Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH3:11])[CH:6]=[C:5]([C:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:4]=1.C([Li])CCC.[CH2:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=[O:32].[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([CH3:19])([CH3:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:6]=[C:7]([O:9][CH2:10][CH3:11])[C:8]=1[CH:31]1[CH2:30][CH2:29][CH2:28][C:27](=[O:32])[CH2:26]1
Reactant: CCCCCCC(C)(C)c1cc(OC)cc(OCC)c1
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1cc(OC)c(C2CCCC(=O)C2)c(OCC)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1-Methoxy-3-(1,1-dimethylheptyl)-5-ethoxybenzene (IIa) (1500 mg, 5.4 mmol) was dissolved in dry ether (25 ml) and the solution was cooled to 0° C. The reaction was placed under nitrogen and butyl lithium (5.94 mmol, 3.6 ml of a solution in hexane) was injected into the reaction. The reaction mixture was brought to room temperature, and was stirred for 4 hrs. Cuprous bromide (360 mg, 2.5 mmol) was added in one portion. The reaction mixture turned dark and became homogeneous. After stirring for 5 min, 2-cyclohexanone (240 mg, 2.5 mmol) was injected into the solution, and the reaction mixture was stirred for 15 min at 0°. Ether (50 ml) and a saturated ammonium chloride solution (150 ml) were added. The organic layer was washed with brine, dried and evaporated to dryness. The oil obtained was purified by medium pressure liquid chromatography (230-400 mesh ASTM, silica gel 60" for column chromatography; elution with petroleum ether, b.p. 60°-80°) to yield the title compound, IIIa (66%).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=C[CH:6]=[C:5]([CH3:9])[CH:4]=1.Cl[C:13]1[CH:22]=[C:21]([CH3:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[C:24](=O)([O-])[O-].[K+].[K+]>C1COCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][C:5]1[CH:6]=[C:16]([C:15]2[C:20]3[C:21](=[CH:23][CH:17]=[CH:18][CH:19]=3)[C:22]([CH3:24])=[CH:13][N:14]=2)[CH:8]=[CH:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(OB([O-])[O-])c1
Reactant: Cc1cc(Cl)nc2ccccc12
Agent: [Pd]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(-c2ncc(C)c3ccccc23)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
3-Methylphenyl borate (1.3 mmol), 2-chloro-4-methylquinoline (1 mmol), tetrakis(triphenylphosphine) palladium(0) (0.05 mmol) and potassium carbonate (3 mmol) were dissolved in THF (30 mL) and H2O (10 mL). The resulting solution was stirred in a bath at 100° C. for 24 hours. After completion of the reaction, the solvents were removed. The reaction mixture was extracted with dichloromethane and water and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography. The eluate was distilled under reduced pressure. The residue was recrystallized from dichloromethane and petroleum ether, and filtered to yield 1-(3-methylphenyl)-4-methylisoquinoline as a solid.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:17][C:18]([N:20]1[CH2:25][C@H:24]([CH3:26])[N:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:22][C@H:21]1[CH3:35])=[O:19])=[O:8])C.O1CCCC1.CO.O.[OH-].[Li+]>O>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH2:17][C:18]([N:20]2[CH2:25][C@H:24]([CH3:26])[N:23]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:22][C@H:21]2[CH3:35])=[O:19])=[C:9]([C:7](=[O:8])[CH2:6][CH2:5][C:4]([OH:36])=[O:3])[CH:14]=1
Reactant: CCOC(=O)CCC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.7 %

Procedure:
To a solution of 4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4-oxo-butyric acid ethyl ester (0.082 g, 0.16 mmol) in 2:2:1 tetrahydrofuran:methanol:water(1.5 mL) was added lithium hydroxide monohydrate (0.34 g, 0.79 mmol). The resulting solution was stirred 12 hours at ambient temperature, then concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with 1 M hydrochloric acid. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.072 g, LRMS: 489.4, 491.4).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[AlH4-].[Li+]>CCOCC>[OH:9][CH2:8][CH:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [AlH4-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1CCC(O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl 4-oxocyclohexanecarboxylate (2.0 g, 0.012 mol) was dissolved in ether (20.0 mL) and was then cooled at 0° C. Into the mixture was added 1 M lithium tetrahydroaluminate in ether (20 mL) and the resulting mixture was stirred at 0° C. for 2 hours. The reaction was quenched with water (2 mL) and 1 N NaOH (2 mL) and ether was added (100 mL). The precipitated solids were filtered off and the residue was used in the next reaction. 1H NMR(CDCl3):δ 4.02 and 3.75 (m, 1H), 3.45-3.61 (m, 2H), 2.02 (m, 2H), 1.84 (m, 1H), 1.52-1.80 (m, 2H), 1.44 (m, 1H), 1,32 (m, 2H), 1.03 (m, 1H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C([Li])CCC.[CH3:24][CH:25]([CH3:31])[CH2:26][CH2:27][C:28](Cl)=[O:29].C([O-])(O)=O.[Na+]>CCCCCC>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:28](=[O:29])[CH2:27][CH2:26][CH:25]([CH3:31])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(C)CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
