Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].[N:25]#[C:26][NH2:27].C(N(CC)CC)C>CN(C=O)C.O>[CH3:22][C:20]([C:7]1[CH:8]=[C:9]([C:11]2[S:12][C:13]([NH:27][C:26]#[N:25])=[N:14][N:15]=2)[CH:10]=[C:5]([C:2]([CH3:3])([CH3:1])[CH3:4])[C:6]=1[OH:24])([CH3:23])[CH3:21]
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Reactant: N#CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1cc(-c2nnc(NC#N)s2)cc(C(C)(C)C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl]phenol (5.0 g, 0.0136 mole) in a mixture of DMF (20 ml) and water (5 ml) is added cyanamide (5.0 g, 0.119 mole) and triethylamine (1.4 g, 0.0136 mole). The mixture is heated to 80° C. and stirred overnight. An additional portion of cyanamide (2.5 g, 0.059 mole) is added and the mixture is stirred six hours at 80° C. The reaction is cooled and partitioned between water and ether. The aqueous layer is acidified with 6M HCl (40 ml). The resulting precipitate is filtered and recrystallized from acetonitrile/water to provide 3.4 g of [5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl]cyanamide (4.5 g theor., 76%) after drying in vacuo at 70° C., mp >250° C.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[N:8]2[CH:25]=[C:26]([Cl:28])[CH:27]=[C:7]2[C:6]=1[OH:29])=[O:4].[NH2:30][C@@H:31]([C:33]([OH:35])=[O:34])[CH3:32].C[O-].[Na+]>>[Cl:28][C:26]1[CH:27]=[C:7]2[C:6]([OH:29])=[C:5]([C:3]([NH:30][C@H:31]([CH3:32])[C:33]([OH:35])=[O:34])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)[N:8]2[CH:25]=1
Reactant: C[C@@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(-c3ccccc3)cc2)c1=O
Agent: C[O-]
Agent: [Na+]
Product: C[C@@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(-c3ccccc3)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-(4-phenyl-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, D-alanine and NaOMe. ESI (m/z): 466 (M+H)+.
Reaction SMILES: [CH2:1]1[O:15][C:14]2[C:3](=[CH:4][C:5]3[O:10][CH2:9][CH:8]([CH2:11][NH2:12])[O:7][C:6]=3[CH:13]=2)[O:2]1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:26]1[C:27]2[C:22](=[C:21]([O:20][CH2:19][CH2:18][CH2:17][NH:12][CH2:11][CH:8]3[O:7][C:6]4[CH:13]=[C:14]5[O:15][CH2:1][O:2][C:3]5=[CH:4][C:5]=4[O:10][CH2:9]3)[CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: BrCCCOc1cccc2ncccc12
Reactant: NCC1COc2cc3c(cc2O1)OCO3
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(OCCCNCC2COc3cc4c(cc3O2)OCO4)c2cccnc2c1
Temperature: 80 °C
Yield: 38.6 %

Procedure:
2,3-Dihydro-6,7-methylenedioxy-1,4-benzodioxin-2-methanamine (2.3 g, 11 mmole), 5-(3-bromopropoxy)quinoline (2.54 g, 9.2 mmole), and diisopropylethylamine (2.6 g, 20 mmole) were combined in 100 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 500 ml of dichloromethane. The mixture was washed with 250 ml each of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 250 g of silica gel using 2% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue (2.0 g) recrystallized from 50 ml of ethanol with the addition of 6 ml of 4N isopropanolic HCl to give 1.4 g of the title compound as an orange solid dihydrochloride, one-quarter hydrate, m.p. 140°-145° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:35]C(=O)OCC2C=CC=CC=2)[C@H:18]([OH:34])[CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[CH:12]=[C:13]([F:15])[CH:14]=1.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[NH2:35][C@@H:17]([CH2:16][C:11]1[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([F:8])[CH:10]=1)[C@H:18]([OH:34])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33]
Reactant: C=CCCCc1ccc(C)cc1CNC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: COCCOC
Product: C=CCCCc1ccc(C)cc1CNC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 55.5 %

Procedure:
Step AL (2): To a solution of benzyl (2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(5-methyl-2-(pent-4-enyl)benzylamino)butan-2-ylcarbamate trifluoroacetate salt (65 mg, 0.102 mmol) in DME (7.0 mL) and water (4.5 mL) was added barium hydroxide monohydrate (625 mg, 3.3 mmol). The reaction mixture was stirred at 110° C. in a high pressure vial for 18 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuum. The residue was purified by reverse phase chromatography to give (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-(5-methyl-2-(pent-4-enyl)benzylamino)butan-2-ol double trifluoroacetate salt (22 mg, 35%) as a colorless oil. LC-MS (M+H)+=389.63.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([O:12][CH:13]=[CH:14]C)[CH3:11].COCCOC.C1(C)C=CC=CC=1.O.CCO>[N+](CC)(CC)(CC)CC.[Cl-].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:5]1[N:4]=[C:3]([NH2:9])[C:2]([CH:11]=[CH:10][O:12][CH2:13][CH3:14])=[CH:7][N:6]=1
Reactant: Nc1nc(Cl)ncc1Br
Reactant: CC=COCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: COCCOC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC=Cc1cnc(Cl)nc1N
Temperature: 25 °C

