Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[S-:23][C:24]#[N:25].[K+].BrBr>O>[NH2:25][C:24]1[S:23][C:21]2[CH:22]=[C:16]([O:15][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=[CH:18][C:19]=2[N:20]=1
Reactant: CCCCCCCCCCOc1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCOc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
Next, acetic acid (100 ml) was added to the 4-decyloxyaniline 3 (23.4 g, 93.7 mmol) thus obtained, and potassium thiocyanate (23.5 g, 242 mmol) was then added thereto. The solution was thoroughly cooled in an ice bath, and an acetic acid solution of bromine (5.8 ml/50 ml) was then added dropwise thereto over a period of about 3 hr. After the completion of the dropwise addition of the solution, the mixture was stirred at room temperature for about 2 hr. Thereafter, water (200 ml) was added, and the mixture was refluxed for about 30 min and was then hot-filtered. The filtrate was made alkaline by the addition of aqueous ammonia, and saturated brine was further added thereto. The precipitated solid was collected by filtration to give 2-amino-6-decyloxybenzothiazole 4 (14.22 g, 49.5%) as a light purple solid. The product was purified by column chromatography on silica gel (hexane: AcOEt=1:2).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[Mg].II.[F:8][C:9]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19](F)[C:10]=1[C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=O>O1CCCC1>[CH:1]1([C:19]2[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=[C:9]([F:8])[C:10]=2[C:11]2[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[N:13]=2)[CH2:3][CH2:2]1
Reactant: BrC1CC1
Reactant: COc1cc(F)c(C(=O)NC(C)(C)CO)c(F)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(F)c(C2=NC(C)(C)CO2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of cyclopropyl bromide (12.1 g, 100 mmol) in anhydrous tetrahydrofuran (100 mL) was added magnesium turnings (2.4 g, 100 mmol) followed by a crystal of iodine, at room temperature. After a few minutes the reaction initiated and came to reflux without any additional heating. When the reflux was complete the reaction was cooled to room temperature and stirred for 2 hours. A solution of the fluoro compound from preparation 2 (9.64 g, 40 mmol) in tetrahydrofuran (50 mL) was cooled in an ice-bath to 0° C., and the grignard solution (50 mL) was added dropwise over 15 minutes, the cooling bath was removed and reaction warmed to room temperature and stirred for 1 hour. Further grignard solution (20 mL) was added and stirred for 1 hour. Further grignard solution (10 mL) was added and stirred for 1 hour. The reaction mixture was then quenched with 1M citric acid (30 mL), as some solid remained undissolved 2M hydrochloric acid (30 mL) was added. The resultant mixture was partitioned between ethyl acetate (400 mL) and water (200 mL), basified with concentrated ammonia solution and the organic layer separated, washed with water (150 mL), brine (150 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with hexane:isopropyl alcohol 85:15) to give the title compound as a clear oil (10.32 g, 98%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.CCCCCC.C([Li])CCC.C([N:24]([CH2:33][CH3:34])[C:25]([C:27]1[CH:31]=[CH:30][O:29][C:28]=1[CH3:32])=[O:26])C.[CH2:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44]CC#N)=[CH:40][CH:39]=1)[CH3:36].Cl>C1COCC1>[CH2:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:34][C:33]2[NH:24][C:25](=[O:26])[C:27]3[CH:31]=[CH:30][O:29][C:28]=3[CH:32]=2)=[CH:40][CH:39]=1)[CH3:36]
Reactant: CCOc1ccc(CCC#N)cc1
Reactant: CCN(CC)C(=O)c1ccoc1C
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(CCc2cc3occc3c(=O)[nH]2)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (11.6 mL, 68.8 mmol) in THF (100 mL) was added 1.6 M n-butyllithium hexane solution (39.0 mL, 62.4 mmol) at −78° C., and the mixture was warmed to −20° C. and stirred at the same temperature for 10 min. To this solution was added a solution of N,N-diethyl-2-methylfuran-3-carboxamide (11.3 g, 62.5 mmol) in THF (10 mL), and the mixture was further stirred for 1 hr. To the solution was added 3-(4-ethoxyphenyl)propanenitrile (11.5 g, 65.6 mmol), and the mixture was stirred at room temperature for hr. 6N Hydrochloric acid was added thereto and the mixture was extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (2.74 g, yield 15%) as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[NH2:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30].C([O-])(O)=O.[Na+].O>ClCCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][C:19]=4[NH:28][C:29](=[O:31])[CH3:30])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine, (Example 163), (0.25 g, 0.65 mmol) in 1,2-dichloroethane (6.5 mL) was added acetic anhydride (0.15 mL, 1.6 mmol). The mixture was stirred at room temperature for 18 h and then treated with satd NaHCO3 and H2O. The mixture was extracted with EtOAc (2×75 mL) and the combined extracts were washed with H2O (75 mL) and brine (75 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 10 to 40% EtOAc/hexanes) afforded the title compound as a yellow solid. Mp: 137–138° C. MS (ESI, pos. ion) m/z: 479.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:14][C:13]=1[CH3:26].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][C:13]=1[CH3:26]
Reactant: COc1ccccc1NC(=O)Nc1ccc(CC(=O)OC(C)(C)C)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1C
Yield: 83.3 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2-methoxyphenyl)ureido]-3-methylphenylacetate (1.32 g, 3.56 mmol) in CH2Cl2 (15 ml) was added trifluoroacetic acid (10 ml), and the resulting mixture was heated under reflux for 30 min. The mixture was concentrated in vacuo and added water to give precipitate which was collected by filtration. The crude solid was recrystallized from EtOH/hexane to give 4-[N′-(2-methoxyphenyl)ureido]-3-methylphenylacetic acid (932 mg, 83%) as a white powder. mp 260–264° C.; 1H-NMR (CD3OD) δ 2.30 (s, 3 H), 3.55 (s, 2 H), 4.87 (s, 3 H), 6.87–6.92 (m, 2 H), 6.97–6.99 (m, 2 H), 7.10–7.24 (m, 2 H), 7.53–7.58 (m, 1 H), 8.04 (d, J=7.2 Hz, 1 H); MS (ESI) m/z 314 (M+).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C@:9]1([F:33])[C@@H:14]2[C@H:10]1[CH2:11][C@@H:12]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[C@@:13]2([NH2:22])[C:15]([O:17][CH:18]([CH2:20][CH3:21])[CH3:19])=[O:16])=[O:8])C.Cl>O1CCCC1.O>[CH3:19][CH:18]([O:17][C:15]([C@:13]1([NH2:22])[C@H:12]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:11][C@@H:10]2[C@H:14]1[C@@:9]2([F:33])[C:7]([OH:8])=[O:6])=[O:16])[CH2:20][CH3:21]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)OC(C)CC)[C@@H]21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)OC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Yield: 30.1 %

