Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]([C:15]2[CH2:19][C:18]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:37]=[C:38]([N:48]1[CH2:53][CH:52]=[C:51](B2OC(C)(C)C(C)(C)O2)[CH2:50][CH2:49]1)[CH2:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>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].O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:51]2[CH2:52][CH2:53][N:48]([C:38](=[O:37])[CH2:39][CH2:40][C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:49][CH:50]=2)=[C:13]([C:15]2[CH2:19][C:18]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH2:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Reactant: CC(C)(C)OC(=O)CCC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)CCC(=O)N1CC=C(c2ccc(OCc3ccccc3)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Yield: 62.1 %

Procedure:
A mixture of di-tert-butyl 2,2′-(3-(5-(benzyloxy)-2-bromophenyl)-4,5-dihydro-1,2-oxazole-5,5-diyl)diacetate (65.4 mg), tert-butyl 4-oxo-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)butanoate (107 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (8.54 mg), a 2 M aqueous cesium carbonate solution (0.3 mL), and DME (1.2 mL) was stirred at 90 C for 1 hour under microwave irradiation in an argon atmosphere. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (52.1 mg).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[S:21][N:20]=[C:19]([CH2:22][CH3:23])[N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[S:21][N:20]=[C:19]([CH2:22][CH3:23])[N:18]=2)=[O:12])[C:3]1=[O:15]
Reactant: CCc1nsc(N)n1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: CCc1nsc(NC(=O)c2c(O)cc(C)n(C)c2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate and 120 mg of 5-amino-3-ethyl-1,2,4-thiadiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 4 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 231 mg of 1,6-dimethyl-N-(3-ethyl-1,2,4-thiadiazol-5-yl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 19) represented by the formula:
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=3)[NH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.[H][H]>[N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=3)[NH:9][N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(N3CCOCC3)c2c1
Reactant: [H][H]
Solvent: CO
Product: Nc1ccc2[nH]nc(N3CCOCC3)c2c1
Reaction time: 24 h

Procedure:
3-Morpholin-4-yl-5-nitro-1H-indazole (210 mg) was dissolved in 10 ml of methanol and the mixture hydrogenated at 1 atm of hydrogen using 10% Pd/C (50 mg) as catalyst. After 24 hrs, the mixture was filtered and evaporated for use in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][N:14](C)[CH2:15]CO.C([Sn](=O)CCCC)CCC>>[CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[C:4]([O:6][CH2:7][CH2:8][N:14]([CH3:15])[CH3:13])=[O:5]
Reactant: CCOC(=O)C1CCCCN1C
Reactant: CN(C)CCO
Agent: CCCC[Sn](=O)CCCC
Product: CN(C)CCOC(=O)C1CCCCN1C
Temperature: 145 °C

Procedure:
A mixture of 85 g (0.5 mol) of ethyl 1-methylpipecolinate, 44.6 g (0.5 mol) of N,N-dimethylethanolamine and 0.82 g of dibutyltin oxide was heated at about 145° C. for 30 hours. The ethanol by-product was collected in a Dean-Stark trap. When the rate of ethanol evolution and amount of ethanol collected showed that the reaction was essentially complete, the reaction was heated at about 180° C. until ethanol evolution ceased. The liquid product was purified by distillation at reduced pressure to provide 2-(N,N-dimethylamino)ethyl N-methylpipecolinate.
Reaction SMILES: [O:1]1[CH2:5][C@H:4]([OH:6])[C@@H:3]([OH:7])[CH2:2]1.[C:8]([Si:12]([CH3:15])([CH3:14])Cl)([CH3:11])([CH3:10])[CH3:9]>ClCCl>[Si:12]([O:6][C@H:4]1[CH2:5][O:1][CH2:2][C@@H:3]1[OH:7])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@H]1COC[C@@H]1O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1COC[C@@H]1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 18.7 %

