting from 4-{3-[6-(3-iodo-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (207 mg, 0.3 mmol) and pyrimidin-5-ylboronic acid (124 mg, 1.0 mmol) to obtain 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-pyrimidin-5-yl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (142 mg, 73%) as a light yellow viscous oil: ES(+)-HRMS m/e calculated for C37H44N2O6S (M+H)+ 645.2993, found 645.2987.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH:4]=O.[CH:11](=[O:15])[CH2:12][CH2:13][CH3:14]>>[CH2:13]([CH:12]([CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:11]=[O:15])[CH3:14]
Reactant: CC(CC=O)CC(C)(C)C
Reactant: CCCC=O
Product: CCC(C=O)CCC(C)CC(C)(C)C

Procedure:
2-Ethyl-5,7,7-trimethyloctanal was prepared from 3,5,5-trimethylhexanal and n-butanal similarly to Examples 1 and 2; it was obtained in the form of a diastereomeric mixture.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:3]=1[C:4](=[N:19][OH:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(O)c(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccccc1)c1ccc(O)c(Cl)c1Cl

Procedure:
A solution of 18.0 g of 2,3-dichloro-4-hydroxybenzophenone and 9.3 g of hydroxylamine hydrochloride in 100 ml of pyridine is refluxed for 2 hours. Thereafter, the pyridine is evaporated under vacuum and the residual liquid is partitioned between 5% hydrochloric acid and ethyl acetate. The ethylacetate extract is washed with water, dried, and evaporated to give 2,3-dichloro-4-hydroxy-benzophenone oxime.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)c(CNCCc2ccccc2)c1
Temperature: 0 °C
Yield: 82 %

Procedure:
2-Chloro-5-nitro-benzaldehyde (5 g, 27 mmol) and 2-phenylethylamine (4.1 g, 33.75 mmol) were dissolved in methanol, cooled to 0° C., and sodium cyanoborohydride (2.1 g, 33.75 mmol) was added. The reaction was adjusted to pH 6 with acetic acid and warmed to room temperature for 6 h. The reaction mixture was quenched with ice and diluted with water. The pH was adjusted to 11 with sodium hydroxide and the mixture was extracted with methylene chloride. The organic extracts were washed with water and brine and dried briefly over sodium sulfate. Filtration of the mixture and concentration of the filtrate in vacuo yielded the title compound (82%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Reactant: CC(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)NCc1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
100 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 55 μl of tert-butylamine and 15 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 170 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)[C:7]1[NH:8][CH:9]=[CH:10][N:11]=1)[CH3:3].O.[NH2:23][NH2:24]>C(O)C>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:23][NH2:24])=[O:17])=[CH:14][CH:13]=1)[C:7]1[NH:8][CH:9]=[CH:10][N:11]=1)[CH3:3]
Reactant: NN
Reactant: COC(=O)c1ccc(C(CCN(C)C)c2ncc[nH]2)cc1
Solvent: O
Solvent: CCO
Product: CN(C)CCC(c1ccc(C(=O)NN)cc1)c1ncc[nH]1

Procedure:
A solution of 4-[3-(N,N-dimethylamino)-1-(imidazol-2-yl)propyl]benzoic acid, methyl ester (3.0 g) and hydrazine hydrate (12.5 ml) in ethanol (50 ml) was boiled under reflux for 1 day. Removal of the solvent gave a white solid which was recrystallised from isopropanol-ether to give the title compound, m.p. 168°-170° (2.46 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:18][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[CH3:20].CO.N>C(O)CCC>[CH3:20][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=3[CH3:16])[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:31]=1)[CH3:18]
Reactant: Cc1ccc(C)c(Nc2ccnc(Cl)n2)c1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCCCO
Product: Cc1ccc(C)c(Nc2ccnc(Nc3ccc(OCC(O)CN(C)C)cc3)n2)c1
Temperature: 100 °C
Yield: 23.9 %

Procedure:
2-Chloro-4-(2,5-dimethylanilino)pyrimidine (Reference Example A-1; 250 mg, 1.07 mmol) was dissolved in n-butanol (5 ml) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline hydrochloride (Reference Example D-1; 295 mg, 1.07 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 100° C. for 8 hours and allowed to cool to ambient temperature. The reaction mixture was then basified to pH 9–10 using methanolic ammonia and then evaporated onto silica (5 ml). The residue was purified by column chromatography eluting with methanol (15%):DCM:aqueous ammonia (1%). The resulting gum was recrystallized from acetonitrile to give the title product as a solid (104 mg, 24%). NMR (300 MHz): 2.13 (s, 3H), 2.25 (s, 3H), 2.79 (s, 6H), 3.19 (m, 2H), 3.88 (m, 2H), 4.21 (m, 1H), 5.88 (brs, 1H), 6.05 (d, 1H), 6.73 (d, 2H), 6.93 (d, 1H), 7.12 (d, 1H), 7.26 (s, 1H), 7.55 (d, 2H), 7.9 (d, 1H), 8.6 (s, 1H), 8.88 (s, 1H); m/z: (ES+) 408.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Mg].[Cl:13][C:14]1[CH:25]=[CH:24][C:17]([C:18](N(OC)C)=[O:19])=[CH:16][N:15]=1.[Cl-].[NH4+]>C1COCC1.BrCCBr.O>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[O:19])=[CH:24][CH:25]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=C(c1ccc(C(F)(F)F)cc1)c1ccc(Cl)nc1