Procedure:
15 mg of lithium hydroxide monohydrate was added to 131 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-butyl ester 6-ethyl ester dissolved in 2 mL of tetrahydrofuran and 1 mL of water, and the mixture was stirred for 1.5 hours at room temperature. After 2 mL of 1N hydrochloric acid was added thereto, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.) eluent: water to a 40% acetonitrile solution), thereby yielding 37 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-butyl ester.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:10]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:7])=[O:8])[CH:14]=1
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCS(=O)(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Yield: 89.9 %

Procedure:
A mixture of 40 g of N-tert-butyl-2-ethylsulfonyl-5-nitrobenzenesulfonamide is dissolved in 1500 ml of methanol, 0.5 g of 10% palladium on charcoal is added and the mixture is stirred under a hydrogen atmosphere (1 atmosphere). When the uptake of hydrogen has ended, the catalyst is separated off and the solution is concentrated. 32.9 g of the aniline derivative are thus obtained;
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH:37]2[CH2:46][CH2:45][C:40]3([O:44][CH2:43][CH2:42][O:41]3)[CH2:39][CH2:38]2)(=O)=O)=CC=1>CC(N(C)C)=O>[O:41]1[C:40]2([CH2:45][CH2:46][CH:37]([N:16]3[C:17]4=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]4[C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:9][CH:10]=4)=[N:15]3)[CH2:38][CH2:39]2)[O:44][CH2:43][CH2:42]1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 15) (4.9 g) in 200 mL dry dimethylacetamide was treated under nitrogen with 60% sodium hydride (2.0 g) and stirred 30 minutes. 1,4-dioxaspiro[4.5]dec-8-yl 4-methyl-1-benzenesulfonate (Intermediate Y) (15 g) was added and the mixture heated at 105° C. for 42 hours. Evaporation in vacuo and treating with water gave solid which was collected and washed well with water then dried in air. The solid was boiled with diethyl ether (6×120 mL) and the filtered solution evaporated. Treatment with acetone gave 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine as an off-white solid which was collected and washed with acetone then dried in air m.p. 200-202.5° C. Calculated for C25H25N5O3 C 67.7 H 5.6 N 15.8 Found C 67.6H5.8 N15.4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[OH-].[K+].Cl[C:15]([O:17][CH3:18])=[O:16].Cl>>[CH3:18][O:17][C:15]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1)=[O:16]
Reactant: COC(=O)Cl
Reactant: O=C(O)CCC1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COC(=O)N1CCC(CCC(=O)O)CC1