(S)-4-Benzyl-2-oxazolidinone (15.1 g, 85.0 mmol) was dissolved in THF (200 mL, 2.5 mol), cooled at −78° C. under nitrogen, and stirred for 10 minutes. 1.6 M of n-butyllithium in hexane (53.1 mL) was added dropwise and stirred for 15 minutes. 4-Methylpentanoyl chloride (12.6 g, 93.5 mmol) was added dropwise, stirred for 30 minutes at −78° C., then warmed to 0° C. for 2 hours. 150 mL of saturated NaHCO3 was added and the mixture was warmed to room temperature for 30 minutes. The mixture was extracted with DCM, washed with Na2 CO3 (5%) and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Excess oxazolidinone was removed using hexanes to provide intermediate (2a) (14.5 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[CH2:10](Br)[CH2:11][CH:12]([CH3:14])[CH3:13]>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: CC(C)CCBr
Product: CCOC(CNCCC(C)C)OCC
Reaction time: 8 h
Yield: 77.2 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-5 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (2.91 ml, 20 mmol) was reacted with isoamylbromide (1.26 ml, 10 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=90:10 to 80:20) to obtain the title compound (1.57 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)[C:39]([O:41][CH3:42])=[O:40].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH:48]1[CH2:52][CH2:51][CH2:50][N:49]1[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)c1ccc(OCC2CCCN2)c(Cl)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (500 mg, 1.04 mmol), methyl 3-chloro-4-(2-pyrrolidinyl)methoxybenzoate (281 mg, 1.04 mmol), Et3N (0.17 mL, 1.25 mmol) in DMF (5 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the residue was chromatographed on silica-gel with n-hexane-EtOAc (1:3, v/v) as eluent to afford methyl 3-chloro-4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]benzoate (620 mg, 1.04 mmol) as a white crystalline solid. To a stirred solution of this compound in THF (8 mL) and H2O (2 mL) was added LiOH (74.9 mg, 3.126 mmol), and the mixture was stirred at room temp for 2 days. The mixture was diluted with CHCl3, and treated with 1N HCl. The solution was washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude solid was recrystallized from n-hexane-EtOAc—CHCl3 to afford 561.2 (98%) 29 as a white crystalline material. IR (KBr) 1676, 1599, 1487, 1267, 758, 754 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ1.82-2.24 (m, 4H), 2.25 (s. 3H), 3.48-3.60 (m, 4H), 3.78 (s, 3H), 4.18 (m, 2H), 4.31 (m, 1H), 6.74 (dd, J=1.5, 8.3 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.91-6.95 (m, 1H), 7.11-7.17 (m, 3H), 7.79 (dd, J=2.0, 8.3 Hz, 2H), 7.85 (d, J=2.0 Hz, 1H), 7.98 (d, J=8.3 Hz, 1H), 8.53 (s, 1H), 8.58 (s, 1H); MS (FAB) m/z 552 (M++1).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[C:20]([O:24][C:25](=[O:28])[CH2:26][NH2:27])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25]([CH2:26][N:27]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])=[O:28])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)n1CC(=O)OC(C)(C)C

Procedure:
13.0 g (0.05 mol) of 6-phthalimido-2,5-hexanedione and 6.6 g (0.05 mol) of glycine tert.-butyl ester are stirred in 250 ml of tetrahydrofuran at 80° C. for 20 hours and the mixture is worked up as in Example 27.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]1[O:12][C:10](=[O:11])[C@@H:8]([OH:9])[C@H:6]1[OH:7])[OH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[O:11]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[C@@H:10]1[O:12][C@@H:5]2[C@@H:3]([C:2]([O:7][C@@H:6]2[C@H:8]1[OH:9])=[O:1])[OH:4]
Reactant: CCCCCCCCCCCCO
Reactant: O=C[C@H](O)[C@H]1OC(=O)[C@@H](O)[C@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCCO[C@@H]1O[C@H]2[C@H](OC(=O)[C@H]2O)[C@H]1O
Temperature: 110 °C

Procedure:
20 g of Glucurono-6,3-lactone (0.11 mole), 0.2 g p-toluenesulfonic acid (1.05×10-3 mole) and 164.0 g of dodecanol (0.88 mole) were placed in a three-necked flask equipped with a mechanical stirrer, thermometer and short path distillation head. The mixture was heated to 110° C. until D-glucurono-6,3-lactone dissolved. The reaction mixture was neutralized with 1 ml of 1N methanolic KOH at 25° C., filtered over silica and washed with methanol. A vacuum was applied to remove the methanol and dodecanol yielding a syrup. Hexane was added and dodecyl β-D-glucofuranosidurono-6,3-lactone crystallized selectively. The yield was 15.9 g (42%). The product was recrystallized from hexane/ether mixture. MP 88°-89° C. (99.9% pure).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[O:9][CH3:10].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH3:10][O:9][C:3]1[C:4]([NH2:8])=[N:5][CH:6]=[N:7][C:2]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: COc1c(N)ncnc1Cl
Solvent: Cc1ccccc1
Product: COc1c(N)ncnc1N1CCCC1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
In a flask was added 6-chloro-5-methoxypyrimidin-4-amine (500 mg, 3.13 mmol) and pyrrolidine (0.523 ml, 6.27 mmol) in toluene (5 ml). The reaction was heated to 80 C for 16 hours and then cooled to room temperature. The reaction was then concentrated to a white solid to give 5-methoxy-6-(pyrrolidin-1-yl)pyrimidin-4-amine (514 mg, 84% yield). LC/MS R.T.=1.25 mins (M+H=195.2).
