Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3Br)=[CH:8][CH:9]=[CH:10][C:3]1=2.C([Mg]Cl)C.CN(C)[CH:26]=[O:27]>O1CCCC1>[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3[CH:26]=[O:27])=[CH:8][CH:9]=[CH:10][C:3]1=2
Reactant: BrC1=C(c2cccc3sccc23)N2CCN=C2S1
Reactant: CN(C)C=O
Agent: Br
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: O=CC1=C(c2cccc3sccc23)N2CCN=C2S1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
3-(Benzo[b]thiophen-4-yl)-2-bromo-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (1.2 g) was added in portions under nitrogen at 5-10° C. over 5 minutes to a stirred solution of ethylmagnesium chloride (2.0 M solution in ether; 4.5 ml) in tetrahydrofuran (20 ml), then the mixture was stirred at 5-15° C. for 2 hours. Dimethylformamide (1.3 ml) was added at 5-10° C. over 5 minutes, then the mixture was stirred at ambient temperature for 3 hours, cooled to 15° C. and quenched by the cautious addition of saturated aqueous ammonium chloride solution (10 ml) and water (10 ml). Ethyl acetate (20 ml) was added and the mixture was stirred at ambient temperature for 18 hours. The product was extracted into ethyl acetate (2×50 ml) and the combined extracts were washed with saturated aqueous sodium chloride solution (50 ml), dried (MgSO4), and the solvents were removed in vacuo. The residue was triturated with propan-2-ol (5 ml) and the resulting solid was collected by filtration, washed with propan-2-ol (5 ml) and dried in vacuo at 60° C. to give 3-(benzo[b]thiophen-4-yl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxaldehyde (0.37 g) as a brown solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([CH2:7][CH2:8]OS(C)(=O)=O)[C:4]([CH3:15])([CH3:14])[O:3]1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O>[N:17]([CH2:8][CH2:7][C@@H:5]1[O:6][C:2]([CH3:16])([CH3:1])[O:3][C:4]1([CH3:15])[CH3:14])=[N+:18]=[N-:19]
Reactant: CC1(C)O[C@@H](CCOS(C)(=O)=O)C(C)(C)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H](CCN=[N+]=[N-])C(C)(C)O1
Temperature: 95 °C
Yield: 81.1 %

Procedure:
Step H To a solution of methanesulfonic acid 2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethyl ester (2.5 g, 9.9 mmol) in N,N-dimethylformamide (50 mL) was added NaN3 (6 g, 70 mmol). The reaction mixture was heated at 95° C. for 4 h. Then the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine several times, dried over MgSO4, concentrated to give (S)-5-(2-azido-ethyl)-2,2,4,4-tetramethyl-[1,3]dioxolane as a yellow oil (1.6 g, 80%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:12]=1.Br[CH2:46][C:47]([O:49][CH3:50])=[O:48].C(N(C(C)C)CC)(C)C>CCO>[CH3:50][O:49][C:47](=[O:48])[CH2:46][N:20]1[CH2:21][CH2:22][N:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([F:42])([F:43])[F:44])[C:3]=3[Cl:2])[CH2:23][CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:12]=2)[CH2:18][CH2:19]1
Reactant: FC(F)(F)c1cccc(CN(CCCOc2cccc(N3CCNCC3)n2)CC(c2ccccc2)c2ccccc2)c1Cl
Reactant: COC(=O)CBr
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirring solution of (2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-piperazin-1-yl-pyridin-2-yloxy)-propyl]-amine hydrochloride (0.1 g, 0.16 mmol) in EtOH (6 ml) was added methyl bromo-acetate (16 uL, 0.17 mmol) and diisopropylethylamine (89 uL, 0.51 mmol). The reaction mixture was stirred for 10 h at RT and then concentrated. Purification by flash silica gel chromatograpy afforded the title compound as a clear oil, 47 mg (42%). MS (ESI) 681.2 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22](Cl)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[S:26]1[CH:30]=[C:29]([NH2:31])[N:28]=[CH:27]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CCOC(C)=O.CCCCCCC>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:31][C:29]3[N:28]=[CH:27][S:26][CH:30]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Reactant: Nc1cscn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cscn1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
