Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:3]([OH:23])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.3 %

Procedure:
A solution of 3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid methyl ester (450 mg, 1.45 mmol) in tetrahydrofuran (5 mL) was treated with a 0.8M aqueous lithium hydroxide solution (2.18 mL, 1.74 mmol). The resulting reaction mixture was stirred at 25° C. for 3 d. The reaction mixture was then partitioned between water (50 mL) and ethyl acetate (50 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was purified by precipitation from methylene chloride/ethyl acetate to afford 3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid (271 mg, 63%) as a white solid: mp 136-138° C.; EI-HRMS m/e calcd for C19H21NO2 (M+) 295.1572, found 295.1572.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:9](=[O:32])[NH:10][C@@H:11]1[C@@H:18]2[C@@H:14]([CH2:15][N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)(=[O:21])=[O:20])[CH2:17]2)[CH2:13][CH2:12]1)(C)(C)C.C(N1C[C@@H]2[C@@H](NC(=O)[C@@H](N(C)C(=O)OCCCC)CC(C)C)CC[C@@H]2C1)C1C=CC=CC=1>>[F:31][C:28]([F:29])([F:30])[C:24]1[CH:23]=[C:22]([S:19]([N:16]2[CH2:17][C@@H:18]3[C@@H:11]([NH:10][C:9](=[O:32])[C@H:8]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH2:7])[CH2:12][CH2:13][C@@H:14]3[CH2:15]2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Agent: CCCCOC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CC(C)C[C@H](N)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21

Procedure:
N1-((3aR,4S,6aS)-2-{[3-(Trifluoromethyl)phenyl]sulfonyl}octahydrocyclopenta[c]pyrrol-4-yl)-L-leucinamide was prepared by substituting tert-butyl-((S)-4-methyl-1-oxo-1-((3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylamino)pentan-2-yl)carbamate from Step A for tent-butyl (S)-1-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate in the procedure described in Example 348: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.44-8.32 (m, 2H), 8.19 (d, J=7.9, 1H), 7.91 (d, J=7.9, 1H), 7.79-7.66 (m, 1H), 4.72-4.38 (m, 3H), 4.29-4.15 (m, 1H), 3.84 (dd, J=9.9, 2.4, 1H), 3.60 (dd, J=9.3, 4.5, 1H), 3.06 (dt, J=21.7, 10.8, 1H), 2.92 (dd, J=9.6, 7.2, 1H), 2.57-2.45 (m, 2H), 1.98-1.76 (m, 4H), 1.61-1.43 (m, 2H), 1.26 (ddt, J=13.2, 9.9, 6.5, 1H), 0.90 (d, J=6.4, 3H), 0.84 (d, J=6.3, 3H); MS (ESI−) m/z 448 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]3[C:17](=[CH2:31])[N:18]([C:21]4[CH:22]=[N:23][N:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:25]=4)[C:19](=[O:20])[C:14]3=[CH:13][CH:12]=2)[CH:6]=[N:7][C:8]=1[O:9][CH3:10]>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]3[CH:17]([CH3:31])[N:18]([C:21]4[CH:22]=[N:23][N:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:25]=4)[C:19](=[O:20])[C:14]3=[CH:13][CH:12]=2)[CH:6]=[N:7][C:8]=1[O:9][CH3:10]
Reactant: C=C1c2nc(-c3cnc(OC)c(OC)c3)ccc2C(=O)N1c1cnn(CC(F)(F)F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc3c(n2)C(C)N(c2cnn(CC(F)(F)F)c2)C3=O)cnc1OC
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 68.5 %