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:42])(=[O:41])/[CH:30]=[CH:31]/[C:32]1[CH:40]=[CH:39][C:37]([OH:38])=[C:34]([O:35][CH3:36])[CH:33]=1.C(OC(C)C)(C)C>CO>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:42])(=[O:41])/[CH:30]=[CH:31]/[C:32]1[CH:40]=[CH:39][C:37]([OH:38])=[C:34]([O:35][CH3:36])[CH:33]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)OC(C)C
Solvent: CO
Product: COc1cc(/C=C/C(=O)[O-])ccc1O
Reaction time: 12 h

Procedure:
Sitagliptin free base (2.0 gms) and ferulic acid (0.95 gms) were dissolved in methanol (12 ml) at 60° C. to 65° C. and the resultant solution was cooled to room temperature. Isopropyl ether (120 ml) was added to the clear solution and stirred for 12 hours. Filtered the precipitated solids and dried at 70° C. to 75° C. for 12 hours to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[CH3:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[S:3][C:4]([C:8]([NH:22][C:23]2[CH:24]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:40][CH2:41]5)=[O:38])[N:35]=4)[N:32]=3)[CH:42]=[CH:43][C:44]=2[CH3:45])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Cl)sc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1sc(Cl)nc1C
Yield: 90.2 %

Procedure:
In the same manner as in Example 259 and using 2-chloro-4-methyl-1,3-thiazole-5-carboxylic acid (140 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (270 mg, 91%) was obtained as a pale-green solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][C:30](=[O:35])[CH2:31]2)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][C:30]([C:19]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[Cl:13])([OH:35])[CH2:31]2)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: Clc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ccncc1Cl)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
n-Butyl lithium (2.5M, 3.88 mL, 9.7 mmol) was added dropwise to a solution of diisopropylamine (1.43 mL, 10.13 mmol) in THF (20 mL) at −78° C. under nitrogen, warmed to 0° C., stirred for 30 minutes then re-cooled to −78° C. This was then added to a solution of 3-chloropyridine (0.83 mL, 8.81 mmol) in THF (12 mL) and stirred for 1.5 hours. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.98 g, 8.81 mmol) in THF (12 mL) was added, the reaction mixture warmed to room temperature for 1.5 hours. Saturated aqueous ammonium chloride and ethyl acetate were added, the organics separated, washed with more saturated aqueous ammonium chloride and brine, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 0-100% ethyl acetate/pentane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.34 g). 1H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 8.47 (d, 1H), 7.69 (d, 1H), 4.38 (m, broad, 2H), 3.05-2.80 (m, broad, 2H), 2.28-2.0 (broad, 5H), 1.6-1.5 (m, broad, 2H), 1.49 (s, 9H).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C1COCC1>[CH3:18][Si:19]([C:22]#[C:23][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1)([CH3:21])[CH3:20]
Reactant: Brc1cccc2nsnc12
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cccc2nsnc12
Temperature: 45 °C
Reaction time: 20 h

Procedure:
4-Bromobenzo[c][1,2,5]thiadiazole (0.378 g, 1.76×10−3 mol), Pd(PPh3)4 (0.125 g, 1.68×10−4 mol), CuI (0.014 g, 7.4×10−5 mol), THF (20 ml), diisopropylamine (1.00 ml), and (trimethylsilyl)acetylene (1.00 ml, 7.1×10−3 mol) were added to a 50-ml Schlenk tube. N2 was bubbled through the mixture for 5 min, following which the reaction was stirred at 45° C. for 20 h. After cooling, the solvent was evaporated and the residue was chromatographed on silica gel using 1:1 hexanes:CHCl3 as the eluent. Yield=0.398 g (97.3% based on 0.378 g of 4-bromobenzothiadiazole). 1H NMR (500 MHz, CDCl3): δ 7.88 (m, 1H, Ph-H), 7.67 (m, 1H, Ph-H), 7.45 (m, 1H, Ph-H), 0.33 (s, 9H, —Si—CH3).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:27]3[CH:28]=[CH:29][N:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[N:26]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccn(-c2ccncc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2ccncc2)n1
