Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[C:19]1[N:24]=[CH:23][C:22]([OH:25])=[CH:21][N:20]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:19]2[N:24]=[CH:23][C:22]([OH:25])=[CH:21][N:20]=2)[CH2:16][CH2:17]1
Reactant: c1ccc2cc(CN3CCNCC3)ccc2c1
Reactant: Oc1cnc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cnc(N2CCN(Cc3ccc4ccccc4c3)CC2)nc1

Procedure:
To a mixture of 4.50 g. of 1-(β-napthylmethyl)piperazine(as prepared in Example 7), 2.5 g. of 2-chloro-5-hydroxypyrimidine in 30 ml. of dimethylformamide is added 2.0 g. of sodium bicarbonate and the mixture is refluxed for six hours. The mixture is cooled and filtered and the filtrate concentrated to a small volume in vacuo. The concentrate is diluted with 100 ml. of water and the insoluble material is washed with water and hexane to yield 1-(β-napthylmethyl)-4-(5-hydroxy-2-pyrimidinyl)piperazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:10]([O:13]C(=O)C)[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)C(C)C.[CH2:30]1[CH2:34]O[CH2:32][CH2:31]1>CCOCC.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:10]([OH:13])[C@@H:11]([OH:12])[CH:30]([CH3:34])[CH2:31][CH3:32])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)O[C@@H](C=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: CC(C)C[Mg]Cl
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CCC(C)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 2 h

Procedure:
The title compound of Step 1 was dissolved under nitrogen in 100 mL of dry THF and cooled to -70° C. To this solution was added 13 mL (26 mmol) of a 2.0M solution of isobutylmagnesium chloride in ether and the stirred mixture was allowed to warm to room temperature and stir for 2 hrs. After decomposition with MeOH/H2O the mixture was diluted with ether, washed with saturated NH4Cl solution twice and dried with magnesium sulfate and the solvents evaporated under vacuum. The residue was allowed to stand overnight in 80% MeOH-H2O containing excess ammonium hydroxide. The MeOH was stripped off and the mixture was extracted with ether. These extracts were combined, washed with water, dilute KHSO4, then dried and evaporated to give 2.36 g of a yellow glass which crystallized from 50 mL of pentane on standing overnight. The yellow-white powder obtained was recrystallized from ether-hexane and furnished the title compound (0.41 g) as white, hairy needles, mp 134°-136° C., Rf (ether): single spot, 0.6. By chromatography of the mother liquors and crystallization of the appropriate fractions, an additional 0.22 g of product, mp 138°-139° C., was obtained. Anal: Calcd. for C19H31NO4 : C, 67.62; H, 9.26; N, 4.15. Found: C, 67.51; H, 9.43; N, 4.24.
Reaction SMILES: C1(O[C:8](=[O:18])[NH:9][C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:17][O:16][C:11]1[C:10]([NH:9][C:8]([N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1ncccc1NC(=O)Oc1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Product: COc1ncccc1NC(=O)N1CCN(c2ccccc2)CC1
Yield: 88 %

Procedure:
Phenyl-N-(2-methoxypyridin-3-yl)carbamate and 1-phenylpiperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[NH:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[OH:31][C@H:32]([CH2:53][NH:54][CH2:55][C:56]1[CH:57]=[N:58][CH:59]=[C:60]([CH:62]([CH3:64])[CH3:63])[CH:61]=1)[C@@H:33]([NH:41][C:42]([C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47](O)=[O:48])=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCN=C=NCCCN(C)C.Cl.O1C2C=CC=CC=2C=C1CNC(=O)OC(C)(C)C>C(Cl)Cl.O.CN(C=O)C>[CH3:1][N:2]([CH3:11])[NH:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:47]([C:46]1[CH:45]=[C:44]([CH:52]=[CH:51][CH:50]=1)[C:42]([NH:41][C@H:33]([C@H:32]([OH:31])[CH2:53][NH:54][CH2:55][C:56]1[CH:57]=[N:58][CH:59]=[C:60]([CH:62]([CH3:64])[CH3:63])[CH:61]=1)[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:43])=[O:48])=[O:5]
Reactant: CN(C)NC(=O)[C@H]1CCCN1
Reactant: CC(C)c1cncc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(C(=O)O)c2)c1
Agent: CC(C)(C)OC(=O)NCc1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cncc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(C(=O)N3CCC[C@@H]3C(=O)NN(C)C)c2)c1
Reaction time: 8 h
Yield: 4.9 %