Procedure:
As shown in step 22-v of Scheme 22, to a solution of 2-(5,6-dimethoxy-3-pyridyl)-7-methylene-6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrrolo[3,4-b]pyridin-5-one (Compound 2071, 436 mg, 1.01 mmol) in THF (20 mL) was added Pd/C (200 mg, 10 wt % dry basis, wet, Degussa type). The reaction vessel was evacuated and then placed under an atmosphere of H2 (balloon). After stirring for 2.5 h, the reaction mixture was filtered through a pad of silica and washed with THF (80 mL). The resulting filtrate was concentrated under reduced pressure and the residue treated with EtOAc (6 mL). After heating to reflux to give a uniform suspension, hexanes (10 mL) were added. The resulting suspension was cooled to 0° C. (ice-water bath), held at 0° C. for 5 min, and the precipitate collected via filtration to give 2-(5,6-dimethoxy-3-pyridyl)-7-methyl-6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-7H-pyrrolo[3,4-b]pyridin-5-one (Compound 254, 300 mg, 68%) as a pale tan-colored solid: ESMS (M+H) 434.44; 1H NMR (DMSO-d6, 300 MHz) δ 8.57 (d, J=3 Hz, 1H), 8.39 (s, 1H), 8.23 (d, J=9 Hz, 1H), 8.18 (d, J=9 Hz, 1H), 8.00 (d, J=3 Hz, 1H), 7.97 (s, 1H), 5.22 (m, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 1.60 (d, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].[H-].[Na+].Cl[C:9]1[C:10]([CH3:20])=[C:11]([CH3:19])[C:12]2[N:13]([C:15]([NH2:18])=[N:16][N:17]=2)[N:14]=1>CN(C=O)C>[C@H:2]([O:5][C:9]1[C:10]([CH3:20])=[C:11]([CH3:19])[C:12]2[N:13]([C:15]([NH2:18])=[N:16][N:17]=2)[N:14]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Reactant: CC[C@@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](C)Oc1nn2c(N)nnc2c(C)c1C

Procedure:
(R)-Butan-2-ol (0.5 ml) was deprotonated analogously to W1.056 with sodium hydride (85 mg) and reacted with 6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 100 mg), suspended in DMF (2 ml), and worked up. 75 mg of the title compound were isolated in sufficient purity.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=S)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:18]>C(O)C>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[NH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C(Nc1ccc(Cl)cc1)NC1CCCCC1
Reactant: N
Solvent: CCO
Product: N=C(Nc1ccc(Cl)cc1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Cyclohexyl-3-(p-chlorophenyl)thiourea (2.0 g.) was dissolved in absolute ethyl alcohol saturated with ammonia (40 ml.). To this was added yellow mercuric oxide (1.7 g.) and the mixture stirred at room temperature for 16 hours. The mixture was then refluxed 15 minutes to coagulate the fine precipitate of mercuric sulphide, filtered and the clear filtrate evaporated to dryness. The residue was recrystallised from toluene to give 1-cyclohexyl-3-(p-chlorophenyl)guanidine, m.p. 187°-190°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([CH:18]=[CH2:19])[CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)C>[C].[Pd].O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([CH2:18][CH3:19])[CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C=Cc1cnc(Cl)c(-n2ncc(C(=O)OCC)c2C)c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cc(CC)cnc2Cl)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
Next, 1-(2-chloro-5-vinylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.902 g) was added to a mixed solvent of ethanol (10 ml) and 1,4-dioxane (8 ml), the atmosphere in the flask was substituted with nitrogen gas, 10% palladium-carbon (containing ca. 50% water; 0.20 g) was added and the mixture was stirred under hydrogen atmosphere at room temperature for three hours. The reaction mixture was filtered through Celite to remove palladium-carbon, the filtrate was concentrated and the residue was purified with column chromatography (n-hexane/ethyl acetate) to give 1-(2-chloro-5-ethylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.639 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]([CH3:31])[CH2:14][CH2:15][N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][CH:13]([CH:12]=[O:11])[CH2:14][CH2:15][N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(CO)CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C=O)CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 34.3 %