Yield: 83 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.058 g, 0.307 mmol), 1-(pyridin-4-yl)-1H-pyrazole-3-carboxylic acid (0.080 g, 0.307 mmol), DIPEA (0.160 ml, 0.921 mmol), HOBt hydrate (0.071 g, 0.460 mmol) and EDCI (0.088 g, 0.460 mmol) using the method of Example 274 affording 0.110 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 4.36 (m, 2H), 4.49 (m, 1H), 6.90 (d, 1H), 6.94 (d, 1H), 7.85 (d, 1H), 7.90 (m, 2H), 7.94 (m, 2H), 8.02 (s, 1H), 8.38 (d, 1H), 8.69 (m, 2H), 8.75 (d, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[CH2:10][C:9]2([CH3:33])[CH3:32])=[O:5])C.Cl>C(O)C.O1CCCC1.[OH-].[Na+].O>[CH:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:11]3[CH2:10][C:9]([CH3:32])([CH3:33])[C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:27][CH:26]=1)([CH3:31])[CH3:30]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(-c3ccc(OC(C)C)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
A mixture of 2-(4′-isopropoxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.44 g, 1.0 mmol) in ethanol (5 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (2 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(4′-isopropoxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.40 g, 91%) as a white solid which was used for next step without further purification: MS (ESI) M+1=416.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([CH:20]4[CH2:23][CH2:22][CH2:21]4)=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:26](I)[CH3:27].O>CN(C)C=O>[CH2:26]([N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18]([CH:20]1[CH2:23][CH2:22][CH2:21]1)=[O:19])[CH3:27]
Reactant: CCI
Reactant: Cc1nnc2ccc(-c3cccc(NC(=O)C4CCC4)c3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)C1CCC1)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 2.0 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]cyclobutanecarboxamide and 0.36 g of sodium hydride (50% in oil) in 200 ml of dry dimethylformamide, under argon, was stirred for 1 hour, then 0.6 ml of ethyl iodide was added. This mixture was stirred overnight, then poured into 200 ml of water and extracted with dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on a silica gel column, eluting with dichloromethane:methanol (97:3). The fractions containing product were combined and evaporated, giving 0.81 g of the desired compound as yellow crystals, mp 157°-159° C.
Reaction SMILES: [H-].[K+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH:13]1[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[N:23][C:17]=2[N:16]2[CH:24]=[CH:25][CH:26]=[C:15]2[C:14]1=[O:27].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C1COCC1>[CH3:28][N:29]([CH3:33])[C:30]([O:27][C:14]1[C:15]2[N:16]([CH:24]=[CH:25][CH:26]=2)[C:17]2[N:23]=[CH:22][CH:21]=[CH:20][C:18]=2[O:19][C:13]=1[C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1)=[O:31]
Reactant: O=C1c2cccn2-c2ncccc2OC1c1ccc2ccccc2c1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C(=O)OC1=C(c2ccc3ccccc3c2)Oc2cccnc2-n2cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a suspension of potassium hydride (0.211 g, 1.84 mmol, 35% in oil) in anhydrous TBF (5.0 mL) was added the the (±)-6-(2-naphthyl)pyrrolo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7(6H)-one (600 mg, 1.84 mmol) dissolved in anhydrous THF (5 mL). The reaction mixture was stirred at rt for 2 h, and then dimethylcarbamoyl chloride (0.228 g, 2.12 mmol) was slowly added. After stirring for 12 h at 30° C., the solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was chromatographed (dichloromethane and hexane 1:3) to give the PBOX-43 in 76% yield. IR (neat) 1730 cm−1; 1HNMR (CDCl3) δ 2.92 (s, 3 H), 3.12 (s, 3 H), 6.44 (m, 2 H), 7.12 (m, 1 H), 7.47-7.55 (m, 3 H), 7.73-7.87 (m, 5 H), 8.24(m, 2H).