Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(=O)([O-])O.[Na+].C1COCC1.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>O>[C:24]([O:23][C:21]([N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)CNCC(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of iminodiacetic acid (5.1 g, 38.3 mmol) and sodium hydrogen carbonate (NaHCO3, 12.9 g, 153 mmol) were dissolved in 50 mL of water. Once the bubbling subsided, 50 mL of THF was added followed by 10.0 g (46.0 mmol) of BOC2O. The mixture was stirred at ambient temperature for 2 days when starting materials were completely consumed as detected by ESI. The reaction was worked up by removing THF and washing the aqueous layer with Et2O twice. The pH of the aqueous layer was then adjusted to 1 using conc. HCl. The product was extracted with EtOAc and solvent removed in vacuo to provide the product as a white solid. The product was purified by crystallization from EtOAc to give 8.04 g (90%) of clear crystals of 27. ES MS [M−H]−232.1.
Reaction SMILES: [O:1]=[S:2]1(=[O:12])[CH2:6][C:5]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3]1.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N1C=CC=CC=1>[CH2:17]([O:16][C:14]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:5]=2[CH2:6][S:2]1(=[O:12])=[O:1])=[O:15])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: O=S1(=O)Cc2c(O)cccc2N1
Solvent: c1ccncc1
Product: CCOC(=O)N1c2cccc(O)c2CS1(=O)=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 26.6 %

Procedure:
Sultam 1c (100 mg, 0.54 mmol) was dissolved in pyridine (2.5 mL) and cooled to 0° C. Ethyl chloroformate (62 μL, 0.65 mmol) was added and the solution was warmed to room temperature and allowed to age for 16 hours. The pyridine was removed in vacuo and the reaction mixture was diluted with EtOAc, washed twice with 1.0 N HCl, once with water and once with brine. The solution was then dried over MgSO4, filtered and the solvent removed in vacuo. Purification via flash chromatography gave the desired phenol 1d (37 mg, 27%).
Reaction SMILES: [O:1]=[C:2]1[CH:8]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.[CH3:26][O+](C)C>C(Cl)Cl>[CH3:26][O:1][C:2]1[CH:8]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: C[O+](C)C
Reactant: COC(=O)c1ccccc1C=CC1CCCCNC1=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1C=CC1CCCCN=C1OC

Procedure:
The product of Example 85 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:27]1([CH2:33][S:34]([Cl:37])(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[ClH:37].[CH2:33]([S:34]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NS(=O)(=O)Cc3ccccc3)cc2)cc1)[C@H]1CN2CCC1CC2

Procedure:
A solution of 80 mg (0.20 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 77.4 mg (0.41 mmol) of phenylmethanesulfonyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is concentrated in vacuo and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 34 mg (32.7% of theory) of the title compound are obtained.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[C:10](=[O:29])[N:11]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)[C:12]2=[O:17])C1C=CC=CC=1.C(OCC)(=O)C>[Pd].C(O)C>[F:28][C:25]([F:26])([F:27])[O:24][C:21]1[CH:22]=[CH:23][C:18]([N:11]2[C:12](=[O:17])[CH:13]3[NH:8][CH:9]([CH2:16][CH2:15][CH2:14]3)[C:10]2=[O:29])=[CH:19][CH:20]=1
Reactant: O=C1C2CCCC(C(=O)N1c1ccc(OC(F)(F)F)cc1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1C2CCCC(N2)C(=O)N1c1ccc(OC(F)(F)F)cc1
Reaction time: 2 h