Procedure:
Dimethyl sulfoxide (5.17 mL) was added to a solution of oxalyl chloride (3.12 mL) in methylene chloride (70 mL) with stirring at −78° C., and the mixture was stirred at the same temperature for 5 minutes. Then, a solution of the crude product of di-tert-butyl (4-hydroxy-3-methylbutyl)imidodicarbonate (19.8 g) in methylene chloride (50 mL) was added thereto. The mixture was stirred at the same temperature for 15 minutes. Then, triethylamine (13.4 mL) was added thereto, and the mixture was heated to room temperature and stirred. The reaction solution was separated into aqueous and organic layers by the addition of water. The organic layer was washed with water and saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the title compound (6.75 g).
Reaction SMILES: O=[C:2]1[NH:7][C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])=[N:5][CH:4]=[C:3]1[C:17]#[N:18].P(Cl)(Cl)([Cl:21])=O>C(#N)C>[Cl:21][C:2]1[C:3]([C:17]#[N:18])=[CH:4][N:5]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[N:7]=1
Reactant: C[C@H](Nc1ncc(C#N)c(=O)[nH]1)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: C[C@H](Nc1ncc(C#N)c(Cl)n1)c1ccccc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
1.69 g of the 6-oxo-2-{[(1S)-1-phenylethyl]amino}-1,6-dihydro-5-pyrimidinecarbonitrile [54-1] was dissolved in 100 mL of acetonitrile, then 5 mL of phosphorus oxychloride was added, and stirred at 85° C. for 2 hours. After concentrating the reaction mixture under reduced pressure, the obtained residue was placed in an ice bath, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine in the subsequent order. After drying over anhydrous magnesium sulfate, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 1.54 g of 4-chloro-2-{[(1S)-1-phenylethyl]amino}-5-pyrimidinecarbonitrile [54-2] was obtained as an oily product.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH3:27])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>C(Cl)Cl>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([C:24](=[O:25])[NH:14][C:13]1[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:27])([CH3:16])([CH3:17])[CH3:18]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccnc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
To a mixture of N2-phenylpyridine-2,3-diamine (2.00 g, 0.011 mol), (S)-2-tertbutoxycarbonylaminopropionic acid (3.06 g, 0.0162 mol), HOBt (2.19 g, 0.0162 mol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.10 g, 0.0162 mol) in DCM (80 mL) cooled to 0° C. under a nitrogen atmosphere was added Et3N (4.5 mL, 0.0324 mol). The reaction mixture was stirred at 0° C. for 5 min, then slowly warmed to RT and stirring was continued for 20 h. The resulting mixture was partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The residue thus obtained was purified column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) affording [(S)-1-(2-phenylaminopyridin-3-ylcarbamoyl)ethyl]carbamic acid tertbutyl ester as a pale pink solid (2.05 g, 4.56 mmol). LCMS: RT 3.75 min [M+H]+ 390.2
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:8]1(O)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH3:15])[CH3:7].[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][SH:23]>O>[CH2:6]([C:8]1([S:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH3:15])[CH3:7]
Reactant: CCC1CCCCC1(O)CC
Reactant: CCCCCCS
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCSC1(CC)CCCCC1CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a cooled (0° C.) mixture of water (13 ml.) and 27 mg. concentrated sulphuric acid was added dropwise 1,2-diethylcyclohexanol (12 g., 77 mmole) and then n-hexylthiol (9.1 g., 77 mmole). The mixture was stirred at 0° C. for 6 hours and at room temperature for 1 hour. The mixture was then poured into 1 liter of cold water and extracted with ether. The ether extract was washed with 2N sodium hydroxide and water and dried (MgSO4). The solvent was removed by distillation and the residue was distilled under reduced pressure to give n-hexyl 1,2-diethylcyclohexyl sulphide (15 g.) as a colourless liquid, b.p. 110°-4°/0.03 mm.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C(O)C>[CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOCc1ccccc1
Agent: NN
Solvent: CCO
Product: NCCOCc1ccccc1
Yield: 75.6 %

