Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O:3]C)=[O:2].CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([OH:3])=[O:2]
Reactant: CCCCCC(O)/C=C/c1ccccc1CCCCCCC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCC(O)/C=C/c1ccccc1CCCCCCC(=O)O

Procedure:
A solution of 1.28 g. of 1-(6-carbomethoxyhexyl)- 2-(3-hydroxy-trans-1-octenyl)benzene in 150 ml. of methanol is cooled to 0° C. and a solution of 3.0 g. of potassium carbonate in 100 ml. of water is added. The ice bath is removed and the mixture is stirred for twenty-four hours. The methanol is removed in vacuo and the basic aqueous solution is washed with ether, cooled in ice and acidified to pH2 with dilute hydrochloric acid. The solution is then extracted with ether and the extract is washed with water and dried. The solvent is removed to yield 1-(6-carboxyhexyl)-2-(3-hydroxy-trans-1-octenyl)benzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C([O-])=O.[C:67]([CH:69]1[CH2:73][CH2:72][NH2+:71][CH2:70]1)#[CH:68]>CN1C(=O)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:21][CH:22]([C:24]([N:71]4[CH2:72][CH2:73][CH:69]([C:67]#[CH:68])[CH2:70]4)=[O:25])[CH2:23]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC1CC[NH2+]C1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCN(C(=O)OC(C)(C)C)CC4)C2)C1
Reaction time: 1 h

Procedure:
To 150 mg (0.29 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) in 1.0 mL NMP was added 105 mg (0.33 mmol) TBTU and 120 μL (0.70 mmol) DIPEA and stirring was continued at room temperature for 1 h. Then 60.7 mg (0.29 mmol) of 3-Ethynyl-pyrrolidinium trifluoro-acetate was added and the reaction mixture was stirred overnight. The reaction mixture was filtered and the purified by HPLC.
Reaction SMILES: [CH3:1][CH2:2][NH:3][C@@H:4]1[C:11]2[CH:12]=[C:13]([S:15]([NH2:18])(=[O:17])=[O:16])[S:14][C:10]=2[S:7](=[O:9])(=[O:8])[C@@H:6]([CH3:19])[CH2:5]1.C1(C)C=CC(C([C@@:28]([C:44]([OH:46])=[O:45])([OH:43])[C@@:29](C(C2C=CC(C)=CC=2)=O)([OH:33])[C:30]([OH:32])=[O:31])=O)=CC=1>CC(O)C>[CH3:1][CH2:2][NH:3][C@@H:4]1[C:11]2[CH:12]=[C:13]([S:15]([NH2:18])(=[O:17])=[O:16])[S:14][C:10]=2[S:7](=[O:8])(=[O:9])[C@@H:6]([CH3:19])[CH2:5]1.[C:30]([CH:29]([CH:28]([C:44]([O-:46])=[O:45])[OH:43])[OH:33])([O-:32])=[O:31]
Reactant: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: CCN[C@H]1C[C@H](C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Solvent: CC(C)O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 20 °C

Procedure:
Dorzolamide trans racemate of formula (II) (0.8 g) and (−)-di-p-toluoyl-L-tartaric acid (0.22 g) were dissolved in refluxing 2-propanol (45 mL). The so obtained solution was distilled at normal pressure up to a final volume of 20 mL. The resulting suspension was stirred at refluxing temperature further 2 hours and then cooled to 20° C. over 7 hours. The solid was isolated by vacuum filtration washing with 2-propanol (4 mL) and then dried in vacuum oven at 40° C. to give Dorzolamide tartrate (1st crop) (0.626 g). This compound (0.601 g) was dissolved in refluxing 2-propanol and the solution was distilled at normal pressure up to a final volume of 18 mL. The resulting suspension was cooled to 20° C. over 7 hours. The solid was isolated by vacuum filtration washing with 2-propanol (4 mL) and then dried in vacuum oven at 40° C. to give Dorzolamide tartrate (2nd crop) (0.49 g). This compound was submitted to a further re-crystallization following the latter procedure (the solution was distilled at normal pressure up to a final volume of 15 mL). The resulting solid was isolated by vacuum filtration then dried in vacuum oven at 50° C. to give the title compound (0.379 g; 85-87% e.e.) as a white solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)=[CH:2][CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Nc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 49.1 %