A round-bottom flask was charged with 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (INTERMEDIATE C, 299.84 mg, 0.657 mmol), thiazol-4-amine (79 mg, 0.788 mmol), and THF (3283 n1) to give a brown mixture. The flask was cooled in an ice-bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (1379 μl, 1.379 mmol) was added dropwise over 30 s. After 30 min, the cooling bath was removed, and the mixture was allowed to warm to room temperature. The reaction mixture was quenched by the addition of aq. 1N hydrochloric acid and a small amount of brine and extracted with EtOAc (3×, emulsion). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography on a 40 g column with 0 to 10% MeOH/DCM. The desired product was repurified again by chromatography on a 40 g silica gel column, this time with 0 to 40% EtOAc/Heptane to give 4-(2-bromo-4-(trifluoromethyl)phenyl)-N-(thiazol-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (73.1 mg, 0.140 mmol) as a cream-colored solid. 1H NMR (400 MHz, DMSO-d6) δ=10.88 (s, 1 H), 8.88 (d, J=2.2 Hz, 1 H), 8.20 (d, J=1.5 Hz, 1 H), 7.89 (dd, J=1.6, 8.5 Hz, 1 H), 7.73 (d, J=8.4 Hz, 1 H), 7.25 (d, J=2.2 Hz, 1 H), 7.16 (dd, J=2.2, 8.6 Hz, 1 H), 6.96 (d, J=2.2 Hz, 1 H), 6.22 (d, J=8.6 Hz, 1 H), 4.36 (d, J=15.8 Hz, 2 H), 3.78-3.63 (m, 2 H). m/z (ESI) 520.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:38])([F:37])[CH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:36])[C:30]=2[CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:36][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:30]=3[CH2:29][CH2:28][CH:27]4[C:26]([F:25])([F:37])[F:38])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cccc2c1CCC2C(F)(F)F
Product: CC(NC(=O)c1coc(Oc2cccc3c2CCC3C(F)(F)F)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 87.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 1-trifluoromethyl-indan-4-ol (53 mg, 0.26 mmol) to give the title compound (62 mg, 87%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:34](Br)(Br)([Br:36])[Br:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH:9]1[CH:10]=[C:34]([Br:36])[Br:35])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C=C(Br)Br
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a stirred cold (minus 50° C.) solution of N-boc-prolinal (5.98 g, 30 mmol) and PPh3 (62.95 g, 240 mmol) in CH2Cl2 (200 mL) was slowly added a solution of CBr4 (39.80 g, 120 mmol) in CH2Cl2 (50 mL), and the stirring was continued for 1 hr at 0° C. To this mixture was added sat. NaHCO3 and the mixture was extracted with CHCl3. The extract was washed with H2O, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with CHCl3 and n-hexane-AcOEt (4:1, v/v) as eluent to give 7.84 g (74%) 1-(tert-butoxycarbonyl)-2-(2,2-dibromoethenyl)pyrrolidine as colorless plates. mp 61-63; IR (KBr) 1693 cm−1; 1H-NMR (CDCl3) δ1.46 (9 H, s), 1.72-2.19 (4H, m), 3.35-3.45 (2H, m),4.35 (1H, br s), 6.36 (1H, br s); MS (FAB) m/z 352, 354, 356, 358; Anal. Calcd. for C11H17NO2Br2: C, 37.21; H 4.83; N, 3.94. Found: C, 37.14; H, 4.83; N, 4.00.