Procedure:
A mixture of (3S,4S)-tetrahydrofuran-3,4-diol (9.35 g, 89.8 mmol), t-butyldimethylchlorosilane (14.9 g, 98.8 mmol), TEA (13.8 mL, 98.8 mmol), and dichloromethane (100 mL) is stirred at room temperature for 4 days. The reaction is concentrated in vacuo and purified on silica gel (330 g, 35-80% EtOAc/hexanes, observed on TLC using KMnO4 staining) to give 3.66 g (19%) of the title compound as a light yellow oil. GC-MS m/z 161 (M-tBu)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.C([O-])([O-])=O.[K+].[K+].[F:28][C:29]([F:33])([F:32])[CH2:30]I.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:21][CH2:30][C:29]([F:33])([F:32])[F:28])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(O)cc(Cl)c2OC1C(F)(F)F
Reactant: FC(F)(F)CI
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(OCC(F)(F)F)cc(Cl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of ethyl 8-chloro-6-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 17a, Step 3 (0.500 g, 1.55 mmole) in anhydrous DMF (5.0 mL) under a dry N2 atmosphere was added KI (26 mg, 0.155 mmole), K2CO3 (0.321 g, 2.33 mmole) and 2,2,2-trifluoroethyl iodide (0.458 mL, 4.65 mmole) and the mixture was stirred at room temperature for 1 h, and then at 40° C. for 1 h. Additional K2CO3 (0.647 g, 4.65 mmole) and 2,2,2-trifluoroethyl iodide (0.458 mL, 4.65 mmole) were added to the mixture and the temperature was raised to 50° C. overnight. Additional 2,2,2-trifluoroethyl iodide (0.458 mL (4.65 mmole) was added and the temperature was raised to 85° C. for 18.5 h. The mixture was then poured into sat. NaHCO3 (100 mL) and extracted with EtOAc (2×200 mL). The combined extracts were then washed with brine (2×200 mL), dried over MgSO4, filtered and concentrated in vacuo to give a brown oil. Purification of the crude product by silica chromatography (6:1 hexanes:EtOAc) gave 0.237 g (41% yield) of the product as a light yellow crystalline solid: EIHRMS m/z 404.0246 (M+, C15H11ClF6O4, Calc'd 404.0250).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:4].C([Li])CCC.[CH3:20][N:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]>O1CCCC1>[CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH:22]([NH:21][CH3:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[O:4]
Reactant: CN=Cc1ccccc1C
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1ccccc1C
Reaction time: 1 h