Procedure:
Using the procedure of example 1, 1,4-phenylenediamine (175 mg) was reacted with compound 1f (100 mg) to provide compound 37 (40 mg, 25%). 1H NMR (400 MHz, CD3OD) δ 8.43 (d, J=8.0 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.20 (s, 1H), 8.18 (d, J=4.8 Hz, 1H), 7.36 (m, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.18 (dd, J=8.0 Hz, 5.6 Hz, 1H), 7.11 (d, J=5.2 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H). MS (ESI) m/z: 301 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])([CH3:6])([CH3:5])[CH3:4].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])([CH3:6])([CH3:4])[CH3:5]
Reactant: COCCOc1cc(O)ccc1C(C)(C)C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C(C)(C)C)c(OCCOC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a tetrahydrofuran (THF) (10 ml) suspension of sodium hydride (60% in mineral oil) (68 mg, 1.7 mmol) was added a tetrahydrofuran (THF) solution (5 ml) of 4-tert-butyl-3-(2-methoxyethoxy)phenol (320 mg, 1.4 mmol) and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added ethyl bromoacetate (190 ul, 1.7 mmol) at ambient temperature. The stirred mixture was refluxed for 4 hours. The reaction mixture was then quenched with saturated aqueous solution of ammonium chloride and then crude products were extracted with ethyl acetate The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=1/9 to furnish 0.26 g (60% yield) of the title compound as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11](N2[C@@H]3C[C@@H]4C(C)(C)[C@]3(CC4)CS2(=O)=O)=[O:12])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(=O)=O.[Cl-].[NH4+]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH:11]=[O:12])=[CH:6][CH:7]=1
Reactant: CC1(C)[C@@H]2CC[C@]13CS(=O)(=O)N(C(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1)[C@@H]3C2
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: O=C[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of the later-eluting, R,R-diastereomer ([(1R,2R)-2-(4-bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λ6-thia-4-azatricyclo[5.2.1.01.5]dec-4-yl)}methanone) described in Example 29D (5.2 g, 11.86 mmol) in dichloromethane (100 mL) was stirred under a dry nitrogen atmosphere at −78° C. A 1 M solution of diisobutylaluminum hydride in dichloromethane (26.1 mL, 26.1 mmol) was added dropwise to the mixture. When the addition was complete, the mixture was stirred at −78° C. for 3 hour. Methanol (27 mL) was then added dropwise at −78° C. The dry ice bath was then replaced with an ice water bath and saturated aqueous ammonium chloride was added to quench the mixture. After 10 minutes, the insoluble material was removed by filtration and the organic layer was isolated, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure to provide a colorless oil that was purified by column chromatography (9:1 hexane/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 1.45-1.57 (m, 1H), 1.70-1.78 (m, 1H), 2.11-2.19 (m, 1H), 2.55-2.63 (m, 1H), 6.99 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 2H), 9.35 (d, J=4.5 Hz, 1H). MS (DCl—NH3) m/z 225 (M+H)+, m/z 242 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16](C(O)=O)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:25]N1C(=O)CCC1=O.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([Br:25])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1c(-c2ccc(F)cc2)nn2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2nn3ccccc3c2Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(4fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.96 g, 3.75 mmol) in dry N,N-dimethylformamide (10 mL) was added sodium bicarbonate (0.95 g, 11.3 mmol) followed by N-bromosuccinimide (0.667 g, 3.75 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for about 90 minutes. The mixture was poured into water (300 mL) and the resulting solid was collected by filtration and washed with water. The solid was dissolved in 10:1 chloroform:methanol (10 mL) and filtered through a pad (0.5 cm) of silica gel using 10:1 chloroform:methanol as eluent. The filtrate was evaporated to leave the title compound as a tan solid, 0.87 g (80%). 1H NMR (d6 DMSO) δ 8.7 (d, 1H, J=6.9 Hz), 8.02 (dd, 2H, J=8.7, 5.7 Hz), 7.61 (d, 1H, J=8.4 Hz), 7.40 (t, 1H, J=6 Hz), 7.38 (t, 2H, J=9 Hz), 7.04 (t, 1H, J=6.9 Hz). MS (+ve ion electrospray) 293 (100), (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:37](F)(F)[C:38]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:37]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:35])[F:34])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:38]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(C(F)(F)F)c1)CC2
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC3)cc1F

