Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][CH:15]([CH2:17][O:18][CH3:19])[CH2:14][CH:13]1[C:20]1[NH:24][C:23]2[C:25]3[C:30]([CH:31]=[CH:32][C:22]=2[N:21]=1)=[CH:29][C:28]1[C:33]2[C:38]([CH2:39][O:40][C:27]=1[CH:26]=3)=[CH:37][C:36]([C:41]1[NH:45][C:44]([CH:46]3[CH2:50][CH:49]([CH3:51])[CH2:48][N:47]3C(OC(C)(C)C)=O)=[N:43][CH:42]=1)=[CH:35][CH:34]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].Cl>C(O)C>[CH3:19][O:18][CH2:17][CH:15]1[CH2:16][N:12]([C:10](=[O:11])[CH:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])[CH:13]([C:20]2[NH:24][C:23]3[C:25]4[C:30]([CH:31]=[CH:32][C:22]=3[N:21]=2)=[CH:29][C:28]2[C:33]3[C:38]([CH2:39][O:40][C:27]=2[CH:26]=4)=[CH:37][C:36]([C:41]2[NH:45][C:44]([CH:46]4[CH2:50][CH:49]([CH3:51])[CH2:48][NH:47]4)=[N:43][CH:42]=2)=[CH:35][CH:34]=3)[CH2:14]1
Reactant: COCC1CC(c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc(C4CC(C)CN4C(=O)OC(C)(C)C)[nH]3)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Agent: Cl
Solvent: CCO
Product: COCC1CC(c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc(C4CC(C)CN4)[nH]3)ccc2-5)N(C(=O)C(NC(=O)OC)C(C)C)C1
Temperature: 60 °C

Procedure:
tert-butyl 2-[5-(2-{1-[N-(methoxycarbonyl)valyl]-4-(methoxymethyl)pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (50 mg, 0.063 mmol) was treated with 2 mL 1.25N HCl in ethanol and heated at 60° C. for 2 h, then it was concentrated under reduced pressure and pumped dry under high vacuum and used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[NH:6][C:7](=[O:22])[CH2:8][CH:9]3[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.Cl>ClCCl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[NH:6][C:7](=[O:22])[CH2:8][CH:9]3[CH2:14][NH:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN2c3cc(Cl)ccc3NC(=O)CC2C1
Agent: Cl
Solvent: ClCCl
Product: O=C1CC2CNCCN2c2cc(Cl)ccc2N1

Procedure:
To a solution of Example 3C (122 mg, 0.347 mmol) in dichloromethane (5 mL) was added HCl (4 M in dioxane, 0.867 mL, 3.47 mmol). After the reaction was complete by LC/MS analysis, the volatiles were removed in vacuo, and the residue was purified by preparative HPLC to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.12-7.20 (m, 2 H), 7.01 (d, J=8.24 Hz, 1 H), 3.61-3.69 (m, J=8.09 Hz, 1 H), 3.27-3.42 (m, 4 H), 2.94-3.08 (m, 2 H), 2.68 (dd, J=13.73, 7.02 Hz, 1 H), 2.08 (d, J=12.51 Hz, 1 H); MS (ESI) m/z 251.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH2:20][CH3:21])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH2:12]([O:11][C:9]1[C:8]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([CH2:20][CH3:21])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:10]=1)[CH:13]=[CH2:14]
Reactant: O=C(O)c1ccccc1
Reactant: C=CCOc1cc(CC(=O)OC)c(CC)c(OCC=C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C=CCOc1cc(OCC=C)c(C(=O)c2ccccc2)c(CC(=O)OC)c1CC
Temperature: 4 °C
Reaction time: 18 h
Yield: 56.6 %

Procedure:
Methyl 3,5-diallyloxy-2-ethylphenylacetate (0.31 g, 1.3 mmol) obtained in Example 5, Step 3 was dissolved in trifluoroacetic acid (2.0 mL). After the solution was cooled to 4° C., benzoic acid (0.40 g, 3.3 mmol) and trifluoroacetic anhydride (1.0 mL) were added thereto, followed by stirring for 18 hours, while the temperature of the reaction mixture was raised to room temperature. The reaction mixture was gradually added to a saturated aqueous solution of sodium hydrogencarbonate for neutralization, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/4) to obtain methyl 3,5-diallyloxy-2-benzoyl-6-ethylphenylacetate (0.29 g, 55%).
Reaction SMILES: O[CH:2]([C:10]1[C:15]2[CH:16]([CH3:19])[CH2:17][O:18][C:14]=2[C:13]([O:20][CH3:21])=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:21][O:20][C:13]1[C:14]2[O:18][CH2:17][CH:16]([CH3:19])[C:15]=2[C:10]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C(O)Cc2ccncc2)c2c1OCC2C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CCc2ccncc2)c2c1OCC2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 7.4 %