Procedure:
The solution from step b) was brought to pH 12 with aqueous potassium hydroxide. To this solution was added 21 mL methyl chloroformate (0.27 mol). After the reaction was complete, the solution was brought to pH 1 with 6 N HCl and extracted with dichloromethane. The organic layer was dried with sodium sulfate and the dichloromethane displaced with isopropyl ether. The product was isolated as a solid by filtration. Yield 39 gm, 84%. M.p. 89-90° C.
Reaction SMILES: O.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:13]([O-])=O)=[C:6]2[NH:16][C:17]1([CH3:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.Cl.N>CCO.[Fe]>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([NH2:13])=[C:6]2[NH:16][C:17]1([CH3:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CC1(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)CCOCC1
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CC1(Nc2c(N)cnc3ccc(Br)cc23)CCOCC1
Temperature: 105 °C
Yield: 86.6 %

Procedure:
Water (8.35 mL) was added to a stirred mixture of 6-bromo-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine (1.07 g, 2.92 mmol), iron (0.979 g, 17.53 mmol) and ammonia hydrochloride (0.109 g, 2.05 mmol) in EtOH (50.1 mL) and the resulting slurry heated to 105° C. for 2 h. The reaction was filtered warm through a pad of celite, washing with MeOH, and the filtrate evaporated to dryness. The crude solid was dissolved in DCM (10 mL) and washed with a sat. aqueous solution of NaHCO3 (10 mL) and sat. brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the desired material (0.850 g, 87%) as a pale orange solid. This was used without further purification. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.19 (3H, s), 1.51 (2H, d), 1.76 (2H, td), 3.43 (2H, td), 3.73 (2H, dt), 4.15 (1H, s), 5.45 (2H, s), 7.39 (1H, dd), 7.67 (1H, d), 8.22 (1H, d), 8.51 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=336, 338.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([O:30][CH3:31])[C:24]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[C:23]3[Cl:43])([OH:19])[C:13]2[N:17]([CH3:18])[N:16]=[N:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)=O.Cl>CO>[NH:8]1[CH2:11][CH:10]([C:12]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([O:30][CH3:31])[C:24]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:37][CH:38]=2)=[C:23]3[Cl:43])([C:13]2[N:17]([CH3:18])[N:16]=[N:15][CH:14]=2)[OH:19])[CH2:9]1
Reactant: COc1nc2ccc(C(O)(c3cnnn3C)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: O=CO
Product: COc1nc2ccc(C(O)(c3cnnn3C)C3CNC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a flask containing tert-butyl 3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)azetidine-1-carboxylate (165 mg, 0.27 mmol, Example 123) was added formic acid (5 mL) at room temperature followed by 6 N aqueous HCl (0.21 mL). The mixture was stirred at room temperature for 40 minutes and then MeOH (5 mL) was added and the mixture was stirred for 20 minutes before concentrating. The resulting oil was chromatographed directly on silica gel (10% 2 M NH3-MeOH-DCM increasing to 12% 2 M NH3-MeOH) to provide the title compound as an off white powder. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J=2.1 Hz, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.1 Hz, 2H), 7.42-7.32 (m, 3H), 4.52-4.34 (m, 2H), 4.33-4.16 (m, 3H), 4.05 (s, 3H), 3.96-3.80 (m, 1H), 3.71 (s, 4H); MS (ESI): mass calcd. Chemical Formula: C25H23ClF3N5O2; Exact Mass: 517.2. m/z found 517.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Clc1cnc2ccccc2n1
Product: c1ccc2nc(N3CCNCC3)cnc2c1