Procedure:
2-Fluoro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}benzoic acid, m/z (ES+): 509.2 (M+H+.), was prepared in analogy to example 9, steps 1 to 5. Step 4 was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 2-fluoro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:27][C:28](=[O:40])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:40]=[C:28]1[CH2:29][C:30]([C:32]2[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=2)[C:38]#[N:39])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[NH:27]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccc(OC(F)(F)F)cc4)cc3NC(=O)C2)c1
Yield: 83.8 %

Procedure:
Prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-(4-trifluoromethoxy-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example K30) (170 mg, 0.3 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige solid (112 mg).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32][C:33]1[CH:34]=[CH:35][C:36]2[C:37]3[S:45][C:44]([CH2:46]O)=[N:43][C:38]=3[CH:39]=[N:40][C:41]=2[CH:42]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:32][C:33]1[CH:34]=[CH:35][C:36]2[C:37]3[S:45][C:44]([CH2:46][O:1][N:2]4[C:3](=[O:12])[C:4]5[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=5)[C:6]4=[O:7])=[N:43][C:38]=3[CH:39]=[N:40][C:41]=2[CH:42]=1
Reactant: OCc1nc2cnc3cc(Br)ccc3c2s1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1nc2cnc3cc(Br)ccc3c2s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
N-Hydroxyphthalimide (4.15 g, 25.4 mmol) and triphenylphosphine (6.66 g, 25.4 mmol) were added to a suspension of (7-bromo[1,3]thiazolo[4,5-c]quinolin-2-yl)methanol (5.00 g, 16.9 mmol) in THF (170 mL). Diethyl azodicarboxylate (4.43 g, 25.4 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 1.5 hours. A precipitate formed and was isolated by filtration, washed with THF, and dried in a vacuum oven to provide 5.59 g of 2-[(7-bromo[1,3]thiazolo[4,5-c]quinolin-2-yl)methoxy]-1H-isoindole-1,3(2H)-dione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(Br)c(F)cc1F
Temperature: 28 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-bromo-2,4-difluorobenzene (0.512 g, 2.65 mmol, Aldrich, used as received) in conc. H2SO4 (5.0 mL) at 0° C., KNO3 (0.275 g, 2.72 mmol) was added in one lot. The resulting solution was allowed to warm to 28° C. and stirred at that temperature overnight. It was then poured into ice (50 g) and extracted with ethyl acetate (50 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum and the resulting oil dried further under vacuum to afford 0.576 g (91%) of the pure (1H NMR) title compound as a light red oil; 1H NMR (CDCl3); δ 7.141 (dd, 1H, J1 =10.2 Hz, J2 =7.8 Hz), 8.375 (t, 1H, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C.O>[NH2:1][C:2]1[C:11]([Br:15])=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1Cc2cc(N)ccc2C(C)(C)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: CN1Cc2c(ccc(N)c2Br)C(C)(C)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 7-amino-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinoline from D3 (7 g) in acetonitrile (200 ml), was added N-bromo succinimide (7.21 g) portionwise over 10 min. The reaction mixture was cooled in an ice/methanol bath to prevent any large exotherm. and then stirred under argon for 45 min. The reaction was allowed to warm to 25° C., diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness in vacuo. The resultant brown solid was purified using dry flash column chromatography with ethyl acetate. Combination of appropriate fractions gave the title compound as an orange gum (3.95 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([OH:43])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.[I-].[Na+]>CN(C=O)C>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([OH:43])[CH2:38][CH2:39][N:40]([CH2:2][CH2:3][CH2:4][CH:5]3[C:19](=[O:20])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:41][CH2:42]2)=[CH:33][CH:32]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3)noc2CCC1CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 32.3 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (5.02 g) and DMF (170 ml) was added diisopropylethyl amine (7.50 ml), 4-(4-chlorophenyl)-4-hydroxypiperidine (4.03 g) and sodium iodide (2.59 g) at room temperature with stirring. The reaction was flushed with nitrogen and warmed to 78°-80° C. for 11 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous layers extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude amine product. Purification via flash chromatography (silica gel, 2% Et3N/ether) afforded 2.60 g of the desired product as an oil. Addition of ether, heat, and slow evaporation gave a powder. The ether was then decanted and the powder was washed with pentane to yield 5-[3-(4-(4-chlorophenyl)-4-hydroxy-piperidinyl)-propyl]-6,7-dihydro-3-phenyl-1,2-benzisoxazol -4(5H)-one, m.p. 147°-148° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][CH:11]([CH2:31][OH:32])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:33])[NH:10][CH:11]([CH2:31][O:32][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:15]([C:27]([CH3:30])([CH3:28])[CH3:29])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(CC(CO)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(CC(COS(C)(=O)=O)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 2-(4-benzyloxy-3-t-butylphenyl)-1-hydroxymethylethylcarbamic acid benzyl ester (1.87 g, 4.18 mmol) in pyridine (42 ml), methanesulfonyl chloride (0.36 ml, 4.60 mmol) was added under cooling with ice. After stirring for 1 hour, the mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure, giving the titled compound (1.93 g, 88%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32](O)=[O:33]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)=[O:33])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccccn1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccn4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and pyridine-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.C([N-]C(C)C)(C)C.[Li+].[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([CH3:38])=[N:35]2)=[CH:30][CH:29]=1.Cl[Si](C)(C)C.[Br:44]Br>O1CCCC1>[Br:44][CH2:38][C:34]1[CH:33]=[CH:32][C:31]2[C:36](=[CH:37][C:28]([Cl:27])=[CH:29][CH:30]=2)[N:35]=1
Reactant: BrBr
Reactant: Cc1ccc2ccc(Cl)cc2n1
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1ccc2ccc(CBr)nc2c1
Temperature: -10 °C
Yield: 62.4 %