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][C:27]=1[O:36][CH3:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:34])=[CH:28][C:27]=1[O:36][CH3:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Product: COc1cc(CC(=O)Nc2ccc3cnn(CCN4CCCC4)c3c2)ccc1OCc1ccccc1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and (4-benzyloxy-3-methoxy-phenyl)-acetic acid were processed to provide the title compound. MS (DCI/NH3) MS m/z 485 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.81 (m, 2 H), 1.97 (m, 2 H), 3.02 (m, 2 H), 3.51 (m, 2 H), 3.62 (s, 2 H), 3.69 (q, J=5.82 Hz, 2 H), 3.78 (s, 3 H), 4.66 (t, J=6.24 Hz, 2 H), 5.06 (s, 2 H), 6.84 (m, 1 H), 6.99 (m, 2 H), 7.12 (m, 1 H), 7.32 (m, 1 H), 7.40 (m, 4 H), 7.71 (m, 1 H), 8.08 (s, 1 H), 8.27 (s, 1 H), 9.59 (br s, N H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([CH3:15])=[N:10]2)=[O:4].[CH:21]1([C:24](=[O:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.O>[C:17]([NH:16][C:8]1[C:9]([CH3:15])=[N:10][C:11]2[C:6]([N:7]=1)=[C:5]([C:3](=[O:4])[CH2:2][CH:25]([C:24]([CH:21]1[CH2:23][CH2:22]1)=[O:30])[C:26]([O:28][CH3:29])=[O:27])[CH:14]=[CH:13][CH:12]=2)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Reactant: COC(=O)CC(=O)C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (0.27 g, 0.803 mmol), methyl 3-cyclopropyl-3-oxopropanoate (Accela ChemBio, 0.114 mL, 0.803 mmol), K2CO3 (EMD, 0.333 g, 2.409 mmol), in DMF (3.21 ml) was combined and stirred overnight at RT. Reaction mixture was diluted with DCM and water. The aqueous layer was acidified with 1 N HCl solution and back extracted with DCM. The organic layers were combined and washed with water and brine to remove DMF. Volatile solvents were removed by rotovap. The product methyl 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-(cyclopropanecarbonyl)-4-oxobutanoate (418a) was advanced to next step. m/z (ESI, +ve) 398.1 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:16])[CH:10]=[CH:11][C:12]=2[N+:13]([O-])=O)[CH2:3][CH2:2]1.[H][H]>[OH-].[Pd+2].[OH-].[C].CN(C)C=O>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:16])=[CH:8][C:7]=1[N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(O)cc1N1CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ccc(O)cc1N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
3-Fluoro4-nitrophenol (300 mg), morpholine (800 μl), and calcium carbonate (50 mg) were added to dimethylformamide (3 ml), and the mixture was heated at 130° C. for 12 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 3-morpholino-4-nitrophenol (400 mg, yield 94%). The resultant 3-morpholino-4-nitrophenol (400 mg) was added to dimethylformamide (3 ml). Palladium hydroxid-carbon (110 mg) and hydrogen were added thereto, and the mixture was stirred at room temperature for 4 hr. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was then purified by chromatography on silica gel using chloroform/acetone for development to give 4-amino-3-morpholinophenol (296 mg, yield 85%). The resultant 4-amino-3-morpholinophenol (296 mg), 4-chloro-6,7-dimethoxyquinazoline (479 mg), and n-tetraethylammonium bromide (244 mg) were dissolved in ethyl methyl ketone (10 ml) to prepare a solution. A solution (10 ml) of sodium hydroxide (479 mg) in water was added to the solution, and the mixture was sitrred at 80° C. for 4 hr. Water was added to the reaction solution, and the organic layer was extracted and was concentrated. The residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (396 mg, yield 68%).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH3:22][C:23]([CH3:43])([O:25][C:26]([NH:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:27])[CH3:24].O>ClCCl>[CH3:43][C:23]([CH3:22])([O:25][C:26]([NH:28][C@@H:29]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[CH:40][CH:41]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:27])[CH3:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 100 %

Procedure:
Under nitrogen atmosphere, pyridine(130.3 g) and trifluoromethanesulfonic anhydride (170.4 g) were added dropwise to a solution of ethyl (αS)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-4-hydroxybenzenepropionate (170.0 g) in dichloromethane (1.7 L) at 10° C. or below. After stirring for 1 hour at the same temperature, water (850 ml) was added dropwise to the mixture and the mixture was stirred for 2 hours at the same temperature. The organic layer was washed with 10% aqueous citric acid solution and aqueous saturated sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was removed in vacuo to yield ethyl (αS)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-4-(trifluoromethanesulfonyloxy)benzenepropionate (242.5 g) as oil.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1([OH:33])[CH2:11][CH:10]2[C:12]([CH3:14])([CH3:13])[C:7]1([CH2:15][S:16]([N:19]1[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH2:21][CH2:20]1)(=[O:18])=[O:17])[CH2:8][CH2:9]2)C.[OH-].[Na+]>CO.O>[OH:33][C:6]1([CH2:5][C:4]([OH:34])=[O:3])[CH2:11][CH:10]2[C:12]([CH3:13])([CH3:14])[C:7]1([CH2:15][S:16]([N:19]1[CH2:20][CH2:21][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH2:23][CH2:24]1)(=[O:17])=[O:18])[CH2:8][CH2:9]2
Reactant: CCOC(=O)CC1(O)CC2CCC1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)C2CCC1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C(O)(CC(=O)O)C2
Reaction time: 4.5 h

Procedure:
(1S(1.Alpha.,2α,4.alpha))-2-hydroxy-7,7-dimethyl-1-((spiro(1H-indene-1,4'-piperidin)-1'-yl sulfonyl)methyl)bicyclo(2.2.1)heptane-2-acetic acid ethyl ester (3.8 g, 7.8 mmol) was stirred in methanol (40 ml) containing sodium hydroxide (10 ml of a 1.0M solution in water; 10 mmol) for 4.5 hrs. The mixture was evaporated to dryness in vacuo, treated with water (250 ml) and washed with ether. The aqueous layer was acidified with conc HCl and extracted with ether, and the ether layer from this extraction was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed an a silica gel column eluted with CH2Cl2 followed by 90:10:0.1:0.1 of CH2Cl2 :MeOH:HOAc:H2O. The product fractions were evaporated to dryness in vacuo, and the residue was triturated with ether and hexane and filtered to give the title compound as a solid: (mp 137.5°-139.5°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([O:29]CC)=[O:28].COC1C=CC=CC=1C1C2C(=CC=CC=2)C(C2C=CC3OCOC=3C=2)=C1C(OCC)=O>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccccc1OC
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccccc1OC
Solvent: CCO
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Reaction time: 8 h
Yield: 100 %

Procedure:
Ethyl (1RS,2RS,3RS)-1-(2-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (90 mg, 0.22 mmol) in EtOH (10 ml) was added 10% palladium on activated carbon (90 mg). The resulting suspension was shaken on a Parr hydrogenator at 60 psi H2 overnight, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound (90 mg, 100%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[C:12](OC(=O)C)(=O)[CH3:13]>>[CH3:9][N:6]1[C:7]2[N:8]=[C:12]([CH3:13])[NH:1][C:2]=2[C:3](=[O:11])[NH:4][C:5]1=[O:10]
Reactant: Cn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2C
Temperature: 25 °C

Procedure:
A solution of 5,6-diamino-1-methyluracil (2.5 g) in acetic anhydride (25 ml) was heated at reflux for 2 hours and then the acetic anhydride was evaporated under reduced pressure. The residue was dissolved in 10% aqueous sodium hydroxide solution (50 ml) and heated at reflux for 2 hours. After cooling to room temperature, the mixture was acidified to pH 4 by addition of concentrated hydrochloric acid. The precipitate was filtered, washed with water (15 ml), rinsed with acetone (15 ml) and dried under vacuum to provide 3,8-dimethylxanthine (1.8 g).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)(=[O:3])[NH2:2]>O1CCCC1.[Pd]>[C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])(=[O:3])[NH2:2]
