Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:33][C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: O=Cc1ccncc1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccncc2)CC1
Yield: 30.7 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (3 g) as starting compound and 4-pyridinecarboxaldehyde (0.84 g) were reacted and treated in the same manner as in Example 121 to give 1.14 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(4-pyridylmethylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.C(N(CC)CC)C.[Cl:39][CH2:40][C:41](Cl)=[O:42]>O1CCCC1>[Cl:39][CH2:40][C:41]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1)=[O:42]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)CCl)cn5n4)c3)c2)CC1
Yield: 89.5 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (600 mg, 1.46 mmol), triethylamine (305 μL, 2.19 mmol), chloroacetyl chloride (202 μL, 1.75 mmol) and tetrahydrofuran (10 mL) as starting materials and in the same manner as in Example 385, the title compound (636 mg, 89%) was obtained as a gray powder.
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19][NH:20][C:21]([NH2:23])=[O:22].C[O-].[Mg+2].C[O-].CO>>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:23][C:21]([NH:20][CH3:19])=[O:22])=[O:18])=[CH:16][CH:15]=1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 12.3 %

Procedure:
2-(4-Bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (420.0 mg, 1.35 mmol) and methyl urea (299.9 mg, 4.05 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 7.7 mL, 5.40 mmol). The resulting reaction mixture was then heated under reflux for 48 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The celite was thoroughly washed with ethyl acetate, and the filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 1-[2-(4-bromo-phenyl)-3-cyclopentyl-propionyl]-3-methyl urea (58.7 mg, 12%) as a white solid: mp 184-186° C.; EI-HRMS m/e calcd for C16H21BrN2O2 (M+) 352.0786, found 352.0791.
Reaction SMILES: CO[C:3](=[O:17])[CH:4]([NH:6][C:7](=O)[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15])O.[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Li+].S(Cl)(Cl)=O>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[F:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([F:15])[C:8]=1[C:7]1[O:17][CH2:3][CH:4]([C:22]2[CH:23]=[CH:24][C:19]([I:18])=[CH:20][CH:21]=2)[N:6]=1
Reactant: Ic1ccccc1
Reactant: COC(=O)C(O)NC(=O)c1c(F)cccc1F
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1C1=NC(c2ccc(I)cc2)CO1
Temperature: 23 °C
Reaction time: 72 h
Yield: 46.1 %

Procedure:
The compound of Step A of Example 1 (31.0 g, 0.13 mol) and iodobenzene (40.2 g, 0.19 mol) were suspended in sulfuric acid (100 mL) and stirred for 3 days at 23° C. The mixture was poured onto ice and extracted with dichloromethane (200 mL). The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. Methanol (200 mL) and thionyl chloride (6 mL) were added and the mixture and heated at reflux for 30 min. The methanol was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (200 mL). Lithium borohydride (55 mL, 2N in tetrahydrofuran, 0.11 mol) was added slowly and after completion of the addition, the mixture was heated at reflux for 1 h. The mixture was cooled, and quenched by slow addition of aqueous hydrochloric acid (200 mL, 1N). The mixture was extracted with dichloromethane (200 mL), dried over magnesium sulfate and evaporated under reduced pressure. The residue was then treated with toluene (100 mL) and thionyl chloride (23 mL, 0.3 mol). The mixture was heated to reflux for 45 min and then evaporated under reduced pressure. The residue was dissolved in methanol (200 mL) and treated with aqueous sodium hydroxide (30 mL, 50% solution). The mixture was heated to reflux for 30 min and then evaporated under reduced pressure. The residue was partitioned between water (100 mL) and dichloromethane (200 mL). The dichloromethane solution was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel using hexanes/ethyl acetate (10:1) as eluent to give the title compound (23.1 g) as a white solid: m.p.: 105°-106° C. 1H NMR (CDCl3, 200 MHz) δ 7.7 (m,2H), 7.5 (m, 1H), 7.1 (m, 1H), 7.0 (m,2H), 5.4 (m, 1H), 4.8 (m, 1H), 4.3 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:14][CH2:15][OH:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl[CH:18]1[CH:23]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[NH:22][CH2:21][CH2:20][NH:19]1>>[CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:14][CH2:15][O:16][C:18]3[C:23]([N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)=[N:22][CH:21]=[CH:20][N:19]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CNc1ccc2cccc(OCCO)c2n1
Reactant: ClC1NCCNC1N1CCNCC1
Product: CNc1ccc2cccc(OCCOc3nccnc3N3CCNCC3)c2n1
Yield: 31 %

