Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][C:16]([O:21][CH2:22][C:23](O)=[O:24])=[CH:17][C:18]=3[CH3:20])[N:13]([CH3:26])[N:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CCN(CC)CC.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([C@@H:53]([NH2:55])[CH3:54])=[CH:49][CH:48]=1>C(Cl)Cl.O.C(Cl)CCl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][C:16]([O:21][CH2:22][C:23]([NH:55][C@H:53]([C:50]4[CH:51]=[CH:52][C:47]([O:46][CH3:45])=[CH:48][CH:49]=4)[CH3:54])=[O:24])=[CH:17][C:18]=3[CH3:20])[N:13]([CH3:26])[N:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: COc1cc(OC)cc(-c2nn(C)c3nc(OCC(=O)O)cc(C)c23)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc([C@H](C)NC(=O)COc2cc(C)c3c(-c4cc(OC)cc(OC)c4)nn(C)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.4 %

Procedure:
To a solution of [3-(3,5-Dimethoxy-phenyl)-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy]-acetic acid (building block A1, 100 mg, 0.28 mmol) in CH2Cl2 were added HOBt×H2O (64 mg, 0.42 mmol), EDC×HCl (80 mg, 0.42 mmol) and NEt3 (0.12 ml, 0.84 mmol). After stirring at rt for 5 min, (S)-1-(4-methoxyphenyl)ethanamine (64 mg, 0.42 mmol) was added and stirring continued for 18 h. Then, water was added and the mixture extracted 3 times with DCM. The organic phases were dried over Na2SO4 and the solvent removed under reduced pressure. Purification by reverse phase HPLC (Sunfire C18 OBD column) followed by liberation of the free base (SPE cartridge SCX-1, eluent 7M NH3 in methanol) yielded the title compound (17 mg, 12%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.48 (d, 1H), 7.21 (d, 2H), 6.82 (d, 2H), 6.70 (s, 1H), 6.58 (s, 1H), 5.00-4.88 (m, 1H), 4.87 (d, 1H), 4.83 (d, 1H), 3.85 (s, 3H), 3.78 (s, 6H), 3.70 (s, 3H), 2.37 (s, 3H), 1.37 (d, 3H); UPLC-MS RtJ=1.14 min; [M+H]+=491.2]
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6]Br.[OH:8][C:9]([C:18]([F:21])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[C:10](OC)=[O:11].[Cl-].[NH4+]>O1CCCC1>[OH:8][C:9]([C:10]1([OH:11])[CH2:6][CH2:5][CH2:4][CH2:3]1)([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15]
Reactant: COC(=O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: BrCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(C(O)(C(F)(F)F)C(F)(F)F)CCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A flask was charged with 9.7 g of magnesium and 200 ml of tetrahydrofuran, to which 43.2 g of 1,4-dibromobutane was added dropwise at 60° C. After the completion of dropwise addition, the contents were stirred for one hour at 60° C., and 22.6 g of methyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate was added dropwise below 50° C. The mixture was stirred for one hour at room temperature, after which an ammonium chloride aqueous solution was added. This was followed by ordinary work-up and vacuum distillation, obtaining 22.4 g of the target compound (yield 89%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[CH2:17]([O:20]/[N:21]=[C:22](/[C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:25]=1[CH3:32])\[CH3:23])[CH2:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:30][C:28]1[CH:29]=[C:24](/[C:22](=[N:21]/[O:20][CH2:17][CH2:18][CH3:19])/[CH3:23])[C:25]([CH3:32])=[CH:26][C:27]=1[O:31][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCCO/N=C(\C)c1cc(C)c(O)cc1C
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCO/N=C(\C)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
To a solution of (E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (1.0 g, 3.5 mmol) and (E)-1-(4-hydroxy-2,5-dimethylphenyl)ethanone propyloxime (0.6 g, 4.2 mmol) obtained in Step 5 in 20 mL of acetonitrile (CH3CN) was added cesium carbonate (1.7 g, 5.2 mmol), followed by stirring at room temperature for 3 hours. The reaction solvent was removed by concentration in a vacuum. The residue was stirred in water (20 mL) and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to remove the solvent. The concentrate was purified through silica gel chromatography to afford (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(propoxyimino)ethyl)phenoxy)methyl)phenyl)-3-methoxyacrylate as a white oil (0.88 g, yield 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([O:29]CC)=[O:28].OC1(C2C=CC=CC=2OC)C2C(=CC=CC=2)C(C2C=CC3OCOC=3C=2)=C1C(OCC)=O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccccc1OC
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
Ethyl (RS)-1-(2-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (100 mg, 0.23 mmol) in CH2Cl2 (5 ml) was added triethylsilane (32 mg, 0.28 mmol), followed by boron trifluoride etherate (0.13 ml, 1.05 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to provide the title compound (91 mg, 96%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[O:11][N:10]=[CH:9][C:8]=1[C:12](=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH:8]([C:12](=[O:20])[NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:9]#[N:10]
Reactant: Cn1cccc1-c1oncc1C(=O)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1

