Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([OH:18])[CH:13]=[CH:14][C:15]=2[CH3:17])[C:10]([CH3:20])([CH3:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH:29]=[CH2:30]>CN(C)C=O>[CH2:30]([O:18][C:12]1[CH:13]=[CH:14][C:15]([CH3:17])=[C:16]2[C:11]=1[C:10]([CH3:19])([CH3:20])[C:9](=[O:21])[N:8]2[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:29]=[CH2:28]
Reactant: C=CCI
Reactant: Cc1ccc(O)c2c1N(Cc1ccccc1)C(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C)c2c1C(C)(C)C(=O)N2Cc1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 11.6 g (41.2 mmol) of 1-benzyl-2,3-dihydro-4-hydroxy-3,3,7-trimethyl-1H-indol-2-one and 8.6 g (62.2 mmol) of potassium carbonate in 120 ml of N,N-dimethylformamide was added 8.3 g (49.4 mmol) of allyl iodide, and the mixture was stirred overnight at 70° C. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 7:1 mixture of n-hexane and ethyl acetate) to obtain 8.9 g (yield 67.2%) of colorless needles of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([NH2:14])=[O:13])[CH:3]=1.Cl[C:16]([S:18]Cl)=[O:17].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[O:13][C:16](=[O:17])[S:18][N:14]=2)[CH:3]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1cc(Br)c2ccccc2c1
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1oc(-c2cc(Br)c3ccccc3c2)ns1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 4-bromonaphthalene-2-carboxylic amide (1.10 g) in toluene (11.0 mL) was added chlorocarbonylsulfenyl chloride (0.73 mL), and the mixture was stirred at 100° C. for 18 hours. To the reaction solution was added water (50 mL). The precipitated solid was collected by filtration, and washed with water and hexane to give 5-(4-bromonaphthalene-2-yl)-[1,3,4]oxathiazole-2-one (1.13 g). This compound (1.12 g) was dissolved in dichlorobenzene (18 mL). To the solution was added ethyl cyanoformate (1.42 mL), and the mixture was stirred at 160° C. for 22 hours. To the mixture was added water (30 mL) at room temperature, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give the title compound (1.21 g).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][C:13]1[N:18]=[C:17]2[S:19][C:20]3[CH2:21][N:22]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:24][C:25]=3[C:16]2=[C:15]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[C:14]=1[Cl:43].C(N(CC)CC)C>ClCCl>[CH2:26]([N:22]1[CH2:23][CH2:24][C:25]2[C:16]3[C:17]([S:19][C:20]=2[CH2:21]1)=[N:18][C:13]([CH2:12][NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[C:14]([Cl:43])[C:15]=3[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2c(Cl)c(CNS(=O)(=O)c3ccccc3)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Benzenesulfonyl chloride (0.156 g) was added to a mixture of the compound (0.35 g) obtained in Example 18B, triethylamine (0.096 g) and dichloromethane (8 ml) under ice-cooling, the mixture was stirred for 1 hour, the reaction mixture was washed successively with water, an aqueous saturated solution of sodium bicarbonate and water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to yield 7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-2-phenylsulfonylaminomethyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine (0.25 g, 55%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 153 to 154° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].S(OC)(OC)(=O)=O>C1COCC1>[OH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[CH2:4][NH2:5]
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: NCc1cc(CO)ccc1F

Procedure:
2-Fluoro-5-formylbenzonitrile was treated with sodium borohydride and dimethyl sulfate in THF to obtain 5-hydroxymethyl-2-fluorobenzylamine. F: 156.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH:13]=C)[C:5]([O:7][CH3:8])=[O:6].[CH3:16][OH:17]>>[CH3:15][C:3]1[C:2]2[O:1][CH:13]([O:17][CH3:16])[CH2:12][C:11]=2[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=CCc1ccc(C(=O)OC)c(C)c1O
Reactant: CO
Product: COC(=O)c1ccc2c(c1C)OC(OC)C2
Temperature: -78 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
A solution of methyl 3-hydroxy-2-methyl-4-prop-2-en-1-ylbenzoate (1.64 g, 8.0 mmol) in methanol (20 mL) was cooled to −78° C. While maintaining the reaction temperature at −78° C., ozone was bubbled into the reaction mixture for 30 minutes, followed by the addition of dimethyl sulfide (5 mL). The reaction mixture was allowed to warm to room temperature and was then stirred for an additional 15 hours. The reaction mixture was concentrated in vacuo and diluted with diethyl ether. The organic portion was washed with water, brine, dried over sodium sulfate and concentrated to afford (1.59 g, 90%) of methyl 7-methyl-2-(methyloxy)-2,3-dihydro-1-benzofuran-6-carboxylate as a yellow oil. MS (EI) for C12H14O4: 223 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH2:5][C:6]#[N:7].[CH3:18]OS(OC)(=O)=O>C1COCC1.O>[CH3:18][O:3][CH:4]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH2:5][C:6]#[N:7]