Procedure:
Under an argon atmosphere, a solution (17 ml) of Compound 57a (0.6 g) obtained in Step A in methylene chloride was cooled to −78° C., and then boron trifluoride ether complex (0.42 ml) and triethylsilane (0.8 ml) were successively added thereto, followed by stirring at 0° C. for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to give Compound 57 (0.042 g, 9.1%) as a pale-yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:29]=[CH:28][C:24]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:29]=[CH:28][C:24]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=2)=[O:20])[CH2:7]1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: CN(C)c1ccc(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 78 %

Procedure:
Example 36 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 4-isocyanato-N,N-dimethylaniline (0.0221 g) to give the title compound (0.031 g). LC-MS (System A): Rt 1.68 mins, Mass Spectrum m/z 437 [MH+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8](C[C@@H]3CCCN3C(OC(C)(C)C)=O)[N:9]=[C:10](C3C=CC(OC4C=CC=C(F)C=4F)=CC=3F)[C:3]=12.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[CH:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2S)-tert-butyl 2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carboxylate (1.97 g, 3.65 mmol, 1.00 equiv) in DCM (30 mL) was added trifluoroacetic acid (7.5 mL). The resulting solution was stirred for 4 h at room temperature. This solution was concentrated under reduced pressure. This resulted in 2.4 g (Crude) of 3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-(S)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetic acid salt as a reddish oil. MS (ESI, pos. ion) m/z: 441 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[N:17]1[C:21](=[O:22])[CH2:20][CH:19]([C:23]([OH:25])=O)[CH2:18]1.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:23]([CH:19]1[CH2:20][C:21](=[O:22])[N:17]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)=[CH:7][C:2]=2[F:1])[CH2:18]1)=[O:25]
Reactant: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2F)C1
Reactant: CN
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2F)C1

Procedure:
The title compound is prepared in analogy to Example 20d) from (RS)-1-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid and methylamine. Yield: 39% of a brownish solid. MS: m/e=361.2 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([NH2:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([NH:25][C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:4]
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
3.22 ml of bromoacetyl bromide were added dropwise under an inert gas atmosphere at 0° C. to 19.23 g of tritylamine in 50 ml of chloroform and then the mixture was stirred for one hour while allowing the temperature to rise to ambient temperature. After filtration of the precipitate, the organic phase was washed with 1N sodium hydroxide, dried, evaporated under reduced pressure until a residue was obtained which was purified by crystallization from ether to obtain 8.5 g of the expected amide.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([CH:14]=[N:15][OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O.O>CN(C)C=O>[OH:16][N:15]=[C:14]([Cl:21])[C:13]1[CH:17]=[CH:18][C:10]([O:9][C:8]2[CH:19]=[CH:20][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1ccc(Oc2ccc(C=NO)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(Oc2ccc(C(Cl)=NO)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.2 %

Procedure:
To a solution of Example 17C (1.48 g, 5.56 mmol) in N,N-dimethyl formamide (15 mL) was added N-chlorosuccinimide (0.70 g, 5.24 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was poured into water. The aqueous layer was extracted with ether washed with water, then brine, and dried over MgSO4 and concentrated to give the title compound as an oil (1.67 g, 100%),
Reaction SMILES: [CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[N:29]1([CH2:35][CH2:36]O)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[ClH:69]>C(Cl)Cl.CO>[ClH:69].[CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:36][CH2:35][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:25][CH:26]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CCC[C@H](C)NC(=O)Nc1nc2nccc(-c3ccc(O)cc3)n2n1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)CCC[C@H](C)NC(=O)Nc1nc2nccc(-c3ccc(OCCN4CCOCC4)cc3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-1-(1,5-dimethylhexyl)-3-[7-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]urea (the compound obtained in Example 255; 20 mg) was dissolved in methylene chloride (1 ml) in an argon atmosphere. Thereafter, 2-morpholin-4-ylethanol (21 mg) and triphenylphosphine (41 mg) were added to the obtained solution, and the obtained mixture was stirred at a room temperature for 30 minutes. Thereafter, the reaction solution was cooled on ice, and diethyl azodicarboxylate (27 mg) was then added thereto, followed by stirring the mixture at the same temperature for 30 minutes. The reaction solution was further stirred at a room temperature overnight. Thereafter, the reaction solution was concentrated under a reduced pressure. Thereafter, ethyl acetate (3 ml) and 1 M hydrochloric acid (3 ml) were added thereto, and the obtained mixture was separated. After the obtained water layer was washed with ethyl acetate (3 ml), an aqueous 6 M sodium hydroxide solution was added thereto to convert the solution to be alkaline. After extraction with methylene chloride (5 ml), the organic layer was washed with distilled water (5 ml×2), and the solvent was then distilled off under a reduced pressure. The residue was washed by suspension in a mixed solvent (2 ml) consisting of 50% ethyl acetate and hexane to obtain the captioned compound in the form of a free body (18 mg). Thereafter, methanol (1 ml) and 1 M hydrochloric acid (0.2 ml) were added to the obtained compound and dissolved therein, and the obtained mixture was then concentrated under a reduced pressure. The obtained residue was washed by suspension in acetone (0.5 ml) to obtained the captioned compound (17 mg).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([S:20]([OH:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].I[CH3:27].Cl>C1COCC1>[C:3]([C:7]1[CH:25]=[CH:24][C:10]([C:11]([N:13]([C:14]2[CH:15]=[C:16]([S:20]([OH:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[CH3:27])=[O:12])=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc(S(=O)(=O)O)c2)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc(C(C)(C)C)cc1)c1cccc(S(=O)(=O)O)c1
Reaction time: 17 h
Yield: 23 %