Procedure:
The solution of 0.3 g of 5-(1-methyl-2-pyrrolyl)-4-phenylcarbamoylisoxazole, 10 ml of 5% aqueous sodium hydroxide and the minimum amount of ethanol, is warmed on the steam cone for 5 minutes. It is filtered, acidified with 5 N hydrochloric acid and the crystals formed collected. They are washed with water and triturated with methanol to give the 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 170°-172°; it is identical with that prepared as described previously, i.e. Examples 1, 6, 9 or 10.
Reaction SMILES: CCOCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Li]CCCC.[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>[Cl-].[Na+].O>[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:20]=1
Reactant: Brc1ccccc1
Reactant: Cc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1ccnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 36 %

Procedure:
A two necked round-bottom flask (250 mL) containing a stir bar fitted with a reflux condenser was evacuated and purged with nitrogen gas. Dry ether (50 mL) and bromobenzene (0.0191 mol, 3.0 g) were added to the flask followed by the slow addition of n-BuLi (0.0229 mol, 9.17 mL) via a syringe pump. The reaction mixture was stirred at room temperature for 30-40 min and then 4-methyl pyridine (0.0191 mol, 1.779 g) was slowly added. The reaction mixture was then refluxed for 2 to 3 hr. The reaction mixture was then cooled to room temperature, diluted with an aqueous brine solution and extracted with ether (3×30 mL). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using hexanes/EA as eluent. The desired 4-methyl-2-phenylpyridine was obtained. (1.15 g; 36% yield).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[CH:1]1([NH:12][C:11]2[CH:13]=[CH:14][C:8]([F:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])c1cc(NC2CCCC2)ccc1F
Reaction time: 0.5 h

Procedure:
6.7 g (0.08 mol) of cyclopentanone, 12.5 g (0.08 mol) of 4-fluoro-3-nitro-aniline and 30 ml titanium-IV-isopropoxide (0.1 mol) are stirred for 30 minutes at 40° C. and for one hour at ambient temperature. After the addition of 150 ml ethanol the reaction mixture is stirred for 30 minutes and then combined batchwise with 2.4 g (0.066 mol) of sodium borohydride. After 4 hours the reaction mixture is poured onto ice water and combined with ethyl acetate. After filtration the organic phase is separated off, dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (9:1). The desired fractions are combined and concentrated by evaporation.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[NH:4][N:3]=1.[CH2:11](I)[CH3:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH2:11][CH3:12])[N:3]=1
Reactant: Brc1n[nH]c2cccnc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(Br)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3-bromo-1H-pyrazolo[4,3-b]pyridine (2.22 g), EtI (1.08 mL), and K2CO3 (2.32 g) in DMF (15 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue purified by basic silica gel column chromatography (hexane/AcOEt) and crystallized from hexane/AcOEt to give the title compound (1.90 g).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10])([CH3:5])[CH3:4])#[N:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:28]=2)[CH:25]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:15][C:16]1[CH:37]=[CH:36][CH:35]=[C:18]([O:19][C:20]2[CH:21]=[CH:22][C:23]3[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]4[CH2:33][CH2:34]4)=[O:31])[N:28]=3)[CH:25]=2)[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
3-(1-Cyano-1-methylethyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (5.0 mL) was added N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.485 mmol), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), and the obtained oil was triturated with ethyl acetate, toluene and diisopropyl ether to give the title compound (117 mg, 42%) as a colorless powder.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][CH2:15][CH:16]=O)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:16][CH2:15][CH2:14][C:12]3[O:11][N:10]=[C:9]([CH:8]=[CH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:13]=3)[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(C=Cc2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C(=Cc1cc(CCCN2CCN(c3ccccc3)CC2)on1)c1ccccc1
Yield: 48.2 %