Procedure:
A chilled solution (-4° C.) of 126 g of 2,2-dimethyl-N-[(2-methyl)phenyl]propanamide in 900 ml of tetrahydrofuran was treated dropwise over 1.5 hr with n-butyl lithium (500 ml of a 2.5M solution in hexanes). After the addition was complete, the resulting solution was stirred for 1 hr, with cooling, and was then treated over 0.5 hr with a solution of 91.77 g of 2-methylbenzaldehyde methyl imine. The reaction mixture was quenched by rapid addition of water. After concentration the residue was extracted with dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated. A 50 g portion of the residue (213 g) was acidified with 10% hydrochloric acid and partitioned with toluene. The aqueous layer was basified with a 50% sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. Upon standing under nitrogen overnight in a refrigerator a solid formed, which was triturated with hexane to give 2,2-dimethyl-N-[2 -[2-methylamino-2-(2-methylphenyl)ethyl]phenyl]propanamide, mp 77°-79° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]12[CH2:13][C:10]([C:14]3[NH:22][C:21]4[C:20](=[O:23])[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[N:17]([CH2:28][CH2:29][CH3:30])[C:16]=4[N:15]=3)([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2.[OH-].[Na+]>C1COCC1>[O:27]=[C:18]1[N:17]([CH2:28][CH2:29][CH3:30])[C:16]2[N:15]=[C:14]([C:10]34[CH2:13][C:6]([CH2:5][CH2:4][C:3]([OH:31])=[O:2])([CH2:12][CH2:11]3)[CH2:7][CH2:8][CH2:9]4)[NH:22][C:21]=2[C:20](=[O:23])[N:19]1[CH2:24][CH2:25][CH3:26]
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(CCC(=O)OC)(CC3)C4)nc2n(CCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CCC(=O)O)(CC3)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
A solution of 3-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.1]oct-1-yl]-propionic acid methyl ester (0.456 mmol, 0.196 g) in THF (10 ml) was treated with 20% NaOH (2 ml) and stirred overnight at RT. The reaction was concentrated to remove the THF. The aqueous residue was acidified (pH 2-3) with conc. HCl and iPrOH was added to homogeneity. The solution was concentrated on the rotovap until solids just began to separate. After chilling in ice 1 h, the precipitated solids were collected by vacuum filtration, rinsed with a little H2O and chased with Et2O. The solids were dried on the filter to provide the desired product (0.061 g, 32%). 13C NMR (100 MHz, CDCl3): 11.11 (q), 11.26 (q), 20.04 (t), 21.25 (t), 21.31 (t), 29.51 (s), 33.97 (t), 35.15 (s), 36.16 (t), 36.39 (t), 43.32 (t), 43.41 (t), 45.38 (t), 49.18 (t), 106.01 (s), 149.40 (s), 150.90 (s), 156.30 (s), 161.56 (s), 178.54 (s)
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.OS(O)(=O)=O>C(O)(=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2([CH2:16][C:12]3[N:11]4[CH2:29][CH2:30][N:31]([CH:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[C:32](=[O:33])[C:10]4=[C:9]([OH:8])[C:14](=[O:15])[N:13]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:23][CH:24]=1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1C1CCOCC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1c2c(O)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
To a stirred solution of 9-benzyloxy-6-[1-(4-chlorophenyl)-cyclopentylmethyl]-2-(tetrahydro-pyran-4-yl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (335) in acetic acid (1 mL), concentrated H2SO4 (0.001 mL, 0.02 mmol) was added and stirred for 4 h at room temperature (monitored by LC-MS). After completion of the reaction, volatiles were removed from the reaction mixture, and the mixture was quenched with ice-cold water (5 mL). Saturated aqueous NaHCO3 (adjusted pH to 8) was added and the quenched mixture was extracted with ethyl acetate (2×15 mL). The combined extracts were dried and concentrated. The resulting residue was washed with 10% dichloromethane in ether to get 6-[1-(4-chlorophenyl)-cyclopentylmethyl]-9-hydroxy-2-(tetrahydro-pyran-4-yl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (336) (19 mg, 41%) as an off-white solid.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>>[C:2]1([CH2:1][S:8][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [H-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)N1CCCCSCc1ccccc1

Procedure:
Benzyl mercaptan (8.2 g, 66.4 mmol) was reacted with sodium hydride (52.4% in oil, 3.35 g, 73.0 mmol), and then with N-(4-bromobutyl)-phthalimide (19.7 g, 69.7 mmol) as described in Example A, to give the title compound. NMR (CDCl3): thiobenzyl methylene, and methylene bonded to nitrogen, both at δ 3.7. Methylene bonded to sulfur at δ 2.4.
Reaction SMILES: C([NH:8][C@H:9]([C:11](O)=[O:12])[CH3:10])(OC(C)(C)C)=O.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O.Cl.[NH2:38][CH2:39][C@@H:40]([C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=2)[CH:46]=1)[CH2:41][C:42]([OH:44])=[O:43].C(=O)(O)[O-].[Na+]>C(#N)C.O>[ClH:51].[NH2:8][C@@H:9]([CH3:10])[C:11]([NH:38][CH2:39][C@@H:40]([C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=2)[CH:46]=1)[CH2:41][C:42]([OH:44])=[O:43])=[O:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC[C@H](CC(=O)O)c1ccc(Cl)c(OCc2ccncc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC#N
Product: C[C@H](N)C(=O)NC[C@H](CC(=O)O)c1ccc(Cl)c(OCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boc-alanine (0.37 mmol, 1 eq), N,N′-dicyclohexylcarbodiimide (0.47 mmol, 1.2 eq), and N-hydroxysuccinimide (0.47 mmol, 1.2 eq) were dissolved in 2 mL acetonitrile. The mixture was stirred at room temperature for 2 hr. The solid was filtered and added to (3R)-4-amino-3-[4-chloro-3-(4-pyridylmethoxy)phenyl]butanoic acid hydrochloride (68) and sodium bicarbonate (NaHCO3) (1.5 eq) in 1 mL water. The reaction was stirred at room temperature overnight. The solvent was then evaporated and treated with trifluoroacetic acid (TFA). The trifluoroacetic acid (TFA) was evaporated and purified by HPLC to provide the title compound (73). 1H-NMR (400 MHz, CD3OD): δ 8.53 (d, J=6.0 Hz, 2H), 7.57 (d, J=6.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.05 (d, J=1.6 Hz, 1H), 6.87 (d, J=2 Hz, 1H), 5.26 (s, 2H), 3.69-3.74 (q, J=6.8 Hz, 1H), 3.56-3.61 (dd, J=8.4, 13.2 Hz, 1H), 3.28-3.39 (m, 1H), 2.55-2.61 (dd, J=16.0, 8.0 Hz, 1H), 2.44-2.50 (dd, J=15.2, 8.0 Hz, 1H), 1.23 (d, J=6.8, 3H); MS (ESI) m/z 391.87 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[C:20](=[O:21])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:4].[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)C.Cl.CCOCC.CCOCC>[ClH:1].[CH3:4][N:3]([CH2:5][C@@H:6]1[C@H:20]([OH:21])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:2]
Reactant: CN(C)CC1CCc2onc(-c3ccccc3)c2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Solvent: CCOCC
Product: CN(C)C[C@H]1CCc2onc(-c3ccccc3)c2[C@H]1O
Reaction time: 1 h