Reactant: NC(=O)COc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: NC(=O)COc1ccccc1N

Procedure:
2.0 g of 2-(carbamoylmethoxy)nitrobenzene are hydrogenated in the presence of 100 mg of palladium-on-charcoal (10% of Pd) in 50 ml of tetrahydrofuran at room temperature under normal pressure for 2 h. The reaction mixture is filtered over Hyflo® and concentrated. 2-(Carbamoylmethoxy)aniline is obtained as white crystals: mp 117° C.; Rf (O)=0.36; FAB-MS: (M+H)+ =167; anal. calc. for C8H10N2O2 : C57.82%, H6.07%, N16.86%; found C57.71%, H6.04%, N16.87%.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=O.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cnccc2[nH]1
Product: Clc1ccc2cnccc2n1
Temperature: 120 °C
Yield: 58.45 %

Procedure:
1,6-Naphthyridine-2-one (1.0 g, J. Org. Chem. 4744 (1990)) was dissolved in phosphorous oxychloride (19 ml), followed by heating under reflux at 120° C. for 2 hours. After cooling, the solvent was evaporated, and the residue was basified with water and potassium carbonate. Then, the mixture was extracted with ethyl acetate, and the extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (0.658 g, 58.45%) as orange crystals.
Reaction SMILES: [N:1]([N:3]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9]2)[CH2:5][CH2:4]1)=O>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(O)(=O)C.O.[Zn]>[NH2:1][N:3]1[CH2:4][CH2:5][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9]2)[CH2:7][CH2:8]1
Reactant: O=NN1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: NN1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 7.1 g of 1'-nitroso-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine], Example 1, in 75 ml of glacial acetic is added to a stirring suspension pf 7.1 g of zinc dust in 50 ml of glacial acetic acid and 50 ml of water while maintaining the reaction temperature between 10° and 20° C. The reaction mixture is stirred for 15 minutes at ambient temperature and then at 80° C. for 5 minutes; an additional 4.7 g of zinc dust are introduced and stirring is continued for an additional 10 minutes. The heated mixture is filtered, the precipitate is washed with hot 1N hydrochloric acid and the combined filtrate and washings are basified and extracted with chloroform. The organic solution is dried and the solvent is removed, leaving a white crystalline solid, 1'-amino-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine], which is recrystallized from ethanolto to give the pure product, mp 143°-145° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:34])[C:14]2[O:20][C:19]3[C:21]([Cl:30])=[CH:22][C:23]([NH:25][C:26](=[O:29])[CH2:27]Cl)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:31])[C:15]=2[CH:33]=1)=[O:10]>CN(C=O)C>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:34])[C:14]2[O:20][C:19]3[C:21]([Cl:30])=[CH:22][C:23]([NH:25][C:26](=[O:29])[CH2:27][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:31])[C:15]=2[CH:33]=1)=[O:10]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CN3CCCCC3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 5 h

Procedure:
Piperidine (0.2 mL, 1.80 mmol) was added to a solution of Example 133 (0.4 g, 0.90 mmol) in dry DMF (10 mL). The reaction mixture was stirred at 110° C. for 5 h, concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.250 g, (56.30%); 1H NMR (CDCl3): δ 1.65-1.70 (m, 6H, piperidinyl), 2.45-2.50 (m, 4H, piperidinyl), 2.70 (s, 3H, CH3), 3.10 (s, 2H, CH2), 3.95 (s, 3H, OCH3), 4.70 (s, 2H, CH2), 7.55 (s, 1H, Ar), 7.80 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.50 (s, 1H, Ar), 9.50 (s, 1H, NH); MS: m/e (ES+) 493 (M+1).