Reactant: N#CCC(O)c1ccc2ccccc2c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(CC#N)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a suspension of NaH (1.50 g, 37.5 mmol, 60% dispersion) in dry THF (200 mL) cooled to 0° C. was added 3-hydroxy-3-(2-naphthalenyl)propionitrile (4.92 g, 25 mmol) in THF (50 mL) dropwise over 20 minutes. The resulting solution was stirred at 0° C. for 5 minutes and dimethylsulfate (4.72 g, 37.5 mmol) was added in one portion. The reaction mixture was stirred at 0° C. for 20 minutes and room temperature for 1.5 hours. The reaction was then diluted with H2O (50 mL) and the volatiles were removed in vacuo. The residue was partitioned between CH2Cl2 (250 mL) and H2O (200 mL). The aqueous phase was extracted with CH2Cl2 (1×250 mL), the combined organic layers dried (Na2SO4) and concentrated in vacuo to give a thick yellow oil. This was purified by preparative HPLC (SiO2 : gradient EtOAc/hexane) to give the product as a light yellow oil (4.58 g, 87%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[C:26](O)=[O:27])=[O:19])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[F:1][C:2]1[C:3]([NH:17][C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:27])=[O:19])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Reactant: C1COCCN1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Temperature: 70 °C
Reaction time: 60 h
Yield: 41.1 %

Procedure:
A mixture of 5-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (138 mg, 363 μmol), morpholine (253 μl, 2.9 mmol), propylphosphonic anhydride (50% in ethyl acetate, 534 μl, 907 μmol) and diisopropylethylamine (190 μl, 1.09 mmol) in tetrahydrofuran (10 ml) was stirred for 2.5 days (weekend) at 70° C. under nitrogen atmosphere. The solvent was evaporated, the residue was triturated with saturated aqueous sodium hydrogencarbonate solution and the precipitated solid was filtered off and dried in vacuum. The crude material was applied on silica and purified by flash chromatography over a 20 g silica column using heptane/ethyl acetate 10-100% as eluent, affording 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid (6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (67 mg, 41.1%) as white solid. Mp.: 224-225° C. MS: m/z=450.0 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:41]=[CH:40][C:15]([C:16]([NH:18][CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])=[O:17])=[CH:14][CH:13]=1)=[O:10].[CH3:42][NH:43][CH2:44][CH2:45][OH:46].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][NH:18][C:16](=[O:17])[C:15]3[CH:40]=[CH:41][C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]([CH2:44][CH2:45][OH:46])[CH3:42])=[CH:13][CH:14]=3)[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: CNCCO
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(NC(=O)CCCCCCCN(C)CCO)cc1
Temperature: 85 °C

Procedure:
4-[(8-Bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (100 mg, 0.16 mmol, e.g. which can optionally be as prepared in Intermediate 11) was dissolved in N,N-dimethylformamide (4 ml). To one-quarter of this solution, i.e. containing 4-[(8-bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (25 mg, 0.04 mmol) in N,N-dimethylformamide (1 ml), was added 2-(methylamino)ethanol (0.0064 ml (6.4 microliters), 0.08 mmol, 2 equivalents, commercially available e.g. from Aldrich) followed by N,N-diisopropylethylamine (0.04 ml, about 6 equivalents). The reaction mixture was heated at 85° C. for 16 hours. The solvent was evaporated and the residue was purified by eluting through a 5 g silica SPE cartridge, with dichloromethane containing 20% methanol and 1% triethylamine as the eluent, to give the title compound (18.7 mg), in the form of a cream foam, initially thought to be in the form of the “free base”. LCMS showed MH+=622; TRET=2.20 min. However, later re-inspection of the 1H NMR spectrum suggests that the product was isolated as a salt e.g. a mono-salt (presumed to be a hydrobromide salt), e.g. from the signals of protons adjacent to the (2-hydroxyethyl)(methyl)amino group.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[NH:17]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[NH2:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of tert-butyl N-[2-bromo-4-[(4-chlorophenyl)carbonyl]phenyl]carbamate (20 g, 48.70 mmol, 1.00 equip) in dichloromethane (300 mL). To the resulting mixture was then added trifluoroacetic acid (38 mL, 10.00 equip) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of saturated sodium bicarbonate (500 mL). The resulting solution was extracted with DCM (500 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:15 to yield 2-bromo-4-[(4-chlorophenyl)carbonyl]aniline as a light yellow solid. LCMS (ES, m/z) 310 [M+H]+