Procedure:
A solution of 127 (10 g, 35 mmol) in ethanol (200 mL) was treated with hydrazine (84 g, 71 mmol, 80% in water) at reflux for 12 hours. After a filtration, the filtrate was concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 5% methanol in dichloromethane to afford 128 as light yellow oil (4 g, 74%). (ES, m/z) [M+H]+ 152.0; 1H NMR (300 MHz, CDCl3) δ 7.28-7.40 (m, 5H), 4.56 (s, 2H), 3.54 (t, J=5.4 Hz, 2H), 2.94 (t, J=5.1 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][N:19]=1.C1C(=O)N([Br:28])C(=O)C1.C([O-])(O)=O.[Na+]>CC#N>[Br:28][C:18]1[N:19]=[C:14]([C:10]2[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH:13]=[N:12][N:11]=2)[C:15]([NH2:20])=[N:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nccnc1-c1nncn1-c1cccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(Br)nc1-c1nncn1-c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine (700 mg, 2.55 mmol) in dry CH3CN (20 mL) was added NBS (550 mg, 3.09 (mmol). The solution was stirred at RT for 1 h and poured into saturated NaHCO3 solution. The precipitate was collected by vacuum filtration and washed with water (700 mg, 78%) to produce 5-bromo-3-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine [LC-MS m/e=353/354.6 (M+H)]. Using the same procedure, 5-bromo-3-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine, 5-bromo-3-(4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine, 5-bromo-3-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, 5-bromo-3-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, and 5-bromo-3-(4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine can be produced from 3-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine, 3-(4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine, 3-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, 3-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, and 3-(4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, respectively.
Reaction SMILES: NC1C=C(Cl)C(C)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:30][C:31]1[C:55]([CH3:56])=[CH:54][C:34]2[C:35]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])=[N:36][C:37]3[C:38]([N:40](CC=C)[NH:41][C:42]=3[CH3:43])=[N:39][C:33]=2[CH:32]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:30][C:31]1[C:55]([CH3:56])=[CH:54][C:34]2[C:35]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])=[N:36][C:37]3[C:38]([NH:40][NH:41][C:42]=3[CH3:43])=[N:39][C:33]=2[CH:32]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(C)c(Cl)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cc1cc(C(=O)c2ccccc2Cl)c(N)cc1Cl
Product: CC1=C2N=C(c3ccccc3Cl)c3cc(C)c(Cl)cc3N=C2NN1

Procedure:
8-chloro-5-(2-chlorophenyl)-1,2-dihydro-3,7-dimethyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVhh) was prepared by reacting 0.0023 moles of (2-amino-4-chloro-5-methylphenyl)-(2-chlorophenyl)-methanone (Xhh) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 8-chloro-5-(2-chlorophenyl)-1,2-dihydro-3,7-dimethyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVhh) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=357.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].C([Li])CCC.CCCCCC.[CH3:21][CH:22]([CH3:28])[CH2:23][CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[CH3:21][CH:22]([CH3:28])[CH2:23][CH2:24][C:25]([N:5]1[C@@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][O:7][C:6]1=[O:9])=[O:26]
Reactant: CC(C)C1COC(=O)N1
Reactant: CC(C)CCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)CCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4-(2-propyl)-oxazolidine-2-one in anhydrous tetrahydrofuran (250 ml) under a nitrogen atmosphere at -78° C. was added in a dropwise fashion a solution of n-butyllithium in hexane (50 ml, 77.4 mmol) over 5 to 10 min. After stirring an additional 20 min at -78° C., 4-methylpentanoyl chloride (85.2 mmol) was added neat. The reaction was warmed to room temperature and stirred 1 to 2 h at the temperature. The reaction was quenched by adding 100 ml of saturated aqueous ammonium chloride and the volatiles were removed by rotary evaporation. The resulting aqueous residue was extracted three times with ether and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Recrystallization from hexanes/ethyl acetate provided the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:30][C:31]2[CH:40]=[C:39]([CH3:41])[C:34]3[NH:35][C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][O:28][C:26]1[N:25]=[C:24]([O:30][C:31]2[CH:40]=[C:39]([CH3:41])[C:34]3[NH:35][C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)[CH:23]=[C:22]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[N:27]=1
Reactant: COc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5[nH]c(=O)oc5c4)nc(OC)n3)CC1)C(=O)N2