Procedure:
5-Bromo-2-chloro-pyrimidin-4-ylamine (88.0 g, 0.43 mol), 1-ethoxy-propene (220 g, 0.49 mol), Pd(PPh3)2Cl2 (35.0 g, 0.05 mol) and Et4NCl (67.0 g, 0.40 mol) are suspended in solvent (750 mL, DME/toluene/H2O/EtOH 10:1:3:6) under nitrogen. The reaction mixture is heated to reflux for 24 h, cooled to rt, and then diluted with water. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (SiO2, gradient elution, EtOAc/petroleumether 1:10>1:4) to yield the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: Oc1ccc(F)cc1
Product: COc1cccc2c(Oc3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from 4-Fluoro-phenol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-5-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:34])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([F:14])=[CH:13][C:8]2[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=4)[CH:22]=3)[CH2:18][C:17](=[O:34])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(C3=Nc4cc(F)c(Cl)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (4-chloro-5-fluoro-2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M20) (241 mg, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (124 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8](N)=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.N([O-])=O.[Na+].[I-:19].[K+]>Cl.O>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([I:19])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2cc(N)ccc21
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)CCC(=O)c2cc(I)ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4,4-dimethyl-7-amino-1-tetralone (XXIa) (1.82 g, 10.0 mmol) in concentrated hydrochloric acid (4.69 mL) was added ice cold water (3.13 mL). The reaction mixture was then cooled to 0° C. by use of an ice-salt bath. The reaction mixture was then diazotized by the dropwise addition with stirring of a solution of sodium nitrite (0.76 g, 11.0 mmol) in water (3.13 mL) keeping temperature between 0°-5° C. After stirring for 15 minutes, the reaction mixture was added to a solution of potassium iodide (3.63 g, 21.9 mmol) in water (18.8 mL). After standing for 30 minutes, the dark gum was extracted with ethyl acetate (1×100 mL). The organic phase was then concentrated in vacuo and the residue chromatographed on silica gel (eluted with 5% ethyl acetate in hexane) to give 1.56 g (Y: 54%) of the title product. 1H-NMR (CDCl3): δ8.33 (d, J=2.0 Hz, 1H), 7.82 (dd, J=8.3, 2.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 2.72 (t, J=6.8 Hz, 2H), 2.01 (t, J=6.8 Hz, 2H), 1.37 (s, 6H); MS (DCI) m/e: 301 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][NH:23][C:24](=[O:31])[C@@H:25]([NH2:30])[C@@H:26]([CH3:29])[CH2:27][CH3:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[CH2:39]([S:43](Cl)(=[O:45])=[O:44])[CH2:40][CH2:41][CH3:42].O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][NH:23][C:24](=[O:31])[C@@H:25]([NH:30][S:43]([CH2:39][CH2:40][CH2:41][CH3:42])(=[O:45])=[O:44])[C@@H:26]([CH3:29])[CH2:27][CH3:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)NCCc1ccc(OCc2cccc3ccccc23)c(OC)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCc2cccc3ccccc23)c(OC)c1)[C@@H](C)CC
Reaction time: 16 h

Procedure:
3.4 g of (2S,3S)-2-amino-3-methyl-valeric acid N-{2-[3-methoxy-4-(naphthalen-1-ylmethoxy)-phenyl]-ethyl}-amide and 1.2 ml of triethylamine are placed in 50 ml of dioxane at room temperature. 1.0 ml of n-butylsulfonyl chloride is added thereto. Stirring is carried out for 16 hours. The reaction mixture is introduced into 200 ml of water. Extraction is carried out twice using 200 ml of ethyl acetate each time. The organic phases are washed once with 200 ml of saturated sodium chloride solution, combined, dried over magnesium sulfate and concentrated, yielding (2S,3S)-2-(butylsulfonyl-amino)-3-methyl-valeric acid N-{2-[3-methoxy-4-(naphthalen-1-ylmethoxy)-phenyl]ethyl}-amide, which can be purified by chromatography on silica gel with ethyl acetatein-hexane =1:1, in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][CH:12](OC)[C:13]([O:15]C)=O)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C(O)(=O)C.O.[NH2:25][NH2:26]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:15])[NH:25][N:26]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: NN
Reactant: COC(=O)C(CC(=O)c1cc(Cl)c(C)c(Cl)c1)OC
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Yield: 86.2 %