Procedure:
The title compound was prepared according to the procedure of Example 90, Step 2, starting from the product obtained in Step 2 above and 2-chloro-3-(1-piperazinyl)piperazine (from Example 90, Step 1). The crude product was purified by column chromatography (gradient: 1% NH4OH in EtOAc/MeOH (90:10) to 1% NH4OH in EtOAc/MeOH (80:20) in first purification step and gradient 0.5% NH4OH in CHCl3/MeOH (95:5) to 1% NH4OH in CHCl3/MeOH (90:10) in second purification). Yield 31%; mp 54.0-56.5° C.; MS m/z 381 (M+H)+. Anal. (C20H24N6O2.0.5 H2O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:18])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14]CC)=O)=[C:7]2[OH:17].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(OCC)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:12]([C:8]2[CH:9]=[N:10][C:11]3[C:6]([C:7]=2[OH:17])=[CH:5][C:4]([CH3:18])=[CH:3][C:2]=3[F:1])=[O:14])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cnc2c(F)cc(C)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOCC
Product: Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 180 °C

Procedure:
A mixture of 2-fluoro-4-methylaniline (5.0 g) and diethyl ethoxymethylene-malonate (8.64 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The mixture is cooled to 75° C. and diphenyl ether (50 mL) is added. The solution is heated to 250° C. for 2 h with removal of ethanol by a Dean-Stark trap, then cooled to room temperature. The resulting solid is collected, washed with hexanes and dried to yield 5.564 g of ethyl 8-fluoro-4-hydroxy-6-methylquinoline-3-carboxylate. A mixture of this ester (0.50 g) and 4-chlorobenzylamine (3.0 mL) are heated at 180° C. for 1 hour. The reaction is cooled and poured into 50 mL of diethyl ether. The resulting solid is filtered, dried, and purified by trituration in acetone to give the desired product (0.54 g).
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-])=O)=[CH:11][C:6]=2[S:5][C:4]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[CH:2].[H][H]>CO.C1COCC1.[C].[Pd]>[NH2:12][C:10]1[CH:9]=[CH:8][C:7]2[C:3]([CH2:1][CH3:2])=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:5][C:6]=2[CH:11]=1
Reactant: [H][H]
Reactant: C#Cc1c(C(=O)OCC)sc2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1sc2cc(N)ccc2c1CC

