Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)[Cl:2].[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][C:20](=[O:22])[CH3:21])[N:15]=[CH:14][NH:13][C:12]2=O)(=[O:7])[CH3:6].S(Cl)(Cl)=O.C[N:29]([CH3:32])C=O>>[ClH:2].[C:16]([C:11]1[CH:12]=[C:32]([NH:29][C:12]2[C:11]3[C:16](=[CH:17][C:18]([O:19][C:20](=[O:22])[CH3:21])=[C:9]([O:8][C:5](=[O:7])[CH3:6])[CH:10]=3)[N:15]=[CH:14][N:13]=2)[CH:18]=[CH:9][CH:10]=1)#[CH:17]
Reactant: ClC(Cl)Cl
Reactant: CC(=O)Oc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: C#Cc1cccc(Nc2ncnc3cc(OC(C)=O)c(OC(C)=O)cc23)c1
Product: Cl
Temperature: 47.5 °C
Yield: 73.6 %

Procedure:
Into a 3.0 Lt four necked round bottomed flask, equipped with a mechanical stirrer, reflux condenser, pressure equalizing addition funnel and thermometer socket are charged chloroform (500 ml), 6,7-diacetoxy-4(3H)-quinazolinone (25 g) obtained from the process described in step (ii) of example (1) and dimethylformamide (3 ml). Thionyl chloride (46.2 g) was slowly added in about 20-30 minutes. The reaction mass was slowly heated to reflux temperature and maintained at reflux temperature for 6 hours. Reaction was found to be over by HPLC. Cooled to 45-50° C. then added chloroform (500 ml) and distilled out 500 ml of chloroform. Repeated the distillation process another two times with fresh chloroform. Then cooled the reaction mass to 20° C. 3-Ethynylaniline (15 g) was added and maintained for 2-3 hours at 20-25° C. Completion of the reaction is monitored by HPLC. Distilled of the solvent completely under vacuum. Cooled the reaction mass to 20-25° C. and triturated with isopropyl alcohol and filtered and washed the cake with isopropyl alcohol and dried to get N-(3-ethynylphenyl)-6,7-diacetoxy-4-quinazolinamine hydrochloride 28 g (73.6% by theory).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:40](=[O:41])[N:13]3[C:14]([C:37]([OH:39])=[O:38])=[C:15]([CH2:18]OC(=O)C4C=CC=CC=4S(=O)(=O)NC(OCC)=O)[CH2:16][S:17][C@H:12]23)=[O:9])=[CH:4][S:3]1.[SH:42][C:43]1[N:47]([CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])[N:46]=[N:45][N:44]=1.C(=O)([O-])O.[Na+]>O>[NH:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:40](=[O:41])[N:13]3[C:14]([C:37]([OH:39])=[O:38])=[C:15]([CH2:18][S:42][C:43]4[N:47]([CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])[N:46]=[N:45][N:44]=4)[CH2:16][S:17][C@H:12]23)=[O:9])=[CH:4][S:3]1
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(=N)[nH]3)[C@H]2SC1
Reactant: CN(C)CCn1nnnc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(=N)[nH]3)[C@H]2SC1

Procedure:
In water (5 ml) are dissolved 7β-(2-imino-4-thiazolin-4-yl)acetamido-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (313 mg), 5-mercapto-1-[2-(N,N-dimethylamino)ethyl]-1H-tetrazole (113 mg) and sodium hydrogen carbonate (42 mg) and the resultant solution is heated at 55° C. for 60 minutes. The reaction solution is adjusted its pH to 5.8 and purified by column chromatography on Amberlite XAD-2 and the fractions rich in the desired product are pooled and lyophilized. The procedure provides 7β-(2-imino-4-thiazolin-4-yl)acetamido-3-{1-[2-(N,N-dimethylamino)ethyl]-1H-tetrazol-5-yl}thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH2:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4=[C:14]([CH2:17][CH2:18][CH2:19][C:20](=[O:22])/[C:21]/4=[CH:39]/[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=4)[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc2C1
Reactant: O=Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc2/C1=C\c1ccccn1
Temperature: -60 °C
Yield: 79.7 %

Procedure:
A 3 neck round bottom flask with stir bar, nitrogen line and thermometer was charged with 1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6 (1H)-one (6, R1=4-Fluorophenyl) (0.500 g, 1.699 mmol) and THF (15 mL). The solution was cooled to about −60° C. then LiHMDS (1M in THF, 2.0 mL, 2.0 mmol) was added. After complete addition the mixture was removed from the cold bath and allowed to warm to about 0° C. The mixture was cooled to about −65° C. then picolinaldehyde (0.546 g, 5.10 mmol) was added and the temperature of the mixture was raised to about −5° C. After about 15 min the reaction was quenched with AcOH (1 mL) and stirred for about 15 min. The mixture was transferred to a separatory funnel with the aid of EtOAc (25 mL) and sat. aq. NaHCO3 (25 mL). The layers were separated then the aq. layer was extracted with EtOAc (25 mL). The combined organic layers were washed with brine (15 mL) then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-40% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield (E)-1-(4-fluorophenyl)-5-(pyridin-2-ylmethylene)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (0.519 g, 80%); LC/MS, method 3, Rt=2.54 min, MS m/z 384 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.56-8.54 (m, 1H), 8.23 (d, J=0.8 Hz, 1H), 7.89-7.83 (m, 3H), 7.69 (s, 1H), 7.59-7.51 (m, 1H), 7.53 (s, 1H), 7.51-7.41 (m, 2H), 7.22-7.20 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 2.99 (t, J=7.0 Hz, 2H), 2.38 (t, J=6.9 Hz, 2H), 2.09-1.95 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1F>>[ClH:14].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[O:11][CH:10]1[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]2[S:13][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Reactant: Fc1cccc(Cl)c1Cl
Product: Cc1cc2c(s1)CN(C)CCC2Oc1cccc(Cl)c1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[CH2:3][CH2:2]1.CO.[CH:13](I)([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH:13]([NH:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)([CH3:15])[CH3:14]
Reactant: Nc1ccc2c(c1)CCO2
Reactant: CC(C)I
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)Nc1ccc2c(c1)CCO2

Procedure:
To a solution of 40 g. of 2,3-dihydro-5-benzofuranamine in 200 ml. of methanol is added 23 ml. of isopropyl iodide and 35 ml. of triethylamine. The solution is refluxed for 55 hours and then concentrated in vacuo. The resultant oil is extracted several times with diethyl ether, the extract combined, filtered through Celite, and the ether removed in vacuo to obtain an oil of N-isopropyl-2,3-dihydro-5-benzofuranamine.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:35]=[CH:34][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([N:23]4C(=O)C5C(=CC=CC=5)C4=O)[CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O.NN>C(Cl)Cl.C(O)C>[CH:1]([O:4][C:5]1[CH:35]=[CH:34][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)N4C(=O)c5ccccc5C4=O)cc3)s2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of Example 1E (0.65 g, 0.0013 mol) in a mixture of methylene chloride (20 mL) and ethanol (2 mL) was added hydrazine monohydrate (0.66 g, 0.013 mol) and the mixture was refluxed under nitrogen for 2 hours. The white suspension was cooled to room temperature, concentrated, dissolved in methylene chloride, and filtered. The filtrate was concentrated to give 0.46 g of the title compound, which was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=5.88 Hz, 6 H) 139 (d, J=6.62 Hz, 3 H) 4.13 (q, J=6.62 Hz, 1 H) 4.44-4.62 (m, 1 H) 6.86-6.98 (m, 2 H) 7.16-7.25 (m, 2 H) 7.30-7.44 (m, 5 H). MS (ESI), m/z 337.7 (M−17)+.