Procedure:
2-(1-Piperazinyl)quinoxaline is prepared from 2-chloroquinoxaline by reaction with piperazine in a manner similar to the preparation of 2-(1-piperazinyl)quinoxalines described in British Pat. No. 1,440,722, issued June 23, 1976 and assigned to Merck & Co. The preparation of 2-chloroquinoxaline is described at Gowenlock et al., J. Chem Soc. 1945: 622.
Reaction SMILES: [CH3:1][SiH:2]([CH3:35])[O:3][CH:4]([C:29]([CH3:34])([CH3:33])[CH:30]([CH3:32])[CH3:31])[C@H:5]1[N:10]2[C:11]3[CH:12]=[CH:13][C:14]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)=[CH:15][C:16]=3[CH:17]=[C:9]2[C:8](=[O:28])[NH:7][CH2:6]1.[H-].[Na+].Br[CH2:39][CH:40]1[CH2:42][CH2:41]1>>[CH:40]1([CH2:39][N:7]2[CH2:6][C@@H:5]([CH:4]([C:29]([CH3:33])([CH3:34])[CH:30]([CH3:31])[CH3:32])[O:3][SiH:2]([CH3:1])[CH3:35])[N:10]3[C:11]4[CH:12]=[CH:13][C:14]([O:18][CH:19]5[CH2:24][CH2:23][N:22]([CH:25]([CH3:26])[CH3:27])[CH2:21][CH2:20]5)=[CH:15][C:16]=4[CH:17]=[C:9]3[C:8]2=[O:28])[CH2:42][CH2:41]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C(O[SiH](C)C)C(C)(C)C(C)C)CNC2=O)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C(O[SiH](C)C)C(C)(C)C(C)C)CN(CC3CC3)C2=O)CC1
Yield: 38 %

Procedure:
The title compound was synthesized in analogy to example 17, from (S)-4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 12, intermediate a)), sodium hydride and 1-(bromomethyl)cyclopropane, to give the desired product as a colorless oil (38%).
Reaction SMILES: [C:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=O)[O:6]C1=O)(=O)[CH3:2].[OH-].[NH4+:19]>>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:6])[NH:19][C:1]([CH3:2])=[CH:4]2
Reactant: COc1ccc2c(c1)C(C(C)=O)C(=O)OC2=O
Reactant: [NH4+]
Agent: [OH-]
Product: COc1ccc2c(=O)[nH]c(C)cc2c1
Temperature: 25 °C
Yield: 74 %

Procedure:
The cyclic anhydride of step 1 (405 mg; 1.73 mmol) was dissolved in aqueous ammonium hydroxide, and heated at reflux for 1.5 hours. The mixture was cooled to room temperature and the solid was filtered then dried overnight to give 270 mg (74%) of 6-methoxy-3-methylisoquinolin-1(2H)-one.
Reaction SMILES: [CH2:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH2:2][CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>CN(C=O)C>[CH2:1]([C:4]1[C:10]([O:11][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH2:2][CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1c(O)cccc1OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-propyl resorcinol (178.27 g; 1.171 mol) in dry DMF (1200 mL) was added cesium carbonate (104.95 g; 322.12 mmol). The mixture was stirred at room temperature and treated dropwise with a solution of 2-bromoacetophenone (58.29 G; 292.84 mmol) in dry DMF (500 mL) over 2 hours. The was stirred at ambient temperature for 64 hours. The reaction mixture was partitioned between isopropyl acetate and water. The aqueous was adjusted to pH 13 by addition of aq. 5N sodium hydroxide. The organic was dried over magnesium sulfate, filtered and evaporated to a residue. The residue was dissolved in methylene chloride (110 mL) and hexane (350 mL) and heated to reflux. The solution was cooled to -10° C. Stirring was continued for 1 hour. The title compound was recovered by filtration.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:18]2[CH:23]=[C:22]([OH:24])[C:21]([Cl:25])=[CH:20][C:19]=2[F:26])[C:6](=[O:17])[CH:7]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[N:9]=1)[CH3:2].Cl[C:28]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29].N1C=CC=CC=1>C(OCC)C>[C:28](=[O:29])([O:30][CH2:31][CH2:32][O:33][CH3:34])[O:24][C:22]1[CH:23]=[C:18]([N:5]2[C:6](=[O:17])[CH:7]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:12])([F:13])[F:14])[N:9]=[C:4]2[O:3][CH2:1][CH3:2])[C:19]([F:26])=[CH:20][C:21]=1[Cl:25]
Reactant: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: COCCOC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(OC(=O)OCCOC)c(Cl)cc1F

