Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19].O[C:21]1[CH:22]=[CH:23][C:24]2[O:29][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][C:26](=[O:36])[C:25]=2[CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C([O-])(=O)C([O-])=O>O1CCCC1>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:21]3[CH:22]=[CH:23][C:24]4[O:29][C:28]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:27][C:26](=[O:36])[C:25]=4[CH:37]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19]
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: Cn1c(N2CCN(CCO)CC2)cc(=O)n(C)c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])C(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CCOc3ccc4oc(-c5ccccc5)cc(=O)c4c3)CC2)cc(=O)n(C)c1=O
Yield: 61.1 %

Procedure:
The same procedure as in Example 8-(2) was effected so as to react and treat 0.8 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazine-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 30), 1.19 g of 6-hydroxy-2-phenyl-4-oxo-4H-1-benzopyran (Compound 27), 40 ml of tetrahydrofuran containing 1.05 g of triphenylphosphine and 0.63 ml of diethyl azodicarboxylate, in order to obtain 0.89 g (yield 58%) of 1,3-dimethyl-6-(4-[2-(2-phenyl-4-oxo-4H-1-benzopyran-6-yl)oxyethyl]piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (the non-oxalate, of Compound 31).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[N:18]([CH3:25])[N+:17]=3[O-:26])[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[N:18]([CH3:25])[N+:17]=3[O-:26])[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3c4c(n(C)[n+]3[O-])CCCC4)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3c4c(n(C)[n+]3[O-])CCCC4)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82112.1 %

Procedure:
To a pale yellow solution of 3-(7-(isopropylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (45 mg, 92.8 μmol) in dichloromethane (2.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmo140), the reaction mixture turned dark red and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (added few drops MeOH and heating) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 10% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. Pure white solid product was sonicated with hexanes. The solid was separated by decantation and dried under high vacuum to give 3-(7-(isopropylcarbamoyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (27 mg, 76.2 mmol, 82.1%) as a white solid. MS (M+H)+=377 (100% purity); 1H NMR (DMSO-d6) δ: 12.93 (br. s., 1H), 8.93 (s, 1H), 8.45 (s, 1H), 7.45 (d, J=8.1 Hz, 1H), 4.13-4.33 (m, 1H), 3.35 (s, 3H), 2.37-2.46 (m, 2H), 1.83-2.18 (m, 6H), 1.22 (d, J=6.6 Hz, 6H).
Reaction SMILES: Cl.[CH:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[CH:10](C1C=CC(C)=C(C)C=1C)C.[H][H].C12CCC(CC1)CC2C(C1(C)CCCCC1(C)C)C>[Ru].CC1CCCCC1>[CH3:9][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:10]
Reactant: [H][H]
Reactant: Cc1ccc(C(C)C2CC3CCC2CC3)c(C)c1C
Agent: [Ru]
Agent: CC(C1CC2CCC1CC2)C1(C)CCCCC1(C)C
Agent: Cl
Solvent: CC1CCCCC1
Product: Cc1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 2 liter four neck flask equipped with a thermometer and a hydrogen chloride gas trap, 500 ml of 1,2,4-trimethylbenzene and 150 ml of titanium tetrachloride were placed and 150 ml of 2-(1-hydroxyethyl) bicyclo [2.2.2] octane obtained in (1) above was dropped therein over 30 minutes with stirring at room temperature. The so obtained mixture was maintained at 30° C. in an ice-cold water bath and further stirred for 30 minutes. After the evolution of hydrogen chloride gas was stopped, the content of the flask was poured into 1 liter of ice-cold water to stop the reaction. The mixture was stirred well in the ice-cold water, and an organic layer produced therein was washed twice with 200 ml of 2N NaOH aqueous solution, followed by washing twice with 200 ml of water. The so treated organic layer was dried with anhydrous MgSO4 and distilled to obtain 180 g of a fraction having a boiling point of 150 to 160° C./2 mmHg. The analysis with NMR and MS resulted in a finding that the so obtained reaction product was 1-(2-bicyclo [2.2.2] octyl)-1-(trimethylphenyl)-ethane. Said reaction product was placed in a 1 liter autoclave, 20 g of 5% ruthenium/carbon catalyst and 300 ml of methylcyclohexane as the solvent were added and the resulting mixture was hydrogenated under the conditions of a hydrogen pressure of 80 kg/cm2G, a reaction temperature of 200° C. and a reaction time of 6 hours. The NMR analysis showed that the degree of hydrogenation was 99%. The so obtained reaction product was analyzed with NMR, IR and MS, resulting in a finding that it was 1-(2-bicyclo [2.2.2] octyl)-1-(trimethylcyclohexyl)-ethane. Further, the traction coefficient of the obtained reaction product was determined in a temperature range of 40° C. to 140° C. and the results are shown in FIG. 1. The graphs of 1H-NMR, 13C-NMR and MS of the reaction product are respectively shown in FIGS. 4 to 6.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH3:12])[CH:10]=[C:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][C:14]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[NH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.O>CN1C(=O)CCC1>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:27]([NH:26][CH2:25][CH2:24][NH:23][C:2]2[C:3]3[N:11]([CH3:12])[CH:10]=[C:9]([C:13]4[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][C:14]=4[CH3:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(=O)NCCN)cc1
Reactant: COc1cc(C)c(-c2cn(C)c3c(Cl)nc(C)nc23)c(C)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CC(=O)NCCNc2nc(C)nc3c(-c4c(C)cc(OC)cc4C)cn(C)c23)cc1