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]1[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:12].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]2[C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)=[O:12])=[N:27][CH:28]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC(F)(F)CC2CN)c1
Reactant: Clc1ccc(Br)nc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC(F)(F)C[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using (2-(aminomethyl)-4,4-difluoropiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 447 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][C:14]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[OH:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:1]([O:16][CH:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:14]([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:28][CH:27]=1)([CH2:23][CH3:24])[CH2:25][CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(CC)(Cc1ccc(Cl)cc1)C(O)c1cccnc1
Solvent: c1ccncc1
Product: CCC(CC)(Cc1ccc(Cl)cc1)C(OC(C)=O)c1cccnc1
Temperature: 80 °C

Procedure:
10.2 g (0.10 mol) of acetic anhydride are added dropwise to a solution of 12.1 g (0.04 mol) of 2-(4-chlorobenzyl)-2-ethyl-1-(3-pyridyl)-1-butanol in 50 ml of pyridine at room temperature, and the mixture is then heated at 80° C. for 8 h. The reaction mixture is concentrated, the residue is taken up in 200 ml of dichloromethane, and the solution is washed with saturated NaHCO3 solution and then with water. The organic phase is dried and concentrated, and the remaining black oil is purified on silica gel (mobile phase: 5:1 cyclohexane/ethyl acetate). 11.2 g (81% of theory) of the title compound are obtained as a viscous yellow oil. 1H-NMR (CDCl3): δ=8.60(2-Hpy), 8.52(6-Hpy), 7.65(4-Hpy), 7.30(5-Hpy), 7.25(2Hm), 7.05(2Ho), 5.62(CHOAc), 2.68(CH2Ar), 2.08(COCH3), 1.45(CH2), 1.30(CH2), 0.95(CH3), 0.83(CH3).
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][CH2:12][C@H:13]([O:18][CH2:19][CH:20]=[N:21][OH:22])[CH2:14][CH:15]=[CH:16][CH3:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>ClCCl>[CH2:4]([O:11][CH2:12][C@@H:13]1[O:18][CH2:19][C:20]2=[N:21][O:22][C@@H:16]([CH3:17])[C@@H:15]2[CH2:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC=CC[C@H](COCc1ccccc1)OCC=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1ON=C2CO[C@@H](COCc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of sodium hypochlorite (6.15% solution, 6.6 L) was slowly added to a solution of 2-{[(2R)-1-(benzyloxy)hex-4-en-2-yl]oxy}-N-hydroxyethanimine (C12) (660 g, 2.51 mol) and triethylamine (19 g, 0.19 mol) in dichloromethane (6.6 L) at 25° C. After completion of the addition, the reaction mixture was stirred at 25° C. for 30 minutes. The organic layer was washed with water (3×3 L), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via chromatography on silica gel (Eluent: ethyl acetate in petroleum ether) provided (3S,3aR,5R)-5-[(benzyloxy)methyl]-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C13) as a white solid. Yield: 90 g, 0.34 mol, 14%. The indicated relative stereochemistry of compound C13 was assigned based on nuclear Overhauser enhancement studies, which revealed interactions of the methine proton on carbon 3a with both the protons of the methyl group on carbon 3 and the methine proton on carbon 5. LCMS m/z 261.9 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.24-7.39 (m, 5H), 4.69 (d, J=13.7 Hz, 1H), 4.57 (AB quartet, JAB=12.2 Hz, ΔνAB=13.8 Hz, 2H), 4.13-4.25 (m, 2H), 3.62-3.70 (m, 1H), 3.55 (dd, half of ABX pattern, J=10, 6 Hz, 1H), 3.47 (dd, half of ABX pattern, J=10, 4 Hz, 1H), 2.93 (br ddd, J=11, 11, 7 Hz, 1H), 2.11 (br dd, J=12.6, 6.8 Hz, 1H), 1.45-1.56 (m, 1H), 1.45 (d, J=6.2 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:12][C:13]([OH:15])=[O:14])[CH2:3]1.[Mn]([O-])(=O)(=O)=[O:17].[K+]>O.[OH-].[Na+]>[C:13]([CH2:12][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:11][C:2](=[O:1])[C:3]1=[O:17])([OH:15])=[O:14]
Reactant: O=C(O)CN1CC(=O)Nc2ccccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2ccccc21
Yield: 66.6 %

Procedure:
To a solution of 3.0 g (15 mmol) 1,2,3,4-tetrahydro-3-oxoquinoxaline-1-acetic acid in 50 ml water was added gradually a solution of 4. 0 g (25 mmol) potassium permanganate in aqueous sodium hydroxide (4%, w/v) and the mixture was refluxed for 4 h. The reaction mixture was cooled, filtered and the filtrate acidified with concentrated hydrochloric acid to pH 2.5. The precipitate was filtered off and washed with water to give 2.2 g (69%) 1-carboxymethylquinoxaline-2,3(1H,4H)- dione. M.p. >300° C. 1H-NMR (DMSO-d6): 12.0 (1H, broad s), 7.2 (4H, s), 7.0-5.0 (1H, broad s), 4.9 (2H, s).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[N:29]1>>[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([S:33]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:35])=[O:34])=[N:29]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Solvent: CC(=O)O