Reaction SMILES: [B:1]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])OC(C)C.[Br:14][CH2:15]Br.C([Li])CCC.CS(O)(=O)=O.OC(C(O)(C)C)(C)C>CCCCCC.O1CCCC1>[Br:14][CH2:15][B:1]1[O:6][C:7]([CH3:8])([CH3:9])[C:11]([CH3:12])([CH3:13])[O:10]1
Reactant: BrCBr
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: CS(=O)(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OB(CBr)OC1(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.5 %

Procedure:
To the mixture of triisopropyl borate (20 g, 110 mmol), dibromomethane (8.6 ml, 120 mmol), and tetrahydrofuran (150 ml), n-butyllithium (a 2.6 M n-hexane solution, 39 ml, 100 mmol) was added dropwise at −78° C. (an outer temperature) for 1.5 hour, and then the reaction mixture was stirred at the same temperature for 1.5 hours. Subsequently, the obtained mixture was stirred at room temperature for 2 hours, and then was cooled to 0° C. (an outer temperature). To the reaction mixture, methanesulfonic acid (6.5 ml, 100 mmol) was added, and then the reaction mixture was stirred at room temperature for 1 hour. The obtained mixture was cooled to 0° C. (an outer temperature), pinacol (12 g, 100 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 1 hour. The solvents were evaporated under reduced pressure from the reaction mixture, and then the obtained residue was distilled under reduced pressure (74-76° C., 8 mmHg), thereby obtaining the entitled compound (16 g, 72 mmol, 68%).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([CH3:22])=[CH:20][S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:21]([CH3:22])=[CH:20][S:19][C:17]=2[N:18]=1
Reactant: Cc1csc2nc(Cl)nc(Cl)c12
Reactant: NCc1ccc2c(c1)OCO2
Product: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine gives 2-chloro-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:20]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].CCOC(C)=O>CS(C)=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:19])[N:24]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: CCCCNCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)C(=O)Nc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
In a dry 100 mL flask equipped with an N2 inlet adapter, a rubber septum and a magnetic stirring bar, was placed phenyl N-(4-acetylphenyl)carbamate (6.38 g, 25 mmol) in DMSO (50 mL). Dibutylamine (4.42 mL, 26.25 mmol) was slowly added to the mixture. The resulting solution was stirred at room temperature for 15 min, after which time EtOAc (250 mL) was added to the reaction mixture. The latter was washed successively with H2O (2×50 mL), aqueous 1N HCl (100 mL), H2O (100 mL), aqueous 1N NaOH (100 mL) and brine (100 mL), dried (MgSO4) and concentrated under reduced pressure to give a crude solid. The solid was triturated with Et2O/hexane to yield 6.98 g (96% yield) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:29]=[CH:28][C:8]([O:9][CH2:10][CH2:11][C@@H:12]2[CH2:14][C@@H:13]2[CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]3([CH3:27])[CH2:26][CH2:25]3)=[O:22])[CH2:17][CH2:16]2)=[CH:7][CH:6]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:27][C:24]1([O:23][C:21]([N:18]2[CH2:19][CH2:20][CH:15]([C@H:13]3[CH2:14][C@H:12]3[CH2:11][CH2:10][O:9][C:8]3[CH:28]=[CH:29][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:6][CH:7]=3)[CH2:16][CH2:17]2)=[O:22])[CH2:25][CH2:26]1
Reactant: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OC3(C)CC3)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methylcyclopropyl 4-((1R,2S)-2-{2-[4-(2-methoxy-2-oxoethyl)phenoxy]ethyl}cyclopropyl)piperidine-1-carboxylate (Example 53, Step A, 88 mg, 0.21 mmol) in a 1:1:1 mixture of THF/methanol/water (3 mL) was added lithium hydroxide (10.7 mg, 0.44 mmol) and the resulting mixture stirred for 2 h at RT. The mixture was neutralized via addition of 1N aqueous HCl until pH of 7 was obtained. The solution was then extracted with ethyl acetate (3×10 mL). The organics were combined, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to afford the title compound used for the next reaction without further purification. HPLC/MS; 1.22 min, 401 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1/[CH:16]=[N:17]/[C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][O:21][C:22]2=[O:27].[O-:28][CH2:29][CH3:30].[Na+].C(O)C>C(OCC)(=O)CC>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[C:29](=[O:28])[C:30]3[C:23]([C:22]([O:21][CH2:20][CH3:19])=[O:27])=[CH:24][CH:25]=[CH:26][C:18]=3[NH:17][CH:16]2[C:12]2[N:11]([CH3:10])[CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cn1ccnc1/C=N/c1cccc2c1COC2=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CCO