Procedure:
Under an argon gas flow, half of a solution of 4-bromobenzotrifluoride (1.20 g, 5.33 mmol) in THF (6 mL) was added to magnesium (156 mg, 6.41 mmol). The resulting solution was stirred, and further 1,2-dibromoethane (3 drops) was added. Once the reaction began, the balance of the 4-bromobenzotrifluoride in THF solution was added dropwise, and once dropping had finished, the resulting solution was stirred for 30 minutes at 60° C. A solution of 6-chloro-N-methoxy-N-methylnicotinamide (990 mg, 5.36 mmol) in THF (3 mL) was charged into a separate reaction vessel, into which the above reaction solution was added dropwise under an argon gas flow and ice cooling. After dropping had finished, the resulting solution was stirred for 30 minutes at room temperature, and then heated to reflux for 1 hour. The reaction solution was cooled with ice, then aqueous ammonium chloride and water were added. The resulting solution was extracted with ethyl acetate, and washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 610 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[O:7]C2.[O-][Mn](=O)(=O)=O.[K+].[C:21]([O-:24])([O-:23])=O.[Na+].[Na+]>O>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([C:8]([OH:14])=[O:7])[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:21]([OH:24])=[O:23]
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(cc1OC)C(=O)OC2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)O)c(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
5,6-Dimethoxyisobenzofuran-1(3H)-one (3.171 g, 16.33 mmol) was treated with a solution of KMnO4 (2.57 g, 16.26 mmol) and Na2CO3 (1.542 g, 14.55 mmol) in water (110 ml). The solution was stirred at room temperature for 24 hours, then insoluble material was removed by filtration. The filtrate was cooled with an ice-water bath and acidified with concentrated aqueous HCl. The acidic solution was extracted three times with ethyl acetate (500 ml). The combined organic layers were dried over sodium sulfate and evaporated to dryness to give 600 mg of desired compound. The aqueous phase was then concentrated to 20 ml and a white solid precipitated. After filtration 500 mg desired compound were recovered. The two portions were collected to afford 4,5-dimethoxyphthalic acid as a white powder (1.1 g, 4.87 mmol, 30% yield). MS/ESI+ not detectable [MH]+.
Reaction SMILES: OCCCCCC12CC(=O)CC1CCC2.[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][C:25](=[O:30])[CH2:26]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][C:25](=[O:30])[CH2:26]2)=[O:16]
Reactant: O=C1CC2CCC(CCCCCO)C2C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C1CC2CCCC2(CCCCCO)C1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCCC1CCC2CC(=O)CC12

Procedure:
The procedure followed is the same as that described in Example 13 substituting the starting material prepared in Example 11, 2-(5-hydroxypent-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-hydroxypentyl)-2(1H)-pentalenone} (0.3 g, 1.4 mmoles), and pyridinium dichromate (0.80 g, 2.1 mmoles) dissolved in methylene chloride (5 ml). The crude product is chromatographed on silica gel leaving a clear, colorless oil (0.14 g, 0.67 mmoles).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([F:7])[F:6])=[N+]=[N-]>CCOC(C)=O.[Pd]>[F:6][C:5]([F:7])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCC(F)(F)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCC(F)(F)c1ccccc1
Yield: 98.3 %

Procedure:
Dissolve (2-azido-1,1-difluoro-ethyl)-benzene (475 mg, 2.59 mmol) in EtOAc (30 mL). Add 10% Pd/C and submit the mixture to hydrogenation under atmospheric pressure (balloon) for 1 h. Filter the catalyst through Celite® and concentrate the filtrate in vacuo to provide the title compound as an oil (400 mg, 98%) that was used without any further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:30]3[CH2:32][CH2:31]3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[F:33][C:34]1[CH:44]=[CH:43][C:37]([CH2:38][NH:39][C:40]([NH2:42])=[O:41])=[CH:36][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:30]1([C:8]2[C:5]3[CH:6]=[N:7][C:2]([NH:42][C:40]([NH:39][CH2:38][C:37]4[CH:43]=[CH:44][C:34]([F:33])=[CH:35][CH:36]=4)=[O:41])=[CH:3][C:4]=3[N:10]([C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]=2)[CH2:31][CH2:32]1
Reactant: NC(=O)NCc1ccc(F)cc1
Reactant: Clc1cc2c(cn1)c(C1CC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C(NCc1ccc(F)cc1)Nc1cc2c(cn1)c(C1CC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 89.4 %