Procedure:
Sodium hydride (26 mg, 0.66 mmol) was added to a stirred solution of 3-(4-tertbutylbenzamido)benzenesulfonic acid (0.10 g, 0.30 mmol) in THF (5 mL), and after 30 min iodomethane (37 μL, 0.60 mmol) was added. The reaction was stirred for 17 h, and 1 M aqueous hydrochloric acid (1 mL) was added. The solvent was removed under vacuum, and the residue was purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 3-(4-tert-butyl-N-methylbenzamido)benzenesulfonic acid (24 mg, 23% yield). LC/MS: m/z 348.3 (M+H)+ at 3.82 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>N.CO.C1COCC1.[Ni]>[NH2:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([C:17]2[NH:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([NH:9][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])[C:11]=3[CH:18]=2)=[CH:20][CH:21]=1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(C#N)cc3)cc12)c1ccccc1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN)cc3)cc12)c1ccccc1

Procedure:
Raney-Nickel (0.1 g) catalyzed hydrogenation of 0.206 g (0.6 mmol) 4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzonitrile in a mixture of 5% ammonia in methanol (20 ml) and THF (4 ml) for 6 h at atmospheric pressure followed by filtration and evaporation of the solvent gives the title compound; m.p. 253-256° C.; MS-ES+: (M+H)+=344.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=[CH2:18].[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:18]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]#[N:20])[CH:3]=2)[O:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: C=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=C1CC(c2ccccc2)Oc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 120 °C
Yield: 50.8 %