Procedure:
1.53 g (0.005 mole) of methyl 4-(3,5-dichloro-4-methylphenyl)-2-methoxy-4-oxobutyrate were added to 4 ml of acetic acid and the mixture was heated to form a solution, to which was then added 0.275 g (0.0055 mole) of hydrazine monohydrate. The mixture was heated under reflux for 3 hours and then cooled, after which it was diluted with 40 ml of water and stirred. The resulting crystals were collected by filtration, washed successively with water and with a small amount of ethyl acetate and then air-dried, to give 1.1 g (yield 86.2%) of the desired 6-(3,5-dichloro-4-methylphenyl)-3(2H)pyridazinone, having properties the same as those of the preceding Examples.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH:6]=1)=O.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O.CO>[C:11]([NH:10][CH:8]1[CH2:9][C:5]([CH2:3][OH:2])=[CH:6][CH2:7]1)(=[O:13])[CH3:12]
Reactant: COC(=O)C1=CCC(NC(C)=O)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)NC1CC=C(CO)C1
Temperature: -70 °C
Reaction time: 0.67 h

Procedure:
(±)-Methyl-4-acetamido-1-cyclopentene-1-carboxylate (3.66 g, 20.0 mmol) was dried by evaporation of toluene giving a solution with a final volume of 50 mL. This solution was cooled to -70° C. under nitrogen. A solution of diisobutylaluminum hydride in toluene (1.5 M, 42 mL, 63 mmol) was added dropwise over 2 hours. The resulting hazy solution was stirred at -70° C. for an additional 40 minutes. Cold methanol (5 mL) was added dropwise, followed by a solution of sodium potassium tartrate (11.29 g) in water (15 mL) with the temperature maintained at -70° C. The resulting mixture was allowed to stir at 0° C. for several hours, diluted with methanol (150 mL) and filtered. The methanol was evaporated and the residual brown oil (3.44 g) chromatographed on silica gel. Title compound was eluted as pale yellow oil with 5% methanol-chloroform; 1.30 g (42%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:39]([F:42])([F:41])[F:40])[N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][C@H:19]([NH:30]C(OC(C)(C)C)=O)[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=3[F:29])[CH2:13][C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:43]>C(OCC)(=O)C>[ClH:43].[C:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:39]([F:40])([F:41])[F:42])[N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][C@H:19]([NH2:30])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=3[F:29])[CH2:13][C:12]=12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)OC(C)(C)C)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
(R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid tert-butyl ester 36a (0.094 g, 0.15 mmol) and 10 mL of ethyl acetate were added into the reaction flask. A solution of 5.5 N hydrochloric acid in 3 mL of ethyl acetate was added to the reaction flask in a ice-water bath. Upon completion of the addition, the ice-water bath was removed. The reaction mixture was stirred at room temperature for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure, and washed with 20 mL of n-hexane. The filtrate was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid tert-butyl ester hydrochloride 36 (0.084 g, yield 100%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][N:7]([CH2:12][C:13]1[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[CH:14]=1)[CH2:8][CH2:9][CH:10]=[O:11])[CH3:2].C[O-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:5]1[C@H:10]([OH:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[C:16]3[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=3[CH:14]=2)[CH2:6]1)=[O:23])[CH3:2]
Reactant: CCOC(=O)CCN(CCC=O)CC1=Cc2ccc(OC)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CN(CC2=Cc3ccc(OC)cc32)CC[C@H]1O
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 12.78 g (40 mmol) of 3-[N-(5-methoxybenzocyclobuten-1-ylmethyl)-N-(3-oxopropyl)-amino]propionic acid ethyl ester in 100 ml of dimethylformamide is added to a solution of 2.43 g (45 mmol) of sodium methoxide in 15 ml of dimethylformamide and the whole is stirred for 3 hours at 40° C. The solvent is then evaporated off under reduced pressure and the residue is separated into its components by chromatography on 400 g of silica gel with dichloromethane/methanol (95:5). Trans-4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester is isolated first and then cis-4-hydroxy-1-[(5-methoxy- benzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester the hydrochloride of which has a melting point of 156°-160° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[CH:13]=[C:14]2[C:20](=[O:21])[C:19](=[O:22])[NH:18][C:15]2=[N:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:20]([OH:21])([C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=3[O:9][CH3:10])[C:19](=[O:22])[NH:18][C:15]2=[N:16][CH:17]=1
Reactant: O=C1Nc2ncc(Cl)cc2C1=O
Reactant: COc1ccc(C)cc1Br
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ncc(Cl)cc21
Yield: 81.9 %