Procedure:
A mixture of 9-benzyl-3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione (120 mg, 0.3 mmol), 10% Pd/C (20 mg, 0.02 mmol Pd), ethyl acetate (8 mL), and ethanol (2 mL) were stirred vigorously under an atmosphere of H2. After 2 h, more ethanol (2 mL) was added. After an additional 16 h, the reaction was filtered through Celite and concentrated to give 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione: MS (ESI): 315.4 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:21])[NH:16][CH:17]([CH3:20])[CH2:18][OH:19])[CH:10]=1.[NH3:23]>O>[C:3]([CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][CH:17]([CH3:20])[CH2:18][OH:19])=[O:21])(=[O:2])[NH2:23]
Reactant: N
Reactant: COC(=O)CCCC=Cc1cccc(C(=O)NC(C)CO)c1
Solvent: O
Product: CC(CO)NC(=O)c1cccc(C=CCCCC(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
21 (0.030 g, 0.10 mmol) was dissolved in 2 mL of ammonia 33% solution in water and stirred at room temperature for 8 h. The solvent was removed and the product was purify by reverse-phase HPLC chromatography (18% acetonitrile/82% water 20 min isocratic program) to give 19 (7 mg).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])SC)#[N:5]>C(O)C>[C:4]([NH:6][C:7]([NH:3][CH2:1][CH3:2])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])#[N:5]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CCN
Solvent: CCO
Product: CCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
Anhydrous ethylamine (9.0 g.) was added to a solution of N-cyano-N-'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (Example 3(c). 5.0 g.) in ethanol. The solution was heated under reflux for 8 hours and concentrated under reduced pressure. The residue was dissolved in isopropyl alcohol, filtered, and diluted with water. The white solid obtained was recrystallised from isopropyl alcohol-ether to yield N-cyano-N'-ethyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine. m.p. 118°-120°. (Found: C, 49.6; H, 6.8; N, 31.2 S. 11.7. C11H18N6S requires: C, 49.6; H, 6.8; N, 31.6; S, 12.0).
Reaction SMILES: C([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][C:20](=[O:22])[NH2:21])=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.[H][H]>CO.O.[C].[Pd]>[NH2:11][C@H:12]([C:14]([NH:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][C:20](=[O:22])[NH2:21])=[O:15])[CH3:13]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Into a 200 ml three-necked flask was charged 5.0 g (14.2 mmol) of Z-L-Ala-L-Gln, and the peptide was dissolved in 100 ml of a mixture of methanol and water (methanol:water =7:3) and stirred with a magnetic stirrer. After the air in the flask had been replaced with nitrogen, 0.8 g of 2% by weight of palladium-carbon was added thereto, and the protective group was eliminated in a stream of hydrogen. After 2 hours, the completion of the reaction was confirmed by thin layer chromatography, and then the palladium-carbon was filtered off. The filtrate was concentrated to 20 ml under reduced pressure, and 40 ml of isopropyl alcohol was added thereto. The resulting mixture was stirred for 30 minutes, during which time crystals precipitated. The crystals were collected by filtration, washed with isopropyl alcohol and then dried under reduced pressure to give 2.8 g (12.9 mmol) (90%) of L-Ala-L-Gln.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([NH:12]C(=O)C)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])#[CH:22].CS(O)(=O)=O.Cl>C(O)C>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH2:17][CH3:18])[N:5]=[CH:4][C:3]([C:19]#[N:20])=[C:2]2[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[C:23]([C:21]#[CH:22])[CH:24]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O
Reactant: C#Cc1cccc(N)c1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCO
Product: C#Cc1cccc(Nc2c(C#N)cnc3cc(OCC)c(N)cc23)c1
Temperature: 80 °C
Reaction time: 19 h
Yield: 81.1 %

Procedure:
A mixture of N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (23.2 g, 0.08 mol, 1.00 equiv), 3-ethynyl aniline (10.1 g, 0.094 mol, 1.18 equiv), methanesulfonic acid (2.3 ml, 0.0355 mol) in ethanol (60 0 ml) was stirred under refluxed for 6 hours and then 0.6N hydrogen chloride (1000 ml, 0.6 mol) was added. The reaction mixture was heated to 80° C. and held for 19 hours, and then cooled to 0° C. to form precipitate. The precipitate was filtered and added to a solution of 1N potassium carbonate (400 ml) in methanol (600 ml) in which the mixture was stirred for 3 hours. The reaction mixture was filtered, washed with 1:1 methanol/water (500 ml) and dried to give 21.3 g of product. MS (ESI) m/z: 563 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C@@H:12]3[N:6]3[CH2:7][CH2:8][NH:9][C:10]([CH:11]=1)=[C:5]23.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C@@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17][C@@H:12]3[N:6]3[CH2:7][CH2:8][NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCN3
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCN3
Yield: 61.8 %