Product: Cn1ccc(S(=O)(=O)N2CCC3(CCN(c4ccc(OC(F)(F)F)cc4)C3=O)CC2)n1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 1-methyl-1H-pyrazole-3-sulfonyl chloride Off-white solid. MS (ESI): 459.3 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[Br:27]Br.C(O)(=O)C>C(Cl)(Cl)Cl>[Br:27][CH:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: BrBr
Reactant: CC(C)(C)C(=O)CC(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
The bromination of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-(4-chlorophenylsulfonyl)-pentan-3-one was carried out in the same manner as that of Example 3 but using 25 g of 1-(2,4-dichlorophenyl)-1-(4-chlorophenylsulfonyl)-4,4-dimethylpentan-3-one, 8.9 g of bromine, 200 ml of acetic acid and 300 ml of chloroform, and 24.4 g of 2-bromo-1-(2,4-dichlorophenyl)-4,4-dimethyl-1-(4-chlorophenylsulfonyl)pentan-3-one was obtained. m.p. 184°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[I:15]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:15][C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:14])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COC(=O)CCc1ccc(OC)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)CCc1ccc(OC)c(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A 3-neck 5 L RBF equipped with mechanical stirrer, thermometer, and a nitrogen bubbler, was charged with 3-(4-methoxyphenyl)propionic acid methyl ester (100 g, 515 mmol), silver sulfate (161 g, 515 mmol) and iodine (131 g, 515 mmol) in methanol (2 L). The reaction mixture was stirred vigorously at room temperature for 1 hour. The reaction was filtered through Solka-Floc® (ethyl acetate wash). The filtrate was concentrated and the residue was taken up in ethyl acetate (4 L). The organic was washed with water, saturated aq. NaHSO3 (50 mL), and brine (50 mL) before drying over Na2SO4, filtering, and concentrating to dryness. The crude reaction was purified by column chromatography to yield methyl 3-(3-iodo-4-methoxyphenyl)propanoate (155 g, 484 mmol) as a clear oil. MS ESI calc'd. for C11H14IO3 [M+H]+ 321.0, found 321.0.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH2:13][C:14]([C:35](OCC)=O)([CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([O:40][CH3:41])[C:10]([O:42][CH3:43])=[C:9]([O:44][CH3:45])[C:8]=1[O:46][CH3:47].C(O)(=[O:50])C.C(=O)(O)[O-].[Na+]>C1COCC1.CCCCCC>[CH3:41][O:40][C:11]1[C:10]([O:42][CH3:43])=[C:9]([O:44][CH3:45])[C:8]([O:46][CH3:47])=[C:7]2[C:12]=1[CH2:13][C:14]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:35]2=[O:50]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(CCCCOc1ccc(C(=O)OC)cc1)(Cc1c(Br)c(OC)c(OC)c(OC)c1OC)C(=O)OCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(CCCCOc2ccc(C(=O)OC)cc2)Cc2c(OC)c(OC)c(OC)c(OC)c2C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
A hexane solution of n-butyl lithium (1.68 M, 3.27 ml, 5.50 mmols) was dropwise added to a THF (30 ml) solution of ethyl 2-(6-bromo-2,3,4,5-tetramethoxybenzyl)-2-ethoxycarbonyl-6-(4-methoxycarbonylphenoxy)hexanoate (3.00 g, 4.58 mmols), under a nitrogen stream at −90° C. or lower, and stirring was continued for 15 minutes. Then, the temperature was raised to −78° C., and stirring was further continued for 15 minutes. To the reaction mixtures was added a THF (5 ml) solution of acetic acid (1.38 g, 22.9 mmols) at −70° C. or lower, which was then allowed to warm to room temperature, and a saturated aqueous sodium bicarbonate solution was added thereto, which was then extracted with diethyl ether. The organic layer waswashed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out, and the resulting crude product was purified by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (1.22 g) as crystals.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>[OH-].[Na+]>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a solution of 165 g of d,l-phenylalanine in 1100 ml of 1 N sodium hydroxide was added simultaneously 1000 ml of 1 N sodium hydroxide and 146 g of benzoyl chloride over a period of 1 hr with maintenance of the temperature at 2°-5° C. After 3 hr at 5°-10° C., the solution was acidified to pH4 with 5 N hydrochloric acid. The precipitate was collected, washed with water and acetone and dried to leave 234.5 g (87%) of N-benzoyl phenylalanine, mp 185°-188° C. The material was mixed with 2000 ml of acetic anhydride and heated at 95°-100° for 45 minutes. The solvent was removed in vacuo to afford 222 g (100%) of the azlactone, m.p. 60° C.