Procedure:
A mixture of 6-chloro-3-cyclopropyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (60 mg, 0.138 mmol), 1-(4-fluorobenzyl)urea (69 mg, 0.413 mmol), palladium(II) acetate (6 mg, 0.028 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethyxanthene, 24 mg, 0.041 mmol), and cesium carbonate (112 mg, 0.028 mmol) in dioxane (1 mL) was degassed and refilled with nitrogen (3 times) and then heated at 80° C. overnight. The mixture was diluted with dichloromethane (5 mL) and water (1 mL), and then was filtered through celite. The DCM layer was evaporated under reduced pressure and purified by column chromatography on silica gel (eluting with 0-30% EtOAc/hexanes) to give 1-(3-cyclopropyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-fluorobenzyl)urea (70 mg, 90% yield) as a clear-white film. MS ESI calc'd. for C36H30FN5O[M+1]+ 568, found 568.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[O:16][C:7]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[C:14]#[N:15])=[N:6][N:5]=1
Reactant: N#Cc1cccc(C(=O)NNC(=O)CCl)c1
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2nnc(CCl)o2)c1
Yield: 28.5 %

Procedure:
N′-(chloroacetyl)-3-cyanobenzohydrazide (795 mg, 3.34 mmol) and P2O5 (4.7 g, 33.4 mmol) were added to DMF (6 ml) and toluene (4 ml). The reaction mixture was refluxed for 2 h. K2CO3 (aq., sat.) was added until pH was basic and the mixture was extracted with DCM. The combined organic layers were dried (Na2SO4) and purified with flash chromatography using 0 to 100% EA in hep. to give the title compound (209 mg, 29%). 1H NMR: 8.29 (m, 2 H), 7.82 (m, 1 H), 7.66 (t, 1 H), 4.78 (s, 2 H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:5]=1[C:20]#[N:21])=[N+:2]=[N-:3].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[CH:23].CC(O)C>O.S([O-])([O-])(=O)=O.[Cu+2]>[C:20]([C:5]1[CH:6]=[C:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:8]=[CH:9][C:4]=1[N:1]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=[N:2]1)#[N:21]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1ccnc(-c2ccc(N=[N+]=[N-])c(C#N)c2)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccnc(-c2ccc(-n3cc(-c4ccccc4)nn3)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg of methyl 2-(4-azido-3-cyanophenyl)isonicotinate, 54 μl of ethynylbenzene, 72 μl of aqueous 1 M sodium L(+)-ascorbate solution and 2 mg of copper sulfate were added to a mixture of 1.4 ml of water and 1.4 ml of 2-propanol, followed by vigorous stirring overnight at room temperature. The reaction mixture was diluted with 5 ml of water, the precipitate formed was collected by filtration, washed with iced cool water, and dried under reduced pressure to obtain 12 mg of methyl 2-[3-cyano-4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]isonicotinate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([C:17]#[C:18][CH2:19]O)[CH:11]=[CH:12][C:13]=2[N+:14]([O-:16])=[O:15])[CH2:4][CH2:3]1.[CH2:21]([N:23](CC)[CH2:24]C)[CH3:22].CS(Cl)(=O)=O.O>C(Cl)Cl.C(NC)C>[CH2:21]([N:23]([CH3:24])[CH2:19][C:18]#[C:17][C:10]1[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)[CH:9]=1)[CH3:22]
Reactant: CCN(CC)CC
Reactant: CC1CCN(c2cc(C#CCO)ccc2[N+](=O)[O-])CC1
Agent: CCNC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCN(C)CC#Cc1ccc([N+](=O)[O-])c(N2CCC(C)CC2)c1
Yield: 100 %

Procedure:
To a stirred solution of 3-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-prop-2-yn-1-ol (as prepared in the previous step, 47 mg, 0.17 mmol) in 4 mL of DCM at 0° C. was added triethylamine (71 μL, 0.51 mmol) followed by methanesulfonyl chloride (17 μL, 0.22 mmol). The reaction was allowed to stir for 10 min, at which time ethylmethylamine (4 drops) was added. The result was heated at reflux for 20 min. and then poured into water (20 mL). The aqueous layer was extracted with DCM (2×25 mL), the organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC (10%-MeOH—CHCl3) to afford 59 mg (100%) of the title compound as an oil. Mass spectrum (ESI, m/z) Calcd for C18H25N3O2, 316.1 (M+H). found 316.2.