Procedure:
Heat a solution of 4-chloro-7-(4-methoxy-2,6-dimethyl-phenyl)-2,5-dimethyl-5H-pyrrolo[3,2-d]pyrimidine (120 mg, 0.38 mmol) and N-(2-amino-ethyl)-2-(4-methoxyphenyl)-acetamide (125 mg) in NMP (2 mL) for 14 h at 130° C. Pour into water (5 mL) and extract with EtOAc (2×10 mL). Dry the combined organic extracts over Na2SO4, filter, and concentrate under reduced pressure to obtain the title compound which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24](I)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]#[CH:31]>>[C:35]([O:34][C:33](=[O:39])[NH:32][CH2:29][C:30]#[C:31][C:24]1[CH:25]=[CH:26][C:17]2[C:16]3[N:28]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:13]=[CH:14][C:15]=3[CH2:21][C:20](=[O:22])[NH:19][C:18]=2[CH:23]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#CCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method O, 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) and tert-butyl prop-2-ynylcarbamate were converted to I-39 (31%): HRMS Calcd. for C28H29N5O5: 516.2246, Found 516.2244.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].C[Mg]Br.[CH2:8](OCC)C.[CH3:13][C@H:14]1[C:18](=[O:19])[CH2:17][CH2:16][N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(OCC)(=O)C>C1COCC1>[OH:19][C@@:18]1([CH3:8])[CH2:17][CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C@H:14]1[CH3:13]
Reactant: CCOCC
Reactant: C[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Agent: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1N(C(=O)OCc2ccccc2)CC[C@]1(C)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A suspension of cerium chloride (47 g) in THF (300 mL) was cooled to −78° C., methylmagnesium bromide-diethyl ether solution (56 mL, 3 mol/L) was added dropwise while adjusting the solution temperature to −70° C. or below. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 30 min, a solution of benzyl(2S)-2-methyl-3-oxopyrrolidine-1-carboxylate (18 g) in THF (60 mL) was added dropwise while adjusting the solution temperature to −70° C. or below. The reaction mixture was warmed to 0° C. over 2 hr, ethyl acetate (1 L) was added, and insoluble materials were filtered off. The filtrate was partitioned with water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1→1/1) to give the title compound as a colorless oil (yield: 16.2 g, 84%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.Br[Zn][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1
Reactant: Brc1ccnc(Br)c1
Reactant: CCOC(=O)CC[Zn]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(Br)ccn1
Temperature: 85 °C