Procedure:
6,7-Dihydro-5-dimethylaminomethyl-3-phenyl-1,2-benzisoxazol-4(5H)-one hydrochloride (7.5 g) was dissolved in 100 ml ethanol and treated with 5.0 g sodium borohydride. After stirring for 1 hour the reaction mixture was distributed between 5% HCl and ether. The aqueous phase was then made basic with solid sodium bicarbonate and extracted with ether. Concentration under reduced pressure gave the product as a mixture of trans and cis isomers which was chromatographed by preparative high pressure liquid chromatography (HPLC) (ethyl acetate/CH3CN/diethylamine; 90:10:1) to give 2.20 g of the pure cis isomer. The hydrochloride was formed in HCl/ether and then recrystallized from methanol/ether to give 1.81 g of cis-5-(dimethylaminomethyl)-4-hydroxy-3-phenyl-4,5,6,7-tetrahydro-1,2-benzisoxazole hydrochloride, m.p. 235°-236° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])(=[O:15])=[O:14])[CH:6]=[C:5]([CH2:25][OH:26])[N:4]=1.Br[CH:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:26][CH2:25][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])(=[O:14])=[O:15])[CH2:35][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:8]=[C:3]([CH2:2][OH:1])[N:4]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCOc1cc(CO)nc(CO)c1
Reactant: CCOC(=O)CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(CCOc1cc(CO)nc(CO)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 20 h

Procedure:
To a solution of 767 mg of N-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-2-nitro-benzenesulfonamide in 15 ml of DMF, under argon, was added 344 μl of ethyl 3-bromo-butyrate and 1.38 g of K2CO3. The mixture was stirred for about 20 hours at 40° C. and then filtered through a sinter of porosity 4. The cake was washed with EtOAc and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica (Merck SuperVarioPrep 90 g column, Si60 15-40 μm), using a gradient of 0 to 10% MeOH in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 395 mg of ethyl 4-[[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-(2-nitro-benzenesulfonyl)-amino]-butanoate were obtained. LC/MS (B): tr=2.72 min; [M+H]+: m/z 498; [M+HCO2H−H]−: m/z 542.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:22]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[C:22]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32]([NH:1][C:2]2[CH:21]=[CH:20][CH:19]=[C:4]([O:5][C:6]3[C:15]4[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=4)[N:9]=[CH:8][N:7]=3)[CH:3]=2)=[O:33])[CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1O
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O
Temperature: 60 °C
Yield: 82 %