Procedure:
Ethyl 3-ethynyl-6-nitro-1-benzothiophene-2-carboxylate obtained in Example (183d) was dissolved in methanol (16 mL) and THF (24 ml). A 10% palladium-carbon catalyst (120 mg) was added, and the mixture was stirred in a hydrogen atmosphere throughout the day. The reaction solution was filtered through celite and then concentrated under reduced pressure to obtain the title compound. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:26][C:27]([F:42])([F:41])[C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:42][C:27]([F:26])([F:41])[C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([O:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[C:7](=[O:11])[CH2:6][CH2:5]4)[CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C1CCc2cc(O)ccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a stirred solution of 5-hydroxy-2,3-dihydro-1H-inden-1-one (0.74 g, 5.0 mmol) in toluene (30 mL) at room temperature was added diisopropyl azodicarboxylate (1.21 g, 6.0 mmol), 1-(4-trifluoromethylphenyl)piperidin-4-ol (1.47 g, 6.0 mmol), and triphenyl phosphine (1.57 g, 6.0 mmol). The mixture was stirred at 60° C. overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/1) to afford the title compound as a pale yellow solid (1.49 g, 79%). 1H-NMR (CDCl3, 300 MHz): δ 7.70 (m, 1H), 7.49 (m, 2H), 6.93 (m, 4H), 4.65 (m, 1H), 3.59 (m, 2H), 3.30 (m, 2H), 3.09 (m, 2H), 2.68 (m, 2H), 2.12 (m, 2H), 1.96 (m, 2H) ppm; MS (ESI): 376.6 (M+1).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)[C:6]([C:16]2[CH:17]=[C:18]3[CH:24]=[CH:23][NH:22][C:19]3=[N:20][CH:21]=2)=[N:5]1)([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:25][C:24]1[C:18]2[C:19](=[N:20][CH:21]=[C:16]([C:6]3[C:7]([C:9]4[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=4)=[CH:8][N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH:17]=2)[NH:22][CH:23]=1
Reactant: CC(C)n1cc(-c2ccnc(N)c2)c(-c2cnc3[nH]ccc3c2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(C)n1cc(-c2ccnc(N)c2)c(-c2cnc3[nH]cc(Cl)c3c2)n1
Reaction time: 4 h
Yield: 30.5 %

Procedure:
A mixture 4-(1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyridin-2-amine (H-1-10) (40 mg, 0.13 mmol) and N-chlorosuccinimide (19.3 mg, 0.14 mmol) in CH2Cl2 (2 ml) was stirred at room temperature for 18 hours. Another portion of N-chlorosuccinimide (5 mg, 0.04 mmol) was added and stirring continued at room temperature for an additional 4 hours. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to give 14 mg (31% yield) 4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyridin-2-amine (H-1) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.82 Hz, 6H) 4.43-4.69 (m, 1H) 6.22-6.63 (m, 4H) 7.72 (d, J=2.78 Hz, 1H) 7.82 (d, J=5.81 Hz, 1H) 7.92 (d, J=1.77 Hz, 1H) 8.23 (s, 1H) 8.30 (d, J=2.02 Hz, 1H) 12.08 (d, J=1.77 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([Se:21][C:22]#[C:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=4)=[CH:14][C:15]=3[C:16]([CH3:20])([CH3:19])[CH2:17][CH:18]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([Se:21][C:22]#[C:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=4)=[CH:14][C:15]=3[C:16]([CH3:20])([CH3:19])[CH2:17][CH:18]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2=CCC(C)(C)c3cc([Se]C#Cc4ccc(C(=O)O)cc4)ccc32)cc1
Reaction time: 2 h

Procedure:
0.31 g (0.62 mmol) of methyl 4-[5-(4-methoxyphenyl)-8,8-dimethyl-7,8-dihydro-2-naphthylselanylethynyl]benzoate is dissolved in 10 ml of tetrahydrofuran and 2 drops of water. 0.075 g (1.86 mmol) of sodium hydroxide is added. The medium is stirred for 2 hours, acidified with 2N hydrochloric acid solution and then extracted with ethyl acetate. The solid obtained is purified by chromatography (eluent: 3/7 heptane/ethyl acetate). A white solid is obtained (0.28 g; yield=94%; m.p.=167° C.).
Reaction SMILES: C[O:2][C:3]([CH2:5][S:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[NH3:32]>C(O)C>[NH2:32][C:3]([CH2:5][S:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[NH:12][C:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:2]
Reactant: N
Reactant: COC(=O)CS[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: NC(=O)CS[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 4.35 g of (3R,4R)-4-[[(methoxycarbonyl)methyl]thio]-3-tritylamino-2-azetidinone in 45 ml of ethanol is added 11 ml of 25 to 28% aqueous ammonia and the reaction mixture is allowed to stand at room temperature for 2 days. The mixture is further treated in the same manner as described in Reference Example 8 to give 1.804 g of (3R,4R)-4-[[(aminocarbonyl)methyl]thio]-3-tritylamino-2-azetidinone.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]1[O:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH2:3][CH:2]=[CH2:1])=[CH:10][C:8]=2[O:9]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)OCO2
Yield: 96.2 %