Procedure:
A flask containing (R)—N′,N′-dimethylpyrrolidine-2-carbohydrazide was evacuated and back-filling with Ar (×3), followed by the sequential addition of 1 mL anhydrous CH2Cl2 and DIPEA (0.22 ml, 0.16 g, 1.24 mmol, 8 eq). In a separate flask HOBT.H2O (0.023 g, 0.17 mmol, 1.1 eq) was added to a stirred solution of 3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoic acid (0.0714 g, 0.155 mmol, 1 eq) in 4 ml anhydrous CH2Cl2 at and 1 ml anhydrous DMF at 0° C. under Ar. After 30 min EDCI.HCl (0.032 g, 0.17 mmol, 1.1 eq) was added. After both solutions had stirred for at least 1 h the active ester was treated with the free-base amine. The reaction was stirred at 0° C. to room temperature overnight. The solvent was removed in vacuo and the residue partitioned between EtOAc/water. The layers were separated. The aqueous layer was saturated with NaCl and extracted with 10% MeOH in CHCl3 (×4). The combined organic fractions were dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo. Purification via flash chromatography yielded only crude product. The crude was stirred with water and filtered through Celite. The water was removed in vacuo. The resulting solid was dissolved in saturated aqueous NaHCO3 and filtered through Celite. The solution was extracted with 10% MeOH in CHCl3 (×2). The combined organics were dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo. The residue was stirred with water and filtered through cotton. The solvent was removed in vacuo yielding 0.0046 g (0.0077 mmol, 4.9% yield) of 3-((R)-2-(2,2-dimethylhydrazinecarbonyl)pyrrolidine-1-carbonyl)-N-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-yl)benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:4]=1[C:5]([N:7]=[C:8]=[O:9])=[O:6].[Br:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)=[CH:19][CH:18]=1>C(OCC)(=O)C>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([NH:7][C:8]([NH:28][C:25]1[CH:26]=[N:27][C:22]([O:21][C:20]2[CH:29]=[CH:30][C:17]([Br:16])=[CH:18][CH:19]=2)=[CH:23][CH:24]=1)=[O:9])=[O:6]
Reactant: COc1cccc(OC)c1C(=O)N=C=O
Reactant: Nc1ccc(Oc2ccc(Br)cc2)nc1
Solvent: CCOC(C)=O
Product: COc1cccc(OC)c1C(=O)NC(=O)Nc1ccc(Oc2ccc(Br)cc2)nc1

Procedure:
2,6-Dimethoxybenzoyl isocyanate (2.0 grams) and 6-(4-bromophenoxy)-3-aminopyridine (2.3 grams) were mixed in about 50 ml. of ethyl acetate at room temperature, and the reaction mixture stirred overnight (about 17 hours) at room temperature. The product was separated by filtration and crystallized from a mixture of ethyl acetate and ethanol, yield 0.9 gram, m.p., 177°-179° C.
Reaction SMILES: [H-].[K+].[N+:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[C-:4].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#[CH:13].Cl>CC(OC)(C)C>[NH:3]1[CH:4]=[C:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH:13]=[C:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C#CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: CCOC(=O)c1c[nH]c(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.5 %