Procedure:
Nitrogen was bubbled through a solution of 2,4-dibromopyridine (0.25 g, 1.06 mmol) in THF (2 ml) for ˜10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.122 g, 0.106 mmol) was added and the flask sealed with a septa. Bromo (3-ethoxy-3-oxopropyl)zinc (3.17 ml, 1.58 mmol) was added slowly via syringe and the reaction mixture was heated at 85° C. for 16 hours. Upon cooling, the reaction mixture was partitioned between DCM and brine. The organic layer was dried (Na2SO4), concentrated under reduced pressure and the residue was purified by silica gel chromatography (gradient elution with EtOAc/Hexanes 7 to 60%) to give ethyl 3-(4-bromopyridin-2-yl)propanoate as a pale yellow oil. MS ESI calc'd. for C10H13BrNO2 [M+H]+ 258 and 260. found 258 and 260. 1H NMR (500 MHz, CDCl3) δ 8.33 (d, J=5.1 Hz, 1H), 7.39 (bs, 1H), 7.30 (dd, J=5.2, 1.7 Hz, 1H), 4.12 (q, J=6.7 Hz, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.79 (t, J=6.4 Hz, 2H), 1.23 (t, J=6.8 Hz, 3H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[CH2:34][C:35](=[O:41])[NH:36]2>>[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1/[C:34](=[CH:14]/[C:11]1[NH:10][C:7]3[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[C:5](=[O:16])[C:6]=3[C:12]=1[CH3:13])/[C:35](=[O:41])[NH:36]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Yield: 73 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 3d as starting materials to give 2-(Z)-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-[(S)-2-hydroxy-3-morpholin-4-yl-propyl]-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 7 (49 mg, yield 73%) as a red solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:8])=[O:4].[NH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([NH2:35])=[N:30][CH:29]=[CH:28]2.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14](=[O:16])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([NH2:35])=[N:30][CH:29]=[CH:28]2)=[O:8]
Reactant: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Reactant: NCc1ccc2c(N)nccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
A mixture of 1-[(R)-methoxycarbonylamino-cyclohexyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid (0.410 g), 6-aminomethyl-isoquinolin-1-ylamine (0.227 g), N-methyl morpholine (0.58 mL) and 0.423 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 10 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. The mixture was concentrated and the remaining residue was purified by HPLC (RP-18; H2O/CH3OH 95/5→0/100) to give 0.350 g (58%) of the title compound as a white solid. (+)-APCI-MS: 468 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.39 mmol), N-methylpiperazine (117 mg, 1.17 mmol) and acetic acid (117 mg, 1.95 mmol) in dichloromethane (20 mL) was stirred at room temperature overnight. Then the mixture was cooled to 0° C. and sodium triacetoxyborohydride (124 mg, 0.58 mmol) was added. After the addition, the mixture was stirred at room temperature for 5 h. Dichloromethane was removed under reduced pressure. The crude product was purified by prep-HPLC to give the title compound (48 mg, yield 22%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.02 (s, 3H), 3.60-3.81 (m, 8H), 4.36-4.38 (d, J=7.6 Hz, 1H), 4.47 (s, 2H), 4.80-4.82 (d, J=7.6 Hz, 1H), 6.93-6.97 (m, 2H), 7.12-7.15 (m, 2H), 7.22-7.24 (m, 1H), 7.43-7.45 (m, 2H), 7.52-7.57 (m, 3H), 7.64-7.68 (m, 1H). LC-MS (ESI) m/z: 470 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].O=[C:25]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)(=O)C>C(O)C>[C:19]([O:18][C:16]([CH2:15][N:4]1[CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7][CH2:8][CH:2]([NH:1][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:3]1=[O:23])=[O:17])([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCCC1c1ccccc1
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCCC(c2ccccc2)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
A solution of 3.8 g of this amine, 3.7 g ethyl 2-oxo-4-phenylbutyrate and 0.68 ml acetic acid in 50 ml ethanol is hydrogenated and the isomers separated as described in Example 27 to afford 1-t-butoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropyl)amino-7-phenylperhydroazepin-2-one:
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:51]=[C:50]([CH3:52])[C:45]4[O:46][CH2:47][CH2:48][O:49][C:44]=4[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:53]=[CH:54][CH:55]=[CH:56][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:51]=[C:50]([CH3:52])[C:45]4[O:46][CH2:47][CH2:48][O:49][C:44]=4[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:53]=[CH:54][CH:55]=[CH:56][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c4c(c3)OCCO4)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.4 mg (0.06 mmol) LiOH in 0.5 mL water was added to a solution of 28 mg (0.04 mmol) (R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 6.5) in 0.5 mL THF and the reaction solution was stirred for 3 h at RT. The reaction mixture was purified by HPLC without any further working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1>>[CH3:22][O:21][C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:24]=[CH:25][C:13]([O:12][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:14][CH:15]=1)[CH3:23]
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Reactant: Clc1ccc2ccccc2n1
Product: COC(=O)C(C)Oc1ccc(Oc2ccc3ccccc3n2)cc1