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-pentafluoroethyl-6(1H)-pyrimidinone and 2-methoxyethyl chloroformate with pyridine in diethyl ether there is obtained {5-[2-ethoxy-6-oxo-4-pentafluoroethyl-1(6H) -pyrimidinyl]-2-chloro-4-fluorophenyl} 2-methoxyethyl carbonate, 1H-NMR (CDCl3, 400 MHz): 7.39 ppm (d,1H), 7.26 ppm (d,1H), 6.64 ppm (s,1H), 4.39°-4.56 ppm (m,4H), 3.70 ppm (m,2H), 3.43 ppm (s,3H), 1.30 ppm (t,3H):
Reaction SMILES: [NH:1]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([N:11]2[CH2:18][CH:17]3[CH2:19][CH:13]([CH2:14][N:15](CC4C=CC=CC=4)[CH2:16]3)[CH2:12]2)=[O:10])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[H][H]>CO.[Pd]>[NH:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[CH2:12][CH:13]3[CH2:19][CH:17]([CH2:16][NH:15][CH2:14]3)[CH2:18]2)=[O:10])=[CH:27][CH:28]=1)[C:2]([CH3:4])=[O:3]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc(C(=O)N2CC3CC(CN(Cc4ccccc4)C3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)N2CC3CNCC(C3)C2)cc1

Procedure:
78.0 g (0.21 mole) of 3-(4-acetaminobenzoyl)-7-benzyl-3,7-diazabicyclo[3.3.1]nonane (cf. Example 1) were dissolved in 1.3 l of methanol, and 3.0 g of 10% strength palladium/carbon were added. Hydrogenation was carried out until an equimolar amount of hydrogen had been consumed. The reaction mixture was filtered and the filtrate was evaporated down under reduced pressure. Crystalline 3-(4-acetaminobenzoyl)-3,7-diazabicyclo[3.3.1]nonane was obtained. Yield: 59 g, mp.: 186°-189° C.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:8])[NH:4][C:5](=[O:7])[CH:6]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([N:2]1[C:3](=[O:8])[NH:4][C:5](=[O:7])[CH:6]=[N:1]1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1cn[nH]c(=O)[nH]1
Product: CC(=O)n1ncc(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
1,2,4-Triazine-3,5(2H,4H)-dione, commercially available from Alfa Aesar (800 mg, 7.07 mmol) was suspended in acetic anhydride (4 ml, 42.4 mmol) and the mixture was refluxed for 2 h. The reaction mixture was then cooled to room temperature and dried under vacuum. The crude product was repeatedly treated with toluene and concentrated under vacuum to give, as a light brown solid, the title compound (1.05 g, 96%) that was used in the next step without purification.
Reaction SMILES: [CH2:1]([CH:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BrH:18].BrBr>O>[Br:18][C:9]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17]
Reactant: Br
Reactant: CCCCCCCCC1C(=O)NC(=O)NC1=O
Agent: BrBr
Solvent: O
Product: CCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-octylbarbituric Acid (20 g) in 120 ml of water, cooled at 0-5° C., are added 12 ml of 48% hydrobromic acid and successively are dropped 4.72 ml of bromine. Ater 2 hours under stirring, the white solid which separated is recovered by filtration, washed with water and partitioned between 200 ml of diethyl ether and 100 ml of water. The aqueous phase is extracted with additional 50 ml of diethyl ether. The pooled organic phases are washed with 75 ml of saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. 25.8 g of the product as white solid are obtained.