Procedure:
Allyl bromide (1.75 g., 14 mmol) was added to a solution of sesamol (2.0 g, 14 mmol) that had been dissolved in 50 ml of dry acetone, followed by addition of powdered potassium carbonate (2.4 g, 17 mmol) and the resulting cloudy solution was refluxed for 18 h. The solution was cooled and the solvent removed in vacuo. The remaining suspension was extracted into ether and the organic layer was washed with water (1×25 ml), brine solution (1×25 ml), and dried over MgSO4. Concentration of solvent yielded 2.4 g (94%) of a pale yellow oil which was used in the next step with no further purification.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(#N)C>[C:7]([C:6]1[CH:9]=[C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:11]=[CH:12][C:5]=1[O:4][CH:2]([CH3:1])[CH3:3])#[N:8]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1C#N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)-1,2,4-oxadiazol-5-yl]benzonitrile (Example 32) (110 mg, 0.224 mmol) in acetonitrile (10 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.449 mmol) and ethyl bromoacetate (0.05 mL, 0.449 mmol). The reaction mixture was heated to 80° C. for 2 hours. The mixture was allowed to cool to room temperature. The solvent was evaporated to give the title compound as a brown solid (100 mg).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:13]=[C:14]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:15]=1)(C(C)(C)C)(C)C.[C:31](Cl)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:40]1[CH:47]=[CH:46][C:43]([O:44][CH3:45])=[CH:42][CH:41]=1)[C:32]1[CH:39]=[CH:38][C:35]([O:36][CH3:37])=[CH:34][CH:33]=1.C(Cl)(Cl)Cl>CO>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:13]=[C:14]([CH2:16][O:17][C:31]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:40]2[CH:47]=[CH:46][C:43]([O:44][CH3:45])=[CH:42][CH:41]=2)[C:32]2[CH:39]=[CH:38][C:35]([O:36][CH3:37])=[CH:34][CH:33]=2)[CH:15]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccccc2)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(C(OCc2cc(CO)cc(-c3ccccc3)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 96 h
Yield: 79 %

Procedure:
10.7 ml of pyrizine was added to dissolve 0.4596 g of Compound (2) in an Ar atmosphere, and 0.9547 g (2.80 mmol, 1.3 eq) of DMTrCl was added. This was agitated for 96 hours in an Ar atmosphere. After extraction with chloroform the organic layer was washed with H2O, sat. NaHCO3 aq and sat. NaCl aq, and dried by addition of anhydrous NaSO4. The solvent was distilled off under reduced pressure, and 0.4231 g (0.82 mmol, 38%) of Compound (3) was isolated by silica gel chromatography (chloroform:methanol=100:1).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1.O>CN(C=O)C>[C:11]([Si:8]([CH3:10])([CH3:9])[O:7][CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)CCCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 66 h
Yield: 58.6 %

Procedure:
A solution of 3-acetyl-1-propanol (3.000 g, 29.37 mmol), tert-butyidimethylsilyl chloride (4.522 g, 30.00 mmol), and imidazole (5.004 g, 73.5 mmol) in DMF (40 mL) was heated at 40° C. for 5 h and was stirred at room temperature for 66 h. Water (60 mL) was added and the product was extracted into EtOAc (4×50 mL). The combined organic extracts were washed with water (2×50 mL), dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (hexanes:EtOAc 9:1) provided the title compound (3.722 g). 1H NMR (400 MHz, CDCl3) δ 3.59 (t, 2H), 2.49 (t, 2H), 2.13 (s, 3H), 1.76 (m, 2H), 0.86 (s, 9H), 0.02 (s, 6H); MS 217 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[NH:26][CH:25]=3)[C:13]([C:14]3[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3].N.[C:38](P(=O)(OCC)OCC)#[N:39]>>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[NH:26][CH:25]=3)[C:13]([C:14]3[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([NH:39][CH3:38])=[O:22])[CH:15]=3)=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Reactant: CCOP(=O)(C#N)OCC
Agent: N
Product: CNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(C)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{7-isobutyl-5-methyl-2-[(5-methyl-1H-indol-3-yl)methyl]4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and ammonia using diethyl cyanophosphonate as a coupling reagent. Mass: 502.25 (M+H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C@H:16]2[C@@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:6])=[O:5])=[C:8]([C@H:16]2[C@@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH:9]=1
Reactant: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc([N+](=O)[O-])ccc1S(=O)(=O)C1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)C1CC1
Yield: 93.6 %

