Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][C:29]2[CH:30]=[C:31]([O:40][CH3:41])[CH:32]=[C:33]3[C:38]=2[N:37]=[CH:36][CH:35]=[C:34]3[CH3:39])=O)[CH2:17][CH2:16]1.[OH-].[Na+]>O1CCCC1.O>[CH3:41][O:40][C:31]1[CH:32]=[C:33]2[C:38](=[C:29]([NH:28][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][OH:11])[CH2:16][CH2:17]3)[CH:30]=1)[N:37]=[CH:36][CH:35]=[C:34]2[CH3:39]
Reactant: COc1cc(NC(=O)CCCCCN2CCN(CCCO)CC2)c2nccc(C)c2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NCCCCCCN2CCN(CCCO)CC2)c2nccc(C)c2c1
Yield: 49.2 %

Procedure:
A cold (-40°) slurry of 1.8 g (0.0135 mole) of anhydrous aluminum chloride in 60 ml of tetrahydrofuran was added to an equally cold suspension of 1.5 g (0.039 mole) of lithium aluminum hydride in 30 ml of tetrahydrofuran. The mixture was stirred and allowed to warm to -10°. To it was added dropwise a solution of 4.4 g (0.0103 mole) of 4-(3-hydroxypropyl)-N-(6-methoxy-4-methyl-8-quinolinyl)-1-piperazinehexanamide in 15 ml of tetrahydrofuran. The mixture was stirred for 2 hr, then treated with 7 ml of 30% sodium hydroxide solution and enough water to clarify the supernatant and finally filtered through supercell. The filtrate was concentrated in vacuo to remove tetrahydrofuran, diluted with dichloromethane, washed with water, dried, and concentrated to dryness. The residue was chromatographed over 200 g of silica gel with a 15:84:1 mixture of methanol:ethyl acetate-triethylamine. That portion of the eluant containing the product, Rf(silica--25:74:1 mixture of methanol:ethyl acetate:triethylamine)=0.33, was concentrated to dryness in vacuo. Recrystallization of the residue from 2-propanol afforded 2.1 g (49%) of the title compound, mp 100°-102°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].[CH3:10][C:11](=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:12]>C(OCC)C.[Cu]Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:10])[CH3:12])=[CH:3][CH:4]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Reactant: Clc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1 g (5.23 mmol) of 1-bromo-4-chlorobenzene in 2.5 ml of diethyl ether was added slowly to 254 mg (10.45 mmol) of magnesium turnings in 5 ml of diethyl ether. After the reaction had started, a further 1 g (5.23 mmol) of 1-bromo-4-chlorobenzene in 2.5 ml of diethyl ether was metered into the reaction mixture. The reaction mixture was stirred at room temperature for 30 min, 103 mg (1.05 mmol) of copper(I) chloride were added and the mixture was then cooled to −10° C. 2.09 g (10.45 mmol) of diethyl propan-2-ylidenemalonate were then slowly added dropwise. The reaction mixture was subsequently heated to reflux and stirred at this temperature for 3 h. 20 ml of ice-cold 1 M hydrochloric acid were then added very slowly. After separation of the phases, the aqueous phase was extracted three more times with diethyl ether. The combined organic phases were dried over magnesium sulphate and then concentrated to dryness. The crude product was purified by preparative HPLC (mobile phase methanol/water 70:30). This gave 800 mg of the title compound (25% of theory).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])=[CH:5][N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CCOC(C)=O>CN1C(=O)CCC1>[CH3:12][O:11][N:9]([CH3:10])[C:7]([C:6]1[C:2]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:3][N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:5]=1)=[O:8]
Reactant: COc1ccc(Cn2cc(C(=O)N(C)OC)c(Cl)n2)cc1
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc(Cn2cc(C(=O)N(C)OC)c(N3CCCC3)n2)cc1
Yield: 89.7 %