Procedure:
With 1.49 g of 2-bromo-4-methyl anisole and 900 mg of the compound obtained in Step 118-4 as starting materials, 1.23 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=2)[N:12]=1)[C:5](O)=[O:6].O=S(Cl)Cl.Cl.[NH4+:27].[OH-]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=2)[N:12]=1)[C:5]([NH2:27])=[O:6]
Reactant: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)c(Cl)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(-c2ccc3cc(O)ccc3n2)c(Cl)c1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
A mixture of 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid (Compound 8, Example 8) (400 mg, 1.33 mmol) and SOCl2 (10 mL) was refluxed for 1 hour, then concentrated under reduced pressure to give crude product (400 mg) as off-white solid. To this solid was added NH4OH (10 mL) and the reaction mixture was stirred at 30° C. for 1 hour. The resulting mixture was acidified with aqueous HCl (2 M) until pH=6 and extracted with EtOAc (50 mL×3), dried over Na2SO4 and concentrated to give crude product (360 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]([CH3:26])([CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[C:20]([CH3:23])([Cl:22])[CH3:21])=[CH:15][CH:14]=2)Br)=[CH:7][CH:6]=1)=[O:4].ClC(C)(C)C(C1C=CC(C(C2C=CC(C(=O)C(C)(Cl)C)=CC=2)(Br)Br)=CC=1)=[O:30]>>[Cl:1][C:2]([CH3:26])([CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[C:20]([CH3:23])([Cl:22])[CH3:21])=[CH:15][CH:14]=2)=[O:30])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(Cl)C(=O)c1ccc(C(Br)(Br)c2ccc(C(=O)C(C)(C)Cl)cc2)cc1
Reactant: CC(C)(Cl)C(=O)c1ccc(C(Br)c2ccc(C(=O)C(C)(C)Cl)cc2)cc1
Product: CC(C)(Cl)C(=O)c1ccc(C(=O)c2ccc(C(=O)C(C)(C)Cl)cc2)cc1

Procedure:
492.6 g of oil are recrystallised from 300 g of cyclohexane, followed by filtration and washing. 134 g of white crystals are obtained. From the mother liquor there are obtained, by means of concentration, a further 356 g of yellow crystals, which are recrystallised from 300 g of cyclohexane, filtered and washed with 100 g of cyclohexane. 200 g of yellowish crystals are thereby obtained. From the next mother liquor there are obtained, by means of partial concentration, a further 16.1 g of white crystals, and 112.4 g of dark-yellow oil remain. Unfortunately, all those crystal fractions of bis[4-(2-chloro-2-methyl-propionyl)-phenyl]-bromomethane are, according to the 1H NMR spectrum, mixed with the subsidiary product bis[4-(2-chloro-2-methyl-propionyl)-phenyl]-dibromomethane (the first fractions to the greatest extent). The product has been over-brominated in this experiment. The subsidiary product is expected to give rise to bis[4-(2-chloro-2-methyl-propionyl)-phenyl]-methanone during hydrolysis.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>>[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NCc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Following the procedure described in Example 1A, step 1, 4-(trifluoromethyl)benzaldehyde and 4-isopropylaniline gave the title compound as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:23])[CH2:7][C:8]([NH:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:13][N:12]=1)=[O:9])C.C1COCC1>O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:13][N:12]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][C:6]([OH:23])=[O:5])[CH:15]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(-c2ccc(F)cc2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(=O)Nc1cc(-c2ccc(F)cc2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
NaOH (34 mg, 8.5 mmol) was added to a solution of N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-malonamic acid ethyl ester (292 mg, 1.0 mmol) in the mixture of THF (13 mL) and H2O (13 mL) and stirred for 1 hr at room temperature. The reaction mixture was concentrated and the obtained residue was diluted with water, acidified with concentrated HCl, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4 and concentrated to afford 40 mg (90.9% Yield) of N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-malonamic acid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].S(Cl)([Cl:16])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.O>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=1
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc(Cl)cc1OC(F)(F)F
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
1.78 g of o-trifluoromethoxyphenol was dissolved in 5 mL of toluene, and the mixture was stirred in an ice water bath for 20 min. 1.485 g of sulfonyl chloride was added dropwise to the reaction system within 10 min, which was then stirred for 20 min. The solution was moved to a water bath maintained at 30° C., and allowed to stir at this temperature for 1 h. 200 mL of 5% sodium carbonate aqueous solution and 50 mL of toluene were added to the system, which was then violently vibrated and isolated (pH of water layer was 10 upon determination). The pH of water layer was adjusted to 2 with 2 N of hydrochloric acid aqueous solution. The solution was extracted with 50 mL of toluene once again. The toluene layers were combined, successively washed with 100 mL of water and 100 mL of saturated sodium chloride aqueous solution, dried over 5 g of anh. MgSO4 for 30 min, and concentrated via a rotary evaporator to obtain a white granular solid. MS anion peak (M-H: 213).