Procedure:
To 76G (2.9 g) in methanol (60 mL) was added 10% Pd/C (990 mg). The mixture was hydrogenated with a hydrogen balloon for 2.0 h. The Pd/C was removed by filtration and the filtrate was concentrated to afford 76I (2.54 g, 95% yield). 1H NMR (400 MHz, DMSO-d6, 100° C.) δ ppm 0.83-0.93 (m, 5H) 0.95-1.04 (m, 2H) 1.13-1.24 (m, 11H) 2.02-2.07 (m, 1H) 2.09-2.16 (m, 1H) 2.73-2.79 (m, 1H) 3.48-3.56 (m, 1H) 3.63-3.74 (m, 4H) 5.79 (d, J=7.70 Hz, 1H) 6.48-6.54 (m, 2H) 7.40 (d, J=8.79 Hz, 1H), LC-MS 439 (M+H).
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21](=[O:35])[N:22]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]=[O:34])[CH3:23])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:22]([CH3:23])[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([OH:6])=[O:34])=[O:35])([CH3:19])([CH3:17])[CH3:18]
Reactant: CN(CCOc1ccccc1C=O)C(=O)OC(C)(C)C
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CN(CCOc1ccccc1C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 124.1 %

Procedure:
A solution of sodium chlorite (2.85 g; 31.5 mmol; 5.5 eq.) and sodium dihydrogenphosphate (2.47 g; 20.6 mmol; 3.6 eq.) in water (25 mL) was added dropwise to a mixture of 2-methyl-2-butene (5.7 mL) and [2-(2-formyl-phenoxy)-ethyl]-methyl-carbamic acid tert-butyl ester (1.6 g; 5.73 mmol; 1 eq.) in 1,4-dioxane (25 mL). The reaction mixture was stirred at room temperature for 1.5 hour. After dilution with EA, the solution was washed with 1M HCl, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (2.1 g, 93%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.66-7.59 (dd, J=7.7, 1.8 Hz, 1H), 7.52-7.42 (m, OH), 7.16-7.10 (d, J=8.4 Hz, 1H), 7.03-6.94 (td, J=7.5, 1.0 Hz, 1H), 4.18-4.07 (m, 1H), 3.54-3.48 (t, J=5.4 Hz, 2H), 2.96-2.86 (d, J=11.7 Hz, 3H), 1.42-1.31 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)=[CH:18]2)(=O)=O)C=CC=CC=1>>[C:2]1([NH:1][C:28]2[N:27]=[C:26]([C:19]3[C:20]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:17][CH:18]=3)[CH:31]=[CH:30][N:29]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Nc1ccccc1
Product: c1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 46.5 %

Procedure:
Using the procedure of example 1, aniline (83 mg) was reacted with compound 1f (100 mg) to provide compound 3 (36 mg, 47%). 1H NMR (400 MHz, CD3OD) δ 8.88 (d, J=7.8 Hz, 1H), 8.29 (t, J=6.0 Hz, 2H), 8.19 (s, 1H), 7.69 (d, J=7.8 Hz, 2H), 7.36 (t, J=7.6 Hz, 2H), 7.21 (m, 1H), 7.08 (t, J=7.8 Hz, 2H). MS (ESI) m/z: 288 (M+H)+.