Procedure:
According to Scheme 14 Step 1: A solution of 3-chloro-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide (0.97 mmol, 300 mg) and pyrrolidine (14.5 mmol, 1.03 g) in NMP (10 mL) was stirred at 220° C. for 40 minutes under microwave heating. AcOEt was then added and the organic phase was washed with water. The organic layer was dried over MgSO4, was filtered and was concentrated. The crude compound was purified by flash chromatography with silica gel using cyclohexane/AcOEt (100:0 to 50:50) to yield N-methoxy-1-(4-methoxybenzyl)-N-methyl-3-(pyrrolidin-1-yl)-1H-pyrazole-4-carboxamide (0.87 mmol, 300 mg, 90%) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Reactant: O[C@@H]1CCNC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CC[C@@H](O)C5)c34)cc2C)cn1
Yield: 15 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (R)-3-pyrrolidinol to give the title compound in 15% yield; NMR Spectrum: 1.50-1.55 (m, 1H), 1.91-1.96 (m, 1H), 2.19 (s, 3H), 2.41-2.44 (m, 1H), 2.44 (s, 3H), 2.55 (dd, 1H), 2.68 (dd, 1H), 2.82-2.90 (m, 3H), 4.17 (br s, 1H), 4.41 (t, 2H), 4.70 (br s, 1H), 6.95 (d, 1H), 7.17-7.25 (m, 2H), 7.62-7.65 (m, 2H), 8.16 (s, 1H), 8.30 (s, 1H), 8.34 (s, 1H); Mass Spectrum: 462 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].B.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])cc1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
2-Methyl-5-nitrobenzoic acid (2.00 g, 11.0 mmol) was warmed under nitrogen, dissolved in anhydrous THF (25 mL), and treated with a 1N solution of borane in THF (16.5 mL). After stirring 18 hours at ambient temperature the reaction was quenched with a solution of potassium carbonate (1.8 g, 13 mmol) in water (50 mL), and the THF removed in vacuo. The remaining aqueous solution was extracted with DCM, and the organic layer washed with pH 7 buffer and brine, dried over sodium sulfate, and filtered. The evaporated filtrate gave the title compound as a pale yellow solid (1.76 g, 95%). 1H NMR (300 MHz, CDCl3) δ 8.29 (d, 1H, J=2.5 Hz), 8.04 (dd, 1H, J=8.3 Hz, 2.5 Hz), 7.31 (d, 1H, J=8.31 Hz), 4.77 (d, 2H, J=5.5 Hz), 2.41 (s, 3H), 2.09 (t, 1H, J=5.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([CH2:11][CH2:12][OH:13])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)N([O])C(C)(C)CCC1.P([O-])([O-])([O-])=[O:27].[Na+].[Na+].[Na+].Cl[O-].[Na+].Cl([O-])=O.[Na+].[OH-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[C:1]([O:5][C:6]([NH:7][C:8]1([CH2:11][C:12]([OH:27])=[O:13])[CH2:9][CH2:10]1)=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(CCO)CC1
Reactant: O=P([O-])([O-])[O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(CC(=O)O)CC1
Temperature: 35 °C
Reaction time: 55 h

Procedure:
To a solution in acetonitrile (275 mL) of the compound (11.1 g) obtained in step (4) above and 2,2,6,6-tetramethylpiperidin-1-oxyl free radical (602 mg), a sodium phosphate buffer (0.67 mol/L, pH 6.7, 206 mL) was added. After heating to 35° C., an aqueous solution of sodium hypochlorite (0.265%, 32.6 mL) and an aqueous solution of sodium chlorite (14.7%, 110 mL) were added simultaneously over a period of 2 hours and the mixture was stirred at that temperature for 55 hours. The mixture was cooled to room temperature and after adding water (400 mL), it was rendered basic with a solution of 2 mol/L sodium hydroxide in water. The reaction mixture was poured into an aqueous solution of sodium thiosulfate (5.75%, 291 mL) at 0° C. After washing with diethyl ether (750 mL), the aqueous layer was added to 2 mol/L hydrochloric acid (140 mL) for pH adjustment to between 2 and 3. The mixture was extracted with diethyl ether and ethyl acetate and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was crystallized with a liquid mixture of n-hexane/ethyl acetate to give {1-[(tert-butoxycarbonyl)amino]cyclopropyl}acetic acid as a colorless solid (9.45 g).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]([NH:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][C@H:2]1[C@H:7]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: C[C@H]1[C@H](Nc2ncc(C(F)(F)F)cn2)CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1NCCC[C@H]1Nc1ncc(C(F)(F)F)cn1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To the title compound of step A (1.5 g) in DCM (12 mL) was added TFA (4 mL). After 1 h, the reaction was diluted with saturated Na2CO3 (aq) and extracted with DCM. The organic layers were dried (MgSO4) and concentrated to give the title compound (1.03 g) that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([C:22]3[N:23](S(C)(=O)=O)[CH2:24][N:25]=[CH:26][CH:27]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:13](=[O:14])[N:6]12)=[O:4].[C:32]1([OH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([O:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:13](=[O:14])[N:6]12)=[O:4]
Reactant: Oc1ccccc1
Reactant: COC(=O)C1CCCn2c(C3=CC=NCN3S(C)(=O)=O)c(-c3ccc(F)cc3)c(=O)n21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCCn2c(-c3ccnc(Oc4ccccc4)n3)c(-c3ccc(F)cc3)c(=O)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 2-(4fluorophenyl)-1-(3-methanesulfonyl-pyrimidin-4-yl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester, 21, (0.033 g, 0.074 mmol) in THF (3 mL) is added phenol and NaH (0.009 g, 0.22 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction is quenched by the addition of 1 N HCl (20 mL) and the solution is extracted with ethyl acetate (3×25 mL). The organic phases are combined, washed with brine, dried, and concentrated in vacuo to afford the crude product which is purified over silica (hexanes/ethyl acetate 1:3) to afford 0.012 g (35% yield) of the desired product as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J=4.6 Hz 1 H), 7.59-7.63 (m, 2 H), 7.40-7.45 (m, 3 H), 7.28-7.30 (m, 1 H), 7.18 (d, J=8.4 Hz, 2 H), 7.03-7.08 (m, 2 H), 4.50-4.56 (m, 1 H), 3.99-4.04 (m, 1 H), 3.86 (s, 1 H), 3.01-3.10 (m, 1 H), 2.33-2.41 (m, 1 H), 1.86 (brs, 2 H), 1.64 (brs, 3 H); ESI/MS: 461 (M+H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([NH2:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([C:30]1[N:38]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:29]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(Cc1ccccc1)=NO
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cc3ccccc3)no2)C1