Procedure:
About 2 min after dissolving 3-[3-(2-phenylvinyl)isoxazol-5-yl]propanal (20 mg, 0.09 mmol) and 1-phenylpiperazine (13.4, 0.09 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (56 mg, 0.26 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 22 hr and followed the same processes as in Example 1 to obtain 16.2 mg (49.3%) of the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH:8]=[CH:9][C:10]2[C:16]3[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:25])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.[Ni]>[NH2:1][C:4]1[CH:27]=[CH:26][C:7]([CH:8]=[CH:9][C:10]2[C:16]3[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:25])[NH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: COc1cc2c(cc1OC)C(C=Cc1ccc([N+](=O)[O-])cc1)=NNC(C)C2
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OC)C(C=Cc1ccc(N)cc1)=NNC(C)C2
Reaction time: 1 h
Yield: 85.6 %

Procedure:
6.95 g (18.9 mmoles) of 1-(4-nitrostyryl)-4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine prepared according to Example 25 are suspended in 170 ml of methanol, 0.7 g of dry (corresponding to about 1.4 g of wet) Raney nickel catalyst and 3.3 ml (66 mmoles) of 100% hydrazine hydrate are added to it and the reaction mixture is stirred for 1 hour. A solution is obtained, and in the beginning the inner temperature rises to 40-45° C. The catalyst is filtered off, washed three times with 15 ml each of methanol, the filtrate is evaporated in vacuo, the crude product is conveyed to a filter with 80 ml of water, washed three times with 15 ml each of water and dried. Thus 5.46 g of product are obtained. In order to purify the crude product it is recrystallized from 25 ml of 50% ethanol. Thus 4.21 g (66.0%) of the desired product are obtained. M.p.: 152-154° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2C[N:16](C)[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C=CC(C2C=NN(CCCO)C=2)=CC=1[C:53](NOC)=[O:54]>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]([C:15](=[O:20])[NH:16][O:54][CH3:53])[CH:18]=2)[CH:7]=[N:6]1
Reactant: CONC(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)NOC)n2)c(OC)c1)OCC
Yield: 28 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 2-amino-5-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methoxybenzamide (Compound 26C, 169 mg, 583 μmol) to afford 114 mg of the title compound (28%). 1H NMR (400 MHz, CD3OD) δ=8.33 (s, 1H), 8.14 (s, 1H), 7.96 (d, J=0.5 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.71 (dd, J=2.2, 8.7 Hz, 1H), 7.00 (t, J=2.2 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 3.99-4.08 (m, 4H), 3.90 (s, 3H), 3.81 (s, 3H), 3.58 (t, J=6.1 Hz, 2H), 3.24 (d, J=21.0 Hz, 2H), 2.10 (quin. J=6.6 Hz, 2H), 1.24 (t, J=7.1 Hz, 6H). MS (ESI): m/z=708.72 [M+H]+. UPLC: tR=1.13 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][Br:17]
Reactant: Cc1cc(Cl)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)c(CBr)c1
Yield: 45 %

Procedure:
1-bromo-2-(bromomethyl)-4-chlorobenzene was prepared according to literature precedent (J. Am. Chem. Soc. 2002, 124 (7), 1354): a suspension of 1-bromo-2-methyl-4-chlorobenzene (1 eq), NBS (1 eq) and benzoyl peroxide (0.004 eq) in CCl4 (0.7 M) was heated at reflux for 4 h. The reaction was then filtered whilst hot and the volatiles reduced in vacuo. PE was added, and the resultant precipitate filtered off and dried in vacuo to afford the title compound (45%).
Reaction SMILES: C[O:2][C:3](=[O:48])[CH:4]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:31]([NH2:40])=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:25]=1)[O:5][P:6]([CH:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH:10]([CH3:12])[CH3:11])([OH:8])=[O:7].[Li+].[OH-].OS([O-])(=O)=O.[Na+]>CO.O>[C:44]([O:43][C:41]([N:30]([C:26]1[CH:25]=[C:24]([CH:4]([O:5][P:6]([CH:9]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH:10]([CH3:12])[CH3:11])([OH:8])=[O:7])[C:3]([OH:48])=[O:2])[CH:29]=[CH:28][CH:27]=1)[C:31]([NH2:40])=[N:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[O:42])([CH3:46])([CH3:47])[CH3:45]
Reactant: COC(=O)C(OP(=O)(O)C(NC(=O)OCc1ccccc1)C(C)C)c1cccc(N(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)c1
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)C(NC(=O)OCc1ccccc1)P(=O)(O)OC(C(=O)O)c1cccc(N(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)c1
Reaction time: 2 h