Procedure:
45 mg (0.16 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 50 mg (0.15 mmol) 6-(6-chloro-2-methoxypyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 0.10 mL (0.57 mmol) DIPEA in 1.0 mL DMF were stirred for 3 h at 90° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[C:5]([CH3:13])[CH:4]=1)#[N:2].C1COCC1.[Cl-].[Cl-].[Ca+2].[BH4-].[Na+]>O.C(O)C>[OH:8][CH2:7][C:6]1[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:13]
Reactant: COC(=O)c1ccc(C#N)cc1C
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
Charge methyl 4-cyano-2-methylbenzoate (627 mg, 3.57 mmol), THF (12 mL) and ethanol (12 mL) to a flask, followed by CaCl2 (418 mg, 3.57 mmol) and NaBH4 (265 mg, 7.16 mmol). The mixture was then stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic extract was concentrated and purified by flash column chromatograph to give 325 mg of the title compound (62%). 1H NMR (300 MHz, CDCl3): δ 1.83 (1H, t, J=5.4 Hz), 2.33 (3H, s), 4.75 (2H, d, J=5.4 Hz), 7.43 (1H, s), 7.52-7.56 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2OS(C(F)(F)F)(=O)=O.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].ClCCl.C(=O)([O-])[O-].[K+].[K+].[C:53]([O:57][C:58](=[O:69])[NH:59][CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65](Br)=[CH:64][CH:63]=1)([CH3:56])([CH3:55])[CH3:54]>O1CCOCC1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:53]([O:57][C:58](=[O:69])[NH:59][CH2:60][CH2:61][C:62]1[CH:63]=[CH:64][C:65]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:66][CH:67]=1)([CH3:56])([CH3:54])[CH3:55]
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2nccc(-c3ccc(CCNC(=O)OC(C)(C)C)cc3)c2n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 61.8 %

Procedure:
To a stirred solution of 1,1,1-trifluoromethanesulfonic acid 6-methoxy[1,5]naphthyridin-4-yl ester (1.0 g, 3.24 mmole) in dry dioxane (50 mL) at RT was added bis(pinacolato)diboron (1.07 g, 4.22 mmole), potassium acetate (0.95 g, 9.72 mmole), 1,1-bis(diphenylphosphino)ferrocene (0.09 g, 0.16 mmole) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (0.13 g, 0.16 mmole). The reaction contents were heated to 80° C. for 24 h under nitrogen gas and then 1, 1-bis(diphenylphosphino)ferrocene (0.09 g, 0.16 mmole), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (0.13 g, 0.16 mmole), potassium carbonate (1.34 g, 9.72 mmole) and [2-(4-bromophenyl)ethyl]carbamic acid tert-butyl ester (0.97 g, 3.24 mmole) were added to the reaction pot. After 24 h of vigorous stirring at 80° C., the reaction contents were filtered through a scinter-glass funnel containing a bed of celite (EtOAc). The filtrate was concentrated under vacuum and purified on silica (EtOAc) to afford the title compound (0.76 g, 62%) as a tan solid: LC-MS (ES) m/e 380 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:15](=[C:16]([CH3:19])[C:17]=1[CH3:18])[O:14][C:10]1([CH2:13][CH2:12][CH2:11]1)[CH2:9][C:8]2=[O:20].[H-].[Na+].[CH:24](OC)=[O:25]>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:15](=[C:16]([CH3:19])[C:17]=1[CH3:18])[O:14][C:10]1([CH2:11][CH2:12][CH2:13]1)[CH:9]([CH:24]=[O:25])[C:8]2=[O:20]
Reactant: COCOc1c(C)c(C)c2c(c1C)C(=O)CC1(CCC1)O2
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c(C)c(C)c2c(c1C)C(=O)C(C=O)C1(CCC1)O2
Reaction time: 0.08 h

Procedure:
To a solution of 6-(methoxymethoxy)--5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one (2.0 g) in 20 mL of THF was added under stirring, NaH (1.38 g). After 5 minutes, 8.5 mL of methyl formate (137.4 mmol) were added dropwise to the mixture. The reaction was allowed to stir at room temperature overnight. The organic phase was washed with 1N HCl and water, dried over anhydrous MgSO4, and concentrated in vacuo to give 6-(methoxymethoxy)-5,7,8-trimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-3-carbaldehyde as a yellow paste. This intermediate was used directly for subsequent reactions without further purification.