Procedure:
250 mg (0.65 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid and 107 mg (0.71 mmol) of N′-hydroxy-2-phenylethanimidamide were reacted according to the General Method 1. Yield: 44 mg (14% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]4[O:23][CH:22]=[N:21][CH:20]=4)=[CH:17][N:16]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pt]>[O:23]1[C:19]([C:18]2[C:11]3[C:10]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[NH2:1])=[N:15][CH:14]=[N:13][C:12]=3[N:16]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:17]=2)=[CH:20][N:21]=[CH:22]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cnco2)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Agent: [Pt]
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(-c2cnco2)c2c(-c3cccc(N)c3)ncnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5-(4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)oxazole (175 mg, 0.400 mmol) in methanol (5 mL), was added Pt/C (200 mg, 1 wt. % on carbon, Vanadium doped). The atmosphere was then purged with hydrogen gas, and the resulting solution was stirred under hydrogen atmosphere (1 atm) for 3 hours at 25° C. The reaction was filtered and the filtrate concentrated in vacuo to afford crude 3-(5-(oxazol-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline as a solid. LRMS (ESI) calc'd for C21H26N5O2Si [M+H]+: 408, found 408.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([S:15]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])=[O:16])=[CH:10][CH:9]=[CH:8]2)(=O)C.C(O)CC.[ClH:30]>O>[ClH:30].[NH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([S:15]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:17])=[O:16])=[CH:10][CH:9]=[CH:8]2
Reactant: CC(=O)Nc1ccc2c(S(=O)(=O)NCc3ccccc3)cccc2c1
Agent: Cl
Solvent: O
Solvent: CCCO
Product: Nc1ccc2c(S(=O)(=O)NCc3ccccc3)cccc2c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
6-Acetylamino-N-benzylnaphthalene-1-sulfonamide (compound No. 7-1; 188 mg, 0.530 mmol) was suspended to a mixed solvent of 1-propanol (3.0 ml) and water (1.5 ml). Concentrated hydrochloric acid (1.5 ml) was added to the suspension and the mixture was refluxed for 1 hour. After cooling to room temperature, the separated crystal was collected and washed with 1-propanol and isopropyl ether to give the title compound as a light yellow crystal (118 mg, 63.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][N+:19]([O-])=O)[CH2:9][P:10]([CH3:17])(=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:19][CH2:18][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][P:10]([CH3:17])(=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COP(C)(=O)CC(C[N+](=O)[O-])c1ccc(F)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)COP(C)(=O)CC(CN)c1ccc(F)cc1