Procedure:
A solution of diisopropylamine (3.6 ml, 24.86 mmol) in dry tetrahydrofuran (25.0 ml) at -20° C. under nitrogen was treated with a 2.5 M solution of n-butyllithium in hexane (10.0 ml, 24.86 mmol). This lithium diisopropylamide solution was stirred below -10° C. for 30 min and 7-chloroquinaldine (4.0 g, 22.6 mmol) was added in portions. The resulting dark red solution was stirred at -10° C., increasing to 0° C. for 1 h, cooled to -30° C. and treated with chlorotrimethylsilane (4.4 ml, 33.92 mol) dropwise to return a golden yellow solution. After stirring below -20° C. for 2 h a solution of bromine (1.2 ml, 22.6 mmol) in tetrahydrofuran (25.0 ml) was added dropwise over a 30 min period maintaining an addition temperature of below -20° C. at all times. The mixture was stirred below -20° C. for 1 h, quenched with water (300 ml), extracted into ethyl acetate (3×100 ml), the combined organic extracts were washed with saturated ammonium chloride solution (2×200 ml), dried (Na2SO4) and evaporation of the solvent afforded a brown oily solid. Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4) gave the title compound (3.62 g, 76%) as a yellow solid. Crystallised from light petroleum (b.p. 40-60° C.) as white crystals, m.p. 108-112° C. (lit. m.p. 112° C. (dec.)). νmax (nujol)/cm-1 1593.5, 1559.5. δH (270 MHz) 4.68 (2H, s, CH2Br); 7.50 (1H, dd, 6-H, Jo =8.6, Jm =2.0 Hz); 7.56 (1H, d, 3-H, Jo =8.3 Hz); 7.74 (1H, d, 5-H, Jo =8.9 Hz); 8.06 (1H, d, 8-H, Jm =2.0 Hz); 8.14 (1H, d, 4-H, Jo =8.6 Hz). δc (67.8 MHz) 34.0 (CH2Br), 121.4 (3-C), 125.6 (4a-C), 135.9 (8a-C), 137.1 (4-C), 158.0 (2-C). Remaining signals fall in the narrow range 128.0-128.3 ppm.
Reaction SMILES: [CH:1]([Si:4]([O:11][CH2:12][C@@H:13]([OH:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH3:24]I>>[CH:8]([Si:4]([O:11][CH2:12][C@@H:13]([O:23][CH3:24])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])([CH3:9])[CH3:10]
Reactant: CI
Reactant: CC(C)[Si](OC[C@@H](O)CNC(=O)OC(C)(C)C)(C(C)C)C(C)C
Product: CO[C@@H](CNC(=O)OC(C)(C)C)CO[Si](C(C)C)(C(C)C)C(C)C
Yield: 81 %

Procedure:
Using a procedure analogous to Example 57-B, (2S)-3-(t-butoxycarbonylamino)-2-hydroxypropyl triisopropylsilyl ether and methyl iodide gave the title compound (4.2 g, 81%).