Procedure:
Pd(PPh3)2Cl2 (40 mg) in a 100 mL of flask under Ar2 was treated sequentially with 6-bromo-4-methylene-2-phenylchroman (200 mg, 0.67 mmol) in [1,4]dioxane (20 mL), Cs2CO3 (2 N, 3.33 mL) and 3-cyanophenylboronic acid (167 mg, 1.13 mmol). The mixture was heated under 120° C. at Ar2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC to give 3-(4-methylene-2-phenyl-chroman-6-yl)-benzonitrile (110 mg, 51%). 1H-NMR (CDCl3): 2.81 (m, 2H), 4.96 (d, 1H), 5.10 (m, 1H), 5.61 (d, 1H), 7.98 (d, 1H), 7.29 (m, 1H), 7.35 (m, 3H), 7.41 (m, 2H), 7.46 (m, 1H), 7.52 (m, 1H), 7.72 (m, 2H), 7.79 (d, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([N:6]1[CH:10]=[N:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[N:7]1)=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]([N:6]1[CH:10]=[N:9][C:8]([S:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][C:13]=2[Cl:22])=[O:33])=[N:7]1)=[O:5])[CH3:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN(CC)C(=O)n1cnc(Sc2ccc(C(F)(F)F)cc2Cl)n1
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)n1cnc(S(=O)c2ccc(C(F)(F)F)cc2Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
1-(Diethylcarbamoyl)-3-(2-chloro-4-trifluoromethylphenylthio)-1,2,4-triazole (3.79 g) is dissolved in chloroform (100 ml). With the temperature held at 10° C. or below with ice water, m-chloro-perbenzoic acid (1.73 g) is added in small portions over a period of 10 minutes. Thereafter, reaction is performed at 10° C. for 2 h, then at room temperature for 10 h. The chloroform solution is washed twice with a 10% aqueous solution of potassium carbonate (100 ml), then washed with water, and dried with magnesium sulfate. When the solvent is distilled off, an oil remains. This is purified by silica gel chromatography (solvent 1:1 mixture of chloroform and n-hexane) to produce the titled compound, 1-(diethylcarbamoyl)-3-(2-chloro-4-trifluoromethylphenylsulfinyl)-1,2,4-triazole (2.7 g) as an oil; yield, 68.4%.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[C:16]([C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:34][CH3:35])=[C:27]([C:30](=O)[CH2:31][CH3:32])[CH:28]=2)[O:23][C:22]([CH3:37])([CH3:36])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[F:7]/[C:6](=[C:30](/[C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:34][CH3:35])[O:23][C:22]([CH3:37])([CH3:36])[CH:21]=[C:20]2[C:16]([CH3:17])([CH3:19])[CH3:18])\[CH2:31][CH3:32])/[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCC(=O)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)(C)C
Product: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (431 mg, 1.78 mmol) and 1-(4-tert-butyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-propan-1-one (Compound 59, 107 mg, 0.35 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexanes)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.Cl[CH2:13][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:13][C:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[N:15]=3)[N:10]=[CH:11][C:3]=12
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1nc(Cl)c2cnn(Cc3nc4ccccc4n3-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (1.0 g, 5.9 mmol), 2-(chloromethyl)-1-phenyl-1H-benzo[d]imidazole (1.4 g, 5.9 mmol) and K2CO3 (0.86 g, 6.2 mmol) in DMSO (20 mL) was stirred at room temperature overnight. Then the mixture was added H2O (50 mL) and extracted with CH2Cl2 (20 mL×3). The combined organic layers were concentrated in vacuo to give 4-chloro-1-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-1H-Pyrazolo[3,4-d]pyrimidin-6-ylamine (1.5 g, yield 68%) as orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.C(O)(=O)[CH:10]([CH2:12][C:13](O)=O)[OH:11].[S:18](=[O:22])(=[O:21])([OH:20])[OH:19]>>[S:18](=[O:20])(=[O:19])([OH:22])[OH:21].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:10]([OH:11])=[CH:12][CH:13]=2)[N:3]=1
Reactant: O=C(O)CC(O)C(=O)O
Reactant: Nc1cccc(N)n1
Agent: O=S(=O)(O)O
Product: Nc1ccc2ccc(O)nc2n1

Procedure:
In step 1 of the method, commercially available 2,6-diaminopyridine (e.g., Aldrich, Milwaukee, Wis.) is reacted with malic acid in sulfuric acid to provide 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt. It is noted that 2-amino-7-hydroxy-1,8-naphthyridine free base is described in S. Carboni et al., Gazz. Chim. Ital., 95, 1498 (1965).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 40 h
Yield: 56.1 %

Procedure:
A mixture of 2.06 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole and 3.08 g of activated manganese dioxide in 20 mL of methylene chloride at 25° C. was stirred for 40 hours. The reaction mixture was filtered through Celite®, and the filtrate concentrated in vacuo. Column chromatography (elution: ethyl acetate/benzene) provided 1.15 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde. NMR (200 MHz, CDCl3) δ 9.76 (s, 1H); 7.83 (d of d, 1H); 7.52 (t of d, 1H); 7.40 (t of d, 1H); 7.31 (d of d, 1H); 7.17 (A2B2, 4H); 5.58 (s, 2H); 3.63 (s, 3H); 2.67 (t, 2H); 1.70 (quint., 2H); 1.38 (sext., 2H); 0.90 (t, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:17][C:13]1[N:14]([CH3:16])[O:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:24]4[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=4)[C:18]#[N:19])[CH:3]=3)[O:8][CH2:9][CH2:10]2)[N:12]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1OC2(CCOc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CCOc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 10.5 %

Procedure:
Pd(PPh3)2Cl2 (7 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 6-bromo-2′-methyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (59.4 mg, 0.2 mmol) in 1,4-dioxane (2.0 mL), Cs2CO3 (2 N, 1 mL) and 3-cyanophenylboronic acid (58.8 mg, 0.4 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give 3-(3′-amino-2′-methyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (6.7 mg, 10%). 1H-NMR (MeOD): 2.31 (m, 1H), 2.62 (m, 1H), 3.39 (m, 3H), 4.32 (m, 1H), 4.46 (m, 1H), 7.00 (d, 1H), 7.58-7.71 (m, 3H), 7.95 (m, 3H).