Procedure:
A solution of 11.6 g of isobutyl 2-(4-fluorophenyl)-3-nitro-propyl(methyl)phosphinate in 100 ml of ethanol is added to 114 g of a 8% solution of ammonia in ethanol. To this are added 9 ml of Raney Nickel slurry and the resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give isobutyl 3-amino-2-(4-fluorophenyl)-propyl-(methyl)phosphinate as a viscous oil, 31P N.M.R. spectrum: δ=+54.0 and +53.4 ppm (CDCl3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.[C:8]([NH:15][C@H:16]([C:21](O)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:8]([NH:15][C@H:16]([C:21]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:22])[CH2:17][CH:18]([CH3:19])[CH3:20])([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9]
Reactant: C1COCCN1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as Working Example 2, morpholine (1.76 ml) was condensed with Boc-L-leucine monohydrate (5.00 g) to give Boc-L-leucylmorpholine (5.76 g) as a colorless oily product (yield 95%). A portion (2.00 g) of this product was taken, and the Boc group was deprotected by using TFA. The resultant compound was treated in substantially the same manner as Working Example 8 to afford L-leucylmorpholine hydrochloride (1.52 g) as a white powdery product (yield 96%). A portion (807 mg) of this product was condensed, in substantially the same manner as Working Example 8, with (2S,3S)-ethyl hydrogen N-Z-aziridine-2,3-dicarboxylate (Compound 1, 100 g) to afford the above-titled compound (Compound 17; 1.06 g) as a white powdery product (yield 65%).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1(=[O:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1.[Li]>C1COCC1.[I-].[Zn+2].[I-]>[OH:17][C:7]1([CH2:5][NH2:6])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCCc2ccccc21
Agent: [I-]
Agent: [Li]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: NCC1(O)CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
Five and one-half g of trimethylsilylcyanide is added to a mixture of 7.3 g of 1-tetralone and 10 mg of zinc iodide. The mixture is stirred at room temperature overnight. It is dissolved in 25 ml dry THF and slowly added to a suspension of 2.3 g of lithium aluminumhydride in 40 ml of THF. Reaction is refluxed for three hours and upon cooling, carefully quenched with water. Precipitate is filtered and aqueous solution is diluted with 100 ml 1N NaOH. It was extracted with ether (3×100 ml), dried over anhydrous MgSO4, filtered, and ether evaporated yielding an oil which solidifies upon standing giving 6.4 g (73%) of (1-hydroxy-1,2,3,4-tetrahydronaphthyl)methylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]#[N:29])[CH2:24][CH2:23]3)[O:19][C:16]2=[CH:17][N:18]=1.Cl.[NH2:31][OH:32]>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([NH:31][OH:32])=[NH:29])[CH2:24][CH2:23]3)[O:19][C:16]2=[CH:17][N:18]=1
Reactant: NO
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)c(F)c1
Agent: Cl
Product: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)c(F)c1

Procedure:
The title compound is prepared from 4-[5-(2-fluoro-4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and hydroxylamine hydrochloride following a procedure analogous to that described for Intermediate 11. LC (method 6): tR=0.90 min; Mass spectrum (ESI+): m/z=449 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[F:17])[CH:10]([C:18]3[C:27]([OH:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[CH:19]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[F:17])[C:10]3([C:18]4[C:27](=[CH:26][C:21]5[O:22][CH2:23][CH2:24][O:25][C:20]=5[CH:19]=4)[O:28][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2cccc(F)c2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2c(F)cccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-7-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (55%) as a colorless solid: MS (ES+) m/z 479.9 (M+1).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][Si:14](C#C)([CH3:16])[CH3:15]>C(N(CC)CC)C.[Cu](I)I.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>[CH3:13][Si:14]([CH3:16])([CH3:15])[CH:10]=[CH:9][O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C=COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.9 %

Procedure:
A solution of ethyl 4-iodo-benzoate (55.2 g, 0.2 mol) in triethylamine (800 mL) was purged with argon. Copper iodide (1.1 g) and bis(triphenylphosphine)palladium(II) dichloride (7.0 g) were then added and the mixture was purged again. Trimethylsilylacetylene (42 mL, 0.3 mol) was then added at 0° C. for 30 minutes and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated, triturated in hexane and filtered. The filtrate was concentrated to give ethyl 4-(2-trimethylsilylethen-1-yl-benzoate (51.5 g, 100% crude) as a black oil.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([C:24]2[CH:28]=[C:27]([C:29]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[NH:30])[S:26][C:25]=2[S:39][CH3:40])(=[O:23])=[O:22])[CH:16]=1)=[O:6].[OH-].[Na+].[Li+].[OH-]>CO>[C:35]([O:34][C:32]([NH:31][C:29](=[NH:30])[C:27]1[S:26][C:25]([S:39][CH3:40])=[C:24]([S:21]([C:17]2[CH:16]=[C:15]([C:9]3[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:8]=3[NH:7][C:5](=[O:6])[CH2:4][C:3]([OH:41])=[O:2])[CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:22])[CH:28]=1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)CC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CC(=O)O)c1
Reaction time: 2 h

Procedure:
N-{3′-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-malonamic acid methyl ester (20 mg, 0.03 mmol, Example 132: step a) and NaOH (1M, 90 μL, 0.09 mmol) were dissolved into MeOH (1.5 mL). The reaction was stirred for 2 hours. LiOH (1.0 mg, 0.05 mmol) was added and the reaction was stirred at RT overnight. The solvents were removed in vacuo and used with out further purification in the next step. ESI-MS (m/z): Calcd. for C27H29N3O7S3: 604.1 (M+1); found: 504.0 (loss of boc).