Procedure:
Tert-butyl (6bR,10aS)-5-(2,4-dichlorophenyl)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (37 mg, 60%) was prepared via coupling of tert-butyl (6bR,10aS)-5-bromo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (50 mg, 0.13 mmol) with 2,4-dichlorophenyl boronic acid (74 mg, 0.39 mmol) as illustrated above using the general procedure for Suzuki coupling. 1H NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H), 1.82–1.96 (m, 2H), 2.74–2.82 (m, 1H), 2.99–3.05 (m, 1H), 3.16–3.22 (m, 2H), 3.33–3.39 (m, 1H), 3.43–3.50 (m, 1H), 3.52–3.57 (m, 1H), 3.62–3.69 (m, 1H), 3.43–3.50 (m, 1H), 3.52–3.57 (m, 1H), 3.62–3.69 (m, 1H), 3.71–3.79 (m, 1H), 3.80–3.85 (m, 1H), 3.89–4.14 (m, 1H), 6.44 (s, 1H), 6.59 (s, 1H), 7.22 (s, 2H), 7.42 (s, 1H) ppm.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[H-].[Na+].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>C1COCC1>[CH3:7][O:6][C:4](=[O:5])[CH:3]([C:19](=[O:20])[NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([F:10])([F:22])[F:21])=[CH:13][CH:14]=1)[C:1]#[N:2]
Reactant: COC(=O)CC#N
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C#N)C(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
The anion of methyl cyanoacetate (2.20 g, 22.2 mmoles) was made at 0° C. using sodium hydride (0.8 g, 22 mmoles) in 70 ml of THF and treated dropwise with 4-trifluoromethylphenyl isocyanate (4.1 g, 22 mmoles). After one hour at 0° C. the solvent was removed and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine, dried and partially concentrated in vacuo to precipitate the title compound (3.8 g) as a white solid, mp 186°-189° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:29][C:30]3[NH:31][CH:32]=[CH:33][N:34]=3)[CH2:23][C:24]3[NH:25][CH:26]=[CH:27][N:28]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH:25]1[CH:26]=[CH:27][N:28]=[C:24]1[CH2:23][N:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:35])=[CH:20][CH:19]=1)[CH2:29][C:30]1[NH:34][CH:33]=[CH:32][N:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
The compound (111 mg) obtained in Example 32-1 was dissolved in anhydrous methanol (1.0 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (3.0 ml) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off and the residue was added with a 1 mol/l sodium hydroxide aqueous solution, followed by washing with dichloromethane. The aqueous layer was evaporated to dryness, followed by distilling azeotropically with chloroform. Consequently, the subject compound (48.5 mg) was obtained as a yellow oily substance.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[C:18](O[K])(C)(C)C.CI>ClCCl>[CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]([CH3:18])([CH:9]=[O:10])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(C=O)CC1
Reactant: CC(C)(C)O[K]
Solvent: CI
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC(C)(C=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the title compound from step 1 (11.6 g, 50.0 mmol) in abs. dichloromethane (200 mL) was mixed with tert-BuOK (6.50 g, 58.0 mmol) and methyl iodide (3.42 mL, 55.0 mmol) at 0° C. in argon. After 30 min the batch was heated to RT and then stirred overnight (solid separated out). The reaction mixture was washed with water and saturated NaCl solution (50 mL), dried over Na2SO4, concentrated to low volume in a vacuum and the remaining residue purified by flash chromatography with ethyl acetate/MeOH 20:1.
Reaction SMILES: ClCl.[CH3:3][C:4]1[CH:12]=[C:11](Cl)[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:11]1[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:3])[CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Reactant: NCc1ccccc1
Agent: ClCl
Product: Cc1cc(NCc2ccccc2)c(S(C)(=O)=O)cc1C(=O)O

Procedure:
in stage c) the chlorine substituent is converted into a benzylamino group by reacting 2-methyl-4-chloro-5-methylsulfonylbenzoic acid with benzylamine to give the corresponding intermediate 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.Cl[C:15]1[N:24]=[C:23]([NH2:25])[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1>>[NH2:25][C:23]1[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=[C:15]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([CH:1]3[CH2:2][CH:3]=[CH:4][CH2:5]3)=[O:7])[CH2:13][CH2:12]2)[N:24]=1
Reactant: O=C(C1CC=CC1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCN(C(=O)C4CC=CC4)CC3)nc(N)c2cc1OC

Procedure:
N-(3-cyclopentenylcarbonyl)piperazine (2.7 g., 0.015 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (3.6 g., 0.015 mole) are reacted according to the procedure of Example 1(a). The crude product crystallized from methanol affords analytically pure 4-amino-2-[4-(3-cyclopentenylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 215.5°-217.5° C. (corr.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:6][C:7]1[CH:14]=[C:13]([O:15][CH2:2][CH2:3][CH2:4][Cl:5])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: ClCCCBr
Reactant: O=Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCCCCl)cc1Cl
Temperature: 65 °C
Yield: 84.5 %

Procedure:
1-Bromo-3-chloropropane (2.55 g, 16.2 mmol, 1.0 equiv) was added to a solution of 2-chloro-4-hydroxybenzaldehyde (2.54 g, 16.2 mmol) and K2CO3 (4.48 g, 32.4 mmol) in acetonitrile (41 mL). The mixture was heated at 65° C. for 18 h, then cooled to room temperature (rt) and filtered through diatomaceous earth. The filtrate was concentrated to yield the crude product, which was purified by column chromatography (silica gel, 5% EtOAc in hexanes) to afford 3.19 g of a colorless oil (66%). 1H NMR (400 MHz, CD3OD): 10.3 (s, 1H), 7.87 (d, J=8.0, 1H), 7.10 (d, J=4.0, 1H), 7.03 (dd, J=8.0, 4.0, 1H), 4.23 (t, J=8.0, 2H), 3.76 (t, J=8.0, 2H), 2.31-2.22 (m, 2H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:15].[C:16]([CH2:20][C:21](Cl)=[O:22])([CH3:19])([CH3:18])[CH3:17]>N1C=CC=CC=1>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:20][C:21]([NH:15][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:22]
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 61.5 %