Procedure:
A suspension of potassium hydride (0.53 g, 13.26 mmol) in MTBE (10 mL) was added to a stirred solution of ethyl 2-isocyanoacetate (1 g, 8.84 mmol) and ethyl propiolate (1 g, 10.19 mmol) in MTBE (10 mL). The resulting mixture was stirred at rt for 4 h. The solution was then acidified with 1N HCl to pH≦3. The organic layer was washed with sat. NaHCO3 solution (2 mL), brine (2 mL), dried (MgSO4), and concentrated to give a solid residue. Purification via flash chromatography (petroleum ether:EtOAc, 15:1 to 10:1) afforded diethyl 1H-pyrrole-2,4-dicarboxylate (0.7 g, 37%). 1H NMR (CDCl3, 300 MHz) δ9.75 (br, 1 H), 7.49 (s, 1 H), 7.24 (s, 1 H), 4.25 (m, 4 H), 1.29 (m, 6 H).
Reaction SMILES: CC1(C)CO[CH:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([CH:37]5OCC(C)(C)C[O:38]5)=[C:20]5[NH:36][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)[O:4]C1.C(O)(C(F)(F)F)=O.O.C(Cl)Cl.C(OCC)(=O)C>C(Cl)Cl>[CH:5]([C:8]1[C:9]2[NH:13][C:12]([C:14]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)=[C:15]3[N:45]=[C:18]([C:19]([CH:37]=[O:38])=[C:20]4[NH:36][C:23](=[C:24]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:25]5[CH:26]=[CH:27][C:28]=1[N:29]=5)[CH:22]=[CH:21]4)[CH:17]=[CH:16]3)=[CH:11][CH:10]=2)=[O:4]
Reactant: CC1(C)COC(c2c3nc(c(-c4ccccc4)c4ccc([nH]4)c(C4OCC(C)(C)CO4)c4nc(c(-c5ccccc5)c5ccc2[nH]5)C=C4)C=C3)OC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1c2nc(c(-c3ccccc3)c3ccc([nH]3)c(C=O)c3nc(c(-c4ccccc4)c4ccc1[nH]4)C=C3)C=C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
As described for 5, a solution of 14 (30 mg, 44 μmol) in CH2Cl2 (5.0 mL) was treated with TFA/water (2.0 mL, 1:1) with stirring at room temperature for 3 days. Standard workup including chromatography (silica, CH2Cl2/ethyl acetate) gave a purple green solid (18.7 mg, 83%): IR (neat) 1673, 1550, 1120 Cm−1; 1H NMR δ −2.30 (s, 2H), 7.80-7.82 (m, 6H), 8.17-8.19 (m, 4H), 8.59 (d, J=4.8 Hz, 4H), 10.02 (s, 4H), 12.55 (s, 2H); LD-MS obsd 518.90, calcd 518.1743 (C34H22N4O2); λabs 428, 538, 584, 622, 684 nm.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:14]([NH:17][NH2:18])(=O)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:15][C:14]1[N:13]=[C:12]([C:11]2[NH:10][CH:9]=[N:8][C:7]=2[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[NH:18][N:17]=1
Reactant: CC(=O)NN
Reactant: CCCCCNc1nc[nH]c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCCNc1nc[nH]c1-c1nc(C)n[nH]1
Temperature: 165 °C
Reaction time: 14 h
Yield: 9.6 %