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
A mixture of compound 4-fluorobenzaldehyde (248 mg, 2 mmol) and (E)-4-((1-methyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one (482 mg, 2 mmol) in ethyl propionate (10 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (184 mg, 8 mmol) in ethanol (5 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 0.5 hr. The mixture was quenched with water (20 mL) and solvent was removed in vacuum. The residue was dissolved in water and extracted with ethyl acetate three times, washed with water and brine, and then concentrated to give the crude product, which was purified by column chromatography to obtain a yellow solid (200 mg, yield 25%). LC-MS (ESI) m/z: 394 (M+1)+
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=1.[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=1.C[Si](C)(C)Cl.[Cl-].[CH2:33]([Zn+])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CCOCC.C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=2)([NH2:26])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:23][CH:24]=1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: [Zn+]Cc1ccccc1
Reactant: N#Cc1ccc(Cl)cn1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
A dry 200 mL round bottomed flask was equipped a stirring bar and fitted to an adapter connected to the vacuum line. The flask was dried under vacuum and then purged several times with nitrogen. Under a stream of nitrogen, 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (972 mg, 4 mmoles) was added to the flask and dissolved in anhydrous ether (75 mL). The flask was fitted with a septum which was connected to the nitrogen line via a 16 gauge 1½ PrecisionGlide® needle. The stirring solution was cooled to −78° C. for 10 minutes, n-BuLi (1.6M in hexanes, 2.25 mL. 3.6 mmoles) was added drop wise. After 15 minutes, a solution of 5-chloro-2-cyanopyridine (552 mg, 4 mmoles) in anhydrous THF (5 mL) was added from a syringe. The reaction was stirred for 2 hours at −78° C. and trimethylchlorosilane (550 μL, 4 mmoles) was added. The reaction vessel was removed from the acetone/dry ice bath and the reaction was allowed to warm up to room temperature. After 30 minutes, the reaction vessel was cooled to −78° C., Benzylzinc chloride (0.5M in THF, 9.6 mL, 4.8 mmoles) was added and the reaction was allowed to slowly warm to room temperature for 3 h. The reaction was quenched with H2O (10 mL). The crude product was poured into 200 mL ethyl acetate in a 1000 mL separatory funnel. The light brown solution was washed with saturated aqueous NH4Cl (3×100 mL), then with water (2×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified on SCX column (10 g, high load, 0.65 mmole/g) to yield 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine 890 mg (56% yield). LC-MS (methanol) [M+1]=394.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:10]=1[C:11]1[C:12]([CH2:34][O:35][CH3:36])=[C:13]([CH:32]=O)[N:14]=[CH:15][C:16]=1[N:17]2[S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:38][OH:39]>C(O)C>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:10]=1[C:11]1[C:12]([CH2:34][O:35][CH3:36])=[C:13]([CH:32]=[N:38][OH:39])[N:14]=[CH:15][C:16]=1[N:17]2[S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:23])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCc1c(C=O)ncc2c1c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COCc1c(C=NO)ncc2c1c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1

Procedure:
500 mg of 5-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline-3-carbaldehyde is heated in 15 ml of ethanol to 70° C., combined with 84 mg of hydroxylamine hydrochloride in 10 ml of ethanol and heated for 1.5 hours to 70° C. Then the mixture is concentrated to 5 ml, poured on 40 ml of water, and suctioned off. The residue (450 mg) is utilized after drying in the subsequent stage without further purification.