Procedure:
Methyl-2-[4-(2-quinolinyloxy)phenoxy]propionate (24) was prepared from 2-chloroquinoline and methyl 2-(4-hydroxyphenoxy)propionate following essentially the same procedure as that described in Example 1. The compound had a melting point of 95°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:28]3[C:14](=[CH:15][C:16]4[O:17][CH2:18][CH2:19][CH2:20]S[CH2:22][CH2:23][CH2:24][O:25][C:26]=4[CH:27]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].O[O:30][S:31]([O-:33])=O.[K+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:28]3[C:14](=[CH:15][C:16]4[O:17][CH2:18][CH2:19][CH2:20][S:31](=[O:33])(=[O:30])[CH2:22][CH2:23][CH2:24][O:25][C:26]=4[CH:27]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3cc4c(cc23)OCCCSCCCO4)cc1Cl
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=S1(=O)CCCOc2cc3ncnc(Nc4ccc(F)c(Cl)c4)c3cc2OCCC1
Reaction time: 4 h

Procedure:
(3-Chloro-4-fluoro-phenyl)-(2,10-dioxa-6-thia-14,16-diaza-tricyclo[9.8.0.013,18]nonadeca-1-(11),12,14,16,18-pentaen-17-yl)-amine (16, 140 mg, 0.33 mmol) was suspended in MeOH, to which was added a cloudy aqueous solution of oxone (monopersulfate compound) (820 mg, 1.33 mmol) at room temperature. The suspension was stirred and monitored by TLC which indicated that the reaction was completed in 4 h. The reaction mixture was poured into H2O (10 mL), and extracted with EtOAc (3×15 mL). The organic layers were collected, dried and concentrated to give a pale yellow residue which was flash chromatographed to give the product as a white solid: 140 mg (93%). 1H NMR (CDCl3) δ 8.75 (s, 1H), 8.00 (d, 1H), 7.24 (s, 1H), 7.26 (s, 1H), 7.42 (s, 1H), 7.30 (d, 1H), 7.25 (s, 1H), 4.40 (t, 4H), 4.75 (t, 2H), 3.40 (t, 2H), 2.55 (m, 2H), 2.23 (m, 2H); ES-MS m/z: 452 (MH+).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:35]CCl>C(O)C.O>[ClH:35].[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCN2c3ccccc3CCc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above ester was dissolved in ethanol (10 ml) and a 12 N sodium hydroxide solution (1.25 ml) was added. The mixture was stirred at room temperature for 4 h. A concentrated hydrochloric acid solution was added until pH 1. Dichloromethane (300 ml) was added followed by water until the solid material was dissolved. The phases were separated and the organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo to give a residue, which was re-evaporated twice with acetone and then recrystallized from a mixture of acetone and ethyl acetate. This afforded 1.4 g (65%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][P:6]([CH3:8])[OH:7])[CH2:2][CH2:3][CH3:4].[C:9](=[O:16])([O:11][CH2:12][C:13](=[CH2:15])[CH3:14])[NH2:10].C1C(C(OOC(C)(C)C)=O)=CC=CC=1>>[CH2:1]([O:5][P:6]([CH2:14][CH:13]([CH3:15])[CH2:12][O:11][C:9](=[O:16])[NH2:10])([CH3:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C)COC(N)=O
Reactant: CCCCOP(C)O
Agent: CC(C)(C)OOC(=O)c1ccccc1
Product: CCCCOP(C)(=O)CC(C)COC(N)=O
Reaction time: 1 h
Yield: 95 %

Procedure:
In a nitrogen atmosphere 100 g of methane-phosphonous acid mono-n-butyl ester are heated to 140° C. while stirring. Over a period of 2 hours a mixture of 85 g of methallyl carbamate and 3.7 g of tert.butyl perbenzoate is added dropwise and stirring is continued for 1 hour at 135° C. Distillation is then started up to an internal temperature of 140° C. and at 0.8 torr, whereby about 5 g of distillate are obtained. 180 g of (3-carbamoyloxy-2-methyl-propyl)methyl-phosphinic acid n-butyl ester are obtained, ND23 : 1.4725, corresponding to a yield of about 95% of the theory. ##STR7##
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[CH3:27][C:28]1[CH:29]=[C:30]([CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37])[CH:31]=[C:32]([CH3:34])[CH:33]=1.Cl>>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:39][C:36]([CH3:37])([CH3:38])[CH2:35][C:30]2[CH:31]=[C:32]([CH3:34])[CH:33]=[C:28]([CH3:27])[CH:29]=2)[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Reactant: Cc1cc(C)cc(CC(C)(C)N)c1
Agent: Cl
Product: Cc1cc(C)cc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)c1

Procedure:
Prepared analogously to the method for Example 8(d) from 1.47 g (4.1 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.65 g (3.7 mmol) of 2-(3,5-dimethylphenyl)-1,1-dimethylethylamine. Yield: 1.1 g (51%, hydrochloride); melting point: 220° C.-222° C.