Procedure:
To the mixture of 4-(pentylamino)-1H-imidazole-5-carbonitrile (0.40 g, 2 mmol), acetic acid, hydrazide (0.33 g, 4.5 mmol) in1-butanol (10 mL) was added potassium carbonate (0.10 g, 0.72 mmol). The mixture was sealed and stirred at 165° C. for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative LCMS (method A) to yield the desired product (45 mg, 10% yield). LCMS calculated for C11H19N6(M+H): 235.2. found: 235.1.
Reaction SMILES: [C:1]([N:4]1[CH2:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]3[O:20][CH:19]=[N:18][CH:17]=3)=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]1=2)(=[O:3])[CH3:2]>CO.[OH-].[Pd+2].[OH-]>[C:1]([N:4]1[CH2:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]3[O:20][CH:19]=[N:18][CH:17]=3)=[CH:15][C:9]=2[CH2:8][CH2:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1Cc2ccc(-c3cnco3)cc2C=Cc2ccccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1Cc2ccc(-c3cnco3)cc2CCc2ccccc21
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a solution of Example 295 (50 mg, 0.16 mmol) in MeOH (10 mL) was added palladium hydroxide (25 mg). The solution was stirred under a hydrogen atmosphere for 3 hours. The mixture was filtered through a nylon membrane filter, concentrated and recrystallized from EtOAc/hexane to give the title compound as a white solid (35 mg, 69%). HPLC Rt=3.56 min. m/z=319(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([O:30][CH3:31])[CH:22]=2)[N:16]=1.Cl>[Fe].CO>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([N:17]2[C:18](=[O:20])[NH:19][C:15]([C:3]3[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=3[Cl:1])[CH2:6][NH:7][C:8]([CH:10]3[CH2:12][CH2:11]3)=[O:9])=[N:16]2)=[CH:22][C:23]=1[O:30][CH3:31]
Reactant: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1N
Yield: 75.5 %

Procedure:
The title compound was prepared according to the procedure as described in step-2 Intermediate-28 by using N-(4-chloro-3-(1-(3-methoxy-4-nitrophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanecarboxamide (0.500 g, 1.12 mmol), iron powder (catalytic amount), methanol (20 mL), conc. HCl (5.0 mL) to afford 0.350 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (s, 4H), 1.22 (br s, 2H), 1.60 (m, 1H), 3.97 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.45-7.58 (m, 3H), 7.70 (d, J=9.3 Hz, 1H), 7.87 (s, 1H), 8.13 (d, J=9.0 Hz, 1H), 8.71 (m, 1H), 12.30 (br s, 1H); MS (m/z): 414.09 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8]2)[CH2:3][NH:2]1.I[C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][C:24]([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=1)(=[O:30])=[O:29])=[CH:23]2>>[F:41][C:38]([F:39])([F:40])[O:37][C:33]1[CH:32]=[C:31]([S:28]([C:24]2[CH:25]=[N:26][C:27]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[N:2]2[CH2:1][CH:9]3[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8]3)[CH2:3]2)(=[O:29])=[O:30])[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC2C1
Reactant: O=S(=O)(c1cccc(OC(F)(F)F)c1)c1cnc2c(I)cccc2c1
Product: CC(C)(C)OC(=O)N1CCC2CN(c3cccc4cc(S(=O)(=O)c5cccc(OC(F)(F)F)c5)cnc34)CC2C1
Yield: 54 %