Reaction SMILES: C(C1CC(C)(C)CCC1(O[SiH3])[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[NH:16][C:17]2=[O:22])(C)(C)C.C([SiH]([CH2:31][CH3:32])CC)C.[Bi](Br)(Br)Br.[C:37]1([CH2:43][CH:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(#N)C>[C:37]1([CH2:43][CH2:44][O:45][C@H:32]2[CH2:31][CH2:15][C@H:14]([N:16]3[C:15](=[O:23])[C:14]4[C:18](=[CH:19][CH:20]=[CH:21][CH:13]=4)[C:17]3=[O:22])[CH2:13][CH2:21]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC1(C)CCC(O[SiH3])(c2cccc3c2C(=O)NC3=O)C(C(C)(C)C)C1
Reactant: CC[SiH](CC)CC
Reactant: O=CCc1ccccc1
Agent: Br[Bi](Br)Br
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCCc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a solution of 10 g of ethyl phenylacetate in 100 mL of dry toluene cooled to −78° C. under nitrogen was added drop-wise 68 mL of 0.9 M di-isobutyl-aluminum hydride in toluene, keeping the internal temperature below −68° C. When the addition was complete, the reaction was quenched with 200 mL of 10% HCl, and extracted into 2×100 mL portions of ether. The combined ether layers were washed with 2×100 mL portions of 10% HCl, 100 mL of saturated sodium bicarbonate, diluted with 100 mL of toluene, and dried over magnesium sulfate. Concentration under reduced pressure gave 7.1 g of phenyl acetaldehyde as a volatile liquid. 1H NMR (400 MHz, CDCl3) 9.8 (s, 1H), 7.5-7.2 (m, 5H), 3.7 (s 2H). To a stirred mixture of 10 g of trans-2-(4-(tert-butyl-dimethyl-silyloxy-cyclohexyl)-isoindole-1,3-dione (Compound 2), 150 mL of anhydrous acetonitrile, 7 mL of triethylsilane and 0.7 g of bismuth tribromide was added 5 g of the freshly prepared phenyl acetaldehyde slowly keeping the temperature at or below 25° C. by means of a cooling bath. After stirring for 2 h, the reaction was quenched with 50 mL of saturated sodium bicarbonate and extracted with 3×150 mL portions of ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 2%-25% ethyl acetate in hexane gave 9.0 g of product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) 7.8 (m, 2H), 7.7 (m, 2H), 7.3-7.1 (m, 5H), 4.15 (m, 1H), 3.7 (t, 2H), 3.38 (m, 1H), 2.9 (t, 2H), 2.22 (d, 2H), 2.3 (dd, 2H), 2.18 (d, 2H), 1.78 (d, 2H), 1.4 (dd, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([CH:10]([C:15](=O)[CH3:16])[C:11]([O:13][CH3:14])=[O:12])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:21]O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:16][C:15]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([C:7]2[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:9][N:21]=1
Reactant: COC(=O)C(C(C)=O)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1c(C)noc1-c1ccc([N+](=O)[O-])cc1
Temperature: 115 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
Methyl 2-(4-nitrobenzoyl)-3-oxobutanoate (20.0 g, 75.47 mmol) was dissolved in acetic acid (70 mL), and followed by adding hydroxylamine hydrochloride (5.10 g, 73.27 mmol). The reaction was stirred at 115° C. for 2 hours. After cooling the reaction to the RT, 400 mL saturated NaHCO3 was added into the solution and extracted by ethyl acetate for 3 times. The combined organic layer was washed by brine and dried over Na2SO4, and removed under the vacuum. The crude product was further purified by flash chromatography using EA/Hexane=1:9 to give methyl 3-methyl-5-(4-nitrophenyl)isoxazole-4-carboxylate (16.4 g, 83% yield). MS m/z 263.1 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[F:17])(=[O:9])=[O:8].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)=[CH:12][C:11]=1[F:17])(=[O:9])=[O:8]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1F
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1F

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-2-fluorophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 4-trifluoromethylphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 26.4, 29.5, 43.2, 62.2, 115.4 (d, J 25.4), 123.2, 125.7, 129.4, 130.8 (d, J 22.2), 131.6, 137.6, 141.5 (d, J 6.8) and 159.3 (d, J 253.9).
Reaction SMILES: [F:1][C:2]([F:34])([CH2:31][CH2:32][CH3:33])[CH:3]([OH:30])[CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:11]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:10][C@H:9]([OH:19])[C@@H:8]1[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C.Cl>C(Cl)Cl>[F:34][C:2]([F:1])([CH2:31][CH2:32][CH3:33])[C:3](=[O:30])[CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:11]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:10][C:9](=[O:19])[C@@H:8]1[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: CCCC(F)(F)C(O)CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(F)(F)C(=O)CCC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Reaction time: 1 h

Procedure:
To the above solution was added a solution of methyl (Z)-7-[(1R)-(2R,3R,5S)-2-{5,5-difluoro-4(RS)-hydroxyoctyl}-5-hydroxy-3-tetra-hydropyranyloxycyclopentyl]hept-5-enoate (18) (0.244 g) in methylene chloride. The resultant mixture was warmed to -25° C. and stirred for 1 hour. Triethylamine (0.60 ml) was added thereto and the reaction mixture was stirred for additional 30 minutes, poured into 1N hydrochloric acid, and then worked up with the conventional procedure. The obtained product was subjected to silicagel column chromatography to give the titled compound (19).