Procedure:
A stirred mixture of 4-(3-aminophenoxy)-6-methoxyquinazolin-7-ol from the previous step (500 mg, 1.77 mmol) and phenyl 5-tert-butylisoxazol-3-ylcarbamate (460 mg, 1.77 mmol) in dry N,N-dimethylformamide (10 mL) was heated at 60° C. for 5 h. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether and filtered and dried under reduced pressure to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea as a cream solid (650 mg, 82%) which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 10.78 (brs, 1H), 9.58 (brs, 1H), 9.00 (brs, 1H), 8.48 (s, 1H), 7.55-7.57 (m, 2H), 7.40 (m, 1H), 7.24-7.26 (m, 2H), 6.97 (m, 1H), 6.48 (s, 1H), 3.99 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:47])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:32]3([C:36]([O:38]CC)=[O:37])[CH2:35][CH2:34][CH2:33]3)[N:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:47])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:32]3([C:36]([OH:38])=[O:37])[CH2:33][CH2:34][CH2:35]3)[N:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)O)CCC3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 680 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[5-(1-ethoxycarbonyl-cyclobutoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 6 ml of THF, 1.6 ml of a 1 M aqueous NaOH solution was added. After stirring for 2 h at RT the reaction was acidified to pH 1 with diluted aqueous hydrochloric acid and extracted with DCM (3×50 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure.
Reaction SMILES: [CH2:1]([C:3]1([C:13]23[CH2:19][CH:16]([CH:17]=[CH:18]2)[CH2:15][CH:14]3[C:20]([O-:22])=[O:21])[CH2:11][CH:10]2[CH2:12][CH:4]1[CH:5]1[CH:9]2[CH2:8][CH2:7][CH2:6]1)[CH3:2].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH:25]=[CH:24]1.[CH2:30]1[C@@H:34]2[CH:35]3[C:40](=[O:41])[O:39][C:37](=[O:38])[CH:36]3[C@H:31]1[CH:32]=[CH:33]2.[C:42]([O:46][CH2:47][CH2:48][OH:49])(=[O:45])[CH:43]=[CH2:44]>>[CH2:1]([C:3]1([C:13]23[CH2:19][CH:16]([CH:17]=[CH:18]2)[CH2:15][CH:14]3[C:20]([O-:22])=[O:21])[CH2:11][CH:10]2[CH2:12][CH:4]1[CH:5]1[CH:9]2[CH2:8][CH2:7][CH2:6]1)[CH3:2].[C:26]1(=[O:27])[O:28][C:23](=[O:29])[CH:24]=[CH:25]1.[CH2:30]1[C@@H:34]2[CH:35]3[C:40](=[O:41])[O:39][C:37](=[O:38])[CH:36]3[C@H:31]1[CH:32]=[CH:33]2.[OH:49][CH2:48][CH2:47][O:46][C:42]([CH:43]1[CH2:4][CH:3]2[CH2:11][CH:44]1[CH:2]=[CH:1]2)=[O:45]
Reactant: C=CC(=O)OCCO
Agent: CCC1(C23C=CC(CC2C(=O)[O-])C3)CC2CC1C1CCCC21
Agent: O=C1C=CC(=O)O1
Agent: O=C1OC(=O)C2C1[C@@H]1C=C[C@H]2C1
Product: O=C(OCCO)C1CC2C=CC1C2

Procedure:
Polymerization and separation were carried out in the same manner as in Example 18 using 75 mmol of 8-ethyl-8-tricyclo[5.2.1.02,6]decanyl-5-norbornene-2-carboxylate prepared in Example 3, 100 mmol of maleic anhydride, 15 mmol of cis-5-norbornene-endo-2,3-dicarboxylic anhydride and 10 mmol of 2-hydroxyethyl acrylate, to separate 5.74 g of a polymer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][N:13]([CH3:16])[CH:14]=O>>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:12]/[N:13]([CH3:16])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CN(C)C=O
Product: CN(C)/C=C/c1cc(Cl)ncc1[N+](=O)[O-]
Yield: 70 %

Procedure:
A solution of 2-chloro-4-methyl-5-nitropyridine (1.0 equiv), 25.2 mL dimethylacetal dimethylformamide (2.2 equiv.) in dimethylformamide (0.8 M) was heated at 95° C. for 18 hours. Upon cooling the volatiles were removed in vacuo. The crude material was recrystallized from boiling methanol to yield (E)-2-(2-chloro-5-nitropyridin-4-yl)-N,N-dimethylethenamine (70%) as a red solid. 1H NMR (CDCl3): δ 8.80 (s, 1H), 7.32 (d, J=13.2, 1H), 7.25 (s, 1H), 5.95 (d, J=13.2, 1H), 3.02 (bs, 6H).