Procedure:
Following the procedure of Example 1, 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (1.0 g, 5.0 mmol) and t-butylacetyl chloride (0.74 mL, 5.5 mmol) in pyridine (10 mL) provided 3,3-dimethyl-N-[7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-yl]butyramide (0.92 g). Mp 182-183° C.; Anal. Calcd. for C19H25NO2: C, 76.22; H, 8.42; N, 4.68; Found: C, 76.13; H, 8.28; N, 4.71.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18](O)[N:17]3[N:21]=[CH:22][CH:23]=[C:16]3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:35]>>[C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([Cl:35])[N:17]3[N:21]=[CH:22][CH:23]=[C:16]3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1CCC(c2cc(O)n3nccc3n2)CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)OC(=O)C1CCC(c2cc(Cl)n3nccc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
4-(7-Hydroxy-pyrazolo[1,5-a]pyrimidin-5-yl)-cyclohexanecarboxylic acid t-butyl ester (Int-7b, 10.6 g), N,N-dimethylaniline (15.0 ml) and POCl3 (120 mL) were mixed and stirred at room temperature for 18 hours. The solution was reduced in vacuo and cooled to 0° C. in ice bath. The reaction was then quenched with sat. NaHCO3(aq) and extracted with DCM (100 mL×3). The combined organics were dried with Na2SO4 and the solvent was removed in vacuo. The resulting oil was purified via silica gel column on 20% to 100% ethyl acetate in hexanes gradient to yield the title compound (2.5 g, 32% over three steps). LC-MS: 336 [M+H].
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[C:1]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:42][C:38]3[CH:37]=[C:36]([CH:29]([CH:26]4[CH2:27][CH2:28]4)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:41]=[CH:40][CH:39]=3)[CH:13]=[CH:12][C:11]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(C)(C)C)o2)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(C)(C)C)o3)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.1 %

Procedure:
To a solution of 2-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ol (109 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (95 mg) and triphenylphosphine (167 mg) in THF (3.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (250 μL) at 0° C., and the mixture was stirred at room temperature for 23 hr. The solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (115 mg) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4][NH:3]1.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[O:1]=[C:2]1[CH:6]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][CH2:4][N:3]1[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(NC1CCNC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1CCC(NC(=O)OCc2ccccc2)C1=O
Reaction time: 0.92 h

Procedure:
To a stirred solution of benzyl N-(2-oxopyrrolidin-3-yl)carbamate (which may be prepared as described in Description 39) (0.5 g, 2.13 mmol) in dry DMF (6 mL) was added in 3 equal portions a 60% dispersion of NaH in oil (90 mg, 2.25 mmol) over 5 minutes under N2. After stirring for 55 minutes, 2-(chloromethoxy)ethyl-trimethyl-silane (0.42 mL, 2.35 mmol) was added dropwise over 12 minutes. The solution was stirred under N2 at ambient temp for 19 hours. The reaction was quenched by addition of saturated aqueous NH4Cl solution (2 mL). The mixture was evaporated and re-evaporated from toluene (3×100 mL). The residue was partitioned between DCM (30 mL) and water (30 mL). The organic phase was dried (MgSO4) and evaporated to an oily solid. The material was purified by silica column chromatography: it was dissolved in toluene (6 mL) and the solution was applied to a 50 g cartridge which was then eluted on a Biotage SP4 system with a gradient of EtOAc/iso-hexane (30-100%). Relevant fractions were pooled and evaporated to give benzyl N-[2-oxo-1-(2-trimethylsilylethoxymethyl)pyrrolidin-3-yl]carbamate (D40) as a colourless oil, dried under vacuum for 2 hours at room temperature to afford 170 mg;
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][C@H:8]1/[CH:32]=[CH:33]/[C:34]([NH2:36])=[O:35])=[O:6])[CH:2]=[CH2:3].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([SH:12])[CH2:9][C@H:8]1/[CH:32]=[CH:33]/[C:34]([NH2:36])=[O:35])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C/C(N)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1/C=C/C(N)=O
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a suspension of (E)-3-[(2S,4S)-N-allyloxycarbonyl 4-tritylthiopyrrolidin-2-yl]acrylamide (60 g, 120 mmol) in methylene chloride (60 ml) were added trifluoroacetic acid (60 ml) and triethylsilane (20 ml, 125 mmol) under ice-cooling. The reaction mixture was stirred under icecooling for 10 minutes and for additionally 30 minutes at room temperature, and concentrated. The residue was dissolved in methylene chloride (100 ml), and the solution concentrated. The obtained residue was dissolved ethyl acetate (750 ml), and the solution washed with 1M sodium phosphate buffer (pH 5.5, 500 ml and 250 ml×3) and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in ethyl acetate (50 ml), treated with hexane (250 ml) to crystallize to give the title compound (30 g, 97.3% yield).