Procedure:
To a slurry of 2-(3-(N,N′-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester in 10 mL of MeOH and 5 mL of H2O was added LiOH (411.9 mg, 9.82 mmol). After stirring the cloudy yellow solution for 2 hours, the reaction was acidified to pH 2 with 1M NaHSO4 and extracted with CH2Cl2 (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 2-(3-(N,N′-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)-(hydroxy)phosphinoyloxy)ethanoic acid as a yellow oil that was used without further purification.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2][C:3]#[CH:4].Br[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>CCN(CC)CC.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:19][N:18]1[C:14]([C:4]#[C:3][CH2:2][CH2:1][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[N:17]1
Reactant: Cn1ncc([N+](=O)[O-])c1Br
Reactant: C#CCCNC(=O)OC(C)(C)C
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1ncc([N+](=O)[O-])c1C#CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.5 %

Procedure:
A solution of tert-butyl 3-butyn-1-ylcarbamate (123 mg, 0.728 mmol) in NEt3 (4 mL) was treated with 5-bromo-1-methyl-4-nitro-1H-pyrazole (100 mg, 0.485 mmol) and copper(I) bromide dimethyl sulfide complex (10 mg, 0.049 mmol). The mixture was degassed four times by evacuating and refilling with nitrogen gas before tetrakis(triphenylphosphine)-palladium(0) (28 mg, 0.024 mmol) was added. Degassing was repeated twice and the reaction mixture was stirred at room temperature for 20 hr. More tert-butyl 3-butyn-1-ylcarbamate (123 mg, 0.728 mmol) and copper(I) bromide dimethyl sulfide complex (10 mg, 0.049 mmol) were added and the mixture was degassed three times. Tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol) was added and the reaction mixture was stirred at room temperature for 48 hr. The mixture was diluted with EtOAc (100 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (30-40% EtOAc/isohexane) gave tert-butyl 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)but-3-ynylcarbamate as a yellow oil (112 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 5.03 (s, 1H), 3.94 (s, 3H), 3.46 (q, J=6.4 Hz, 2H), 2.79 (t, J=6.4 Hz, 2H), 1.67-1.27 (m, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:12](O)[CH2:13][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.CS(Cl)(=O)=O.C(N(CC)CC)C>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8](/[CH:12]=[CH:13]/[C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1
Reactant: CC(=O)CC(O)c1cccc(-c2ccsc2)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)/C=C/c1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resulting alcohol compound was dissolved in 2 ml of ethyl acetate, and 207 mg of methanesulfonyl chloride and 366 mg of triethylamine were added. The mixture was stirred overnight at room temperature, and then the precipitate was removed by filtration. The filtrate was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=5/1] to give 327 mg of the captioned compound as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[CH3:1][O:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][N:5]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:4]1
Reactant: COC(=O)CBr
Reactant: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCNC1
Product: COC(=O)CN1CCC(OC)(c2cccc(OCc3ccc4ccccc4c3)c2)C1

Procedure:
Using an analogous procedure to that described in Example 3, 3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]pyrrolidine was reacted with methyl bromoacetate to give 3-methoxy-1-(methoxycarbonylmethyl)-3-[3-(naphth-2-ylmethoxy)phenyl]pyrrolidine in 33Z yield, m.p. 78°-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([NH2:14])[CH3:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([NH:14][CH2:12][CH3:13])=[O:6]
Reactant: CCN
Reactant: O=C(O)c1cc(O)ccc1Cl
Product: CCNC(=O)c1cc(O)ccc1Cl

Procedure:
The title compound was prepared from 2-chloro-5-hydroxybenzoic acid and ethylamine, using a method similar to that used for preparation 52, as a colourless solid. 1HNMR (400 MHz, CDCl3) δ: 1.22 (3H, t), 3.42–3.49 (2H, m), 6.48–6.52 (1H, m), 6.80 (1H, dd), 7.13 (1H, d), 7.38 (1H, d); LRMS ESI m/z 200 [M+H]+