Procedure:
The title compound was prepared by analogy to the procedure of Example 1.3, except using tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate and 8-iodo-3-(3-(trifluoromethoxy)phenylsulfonyl)quinoline. 130 mg (54%) of the title compound were obtained as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][CH:13]([CH2:15][OH:16])[CH2:12][C:11]2=[O:17])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:18]1(O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][CH:13]([CH2:15][O:16][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][C:11]2=[O:17])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Oc1ccccc1
Reactant: COc1ccc(N2CC(CO)CC2=O)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(N2CC(COc3ccccc3)CC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-fluoro-4-methoxyphenyl)-4-(hydroxymethyl)pyrrolidin-2-one (Step 2, 1.0 g, 4.18 mmol), phenol (0.786 g, 8.36 mmol) and PPh3 (2.41 g, 9.2 mmol) in 50 mL of CH2Cl2 at 0° C. was added DIAD (1.65 mL, 9.2 mmol) slowly via a syringe. The reaction was warmed to RT and stirred overnight. The mixture was concentrated in vacuo and the residue was purified by chromatography (hexanes to 50% EtOAc/hexanes) to give the title compound as a white solid. MS (ESI pos. ion) m/z: 316.2 (M+H). Calc'd Exact Mass for C18H18FNO3: 315.34.
Reaction SMILES: [NH:1]=[S:2]([CH3:9])([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[H-].[K+].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>COCCOC.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:1]=[S:2]([CH3:9])(=[O:3])[N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH:15][CH:14]=1
Reactant: CS(=N)(=O)N1CCCC1
Reactant: BrCc1ccc(Br)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Solvent: COCCOC
Product: CS(=O)(=NCc1ccc(Br)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Imino(methyl)pyrrolidin-1-yl-λ6-sulfanone (80 mg) is added to potassium hydride (87 mg) in 1,2-dimethoxyethane (2 mL) under an argon atmosphere and the resulting mixture is stirred for 15 min at room temperature. Benzyltriethylammonium chloride (7 mg) and 4-bromobenzyl bromide (148 mg) are added and the mixture is stirred overnight at room temperature. The reaction mixture is cooled in an ice bath and quenched with saturated aqueous NH4Cl solution. The mixture is diluted with diethyl ether and extracted with 3 N hydrochloric acid. The aqueous phase is carefully neutralized with solid K2CO3 and extracted with dichloromethane. The combined organic phases are dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (ethyl acetate/methanol 98:2→90:10) to give the title compound. LC (method 1): tR=0.85 min; Mass spectrum (ESI+): m/z=317, 319 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.P(Cl)(Cl)[Cl:12]>C(Cl)(Cl)Cl>[Cl:12][C:7]1[CH2:9][C:2]([CH3:10])([CH3:1])[CH2:3][C:4](=[O:5])[CH:6]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)C=C(Cl)C1
Temperature: 0 °C
Yield: 40 %

Procedure:
To 200 ml of a chloroform solution containing 100 g (0.71 mol) of dimedone was added 21 ml of phosphorus trichloride and the mixture was refluxed by heating for 3 hours. To the reaction solution was added ice water to terminate the reaction, the chloroform was distilled off under reduced pressure and the aqueous layer was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified by distillation under reduced pressure to obtain 45 g of 3 -chloro-5,5-dimethyl-2-cyclohexene-1-one. Yield: 40%, Boiling Point: 95° C. at 18 mmHg.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][N:35]=[N+:36]=[N-:37])[NH:9]1)=[O:7])(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[N:35]([CH2:34][CH2:33][C:32]([CH3:39])([CH3:38])[CH2:31][CH:10]1[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]1([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[F:30])[C:21]#[N:22])=[N+:36]=[N-:37]
Reactant: CC(C)(CCN=[N+]=[N-])CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CCN=[N+]=[N-])CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 96 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 120b (0.5 g, 0.86 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (0.54 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].CI.[C:12]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(Cl)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C)cccc1Cl
Temperature: 25 °C

Procedure:
2-Chloro-6-methyl-phenol (12.00 g, 84.20 mmol) was mixed with MeI (10.50 mL, 0.17 mol) and K2CO3 (17.40 g, 0.13 mol) in acetone in acetone and the resulting reaction mixture was refluxed for 14 hours. The reaction mixture was cooled to room temperature, and then concentrated. The residue was diluted with Et2O. The resulting solution was washed with H2O (3×150 mL) and brine (1×200 mL), then dried over MgSO4 and concentrated. Purification by column chromatography using hex:EtOAc (4:1) as the eluant afforded the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]1[CH2:19]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li].CN([BH3-])C.C(B(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]1[CH3:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C[C@H]1COS(C)(=O)=O
Agent: CCB(CC)CC
Agent: [BH3-]N(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Yield: 67.6 %

Procedure:
3.4 g of (2S,4S)-2-Methanesulfonyloxymethyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (9.56 mmol) were dissolved in 50 ml tetrahydrofurane. After addition of 15.1 ml lithium-dimethylaminoborohydride (14.34 mmol; 1 M in tetrahydrofurane), 1.93 ml triethylborane (1 M in tetrahydrofurane) were added and the reaction mixture stirred under reflux for 20 min. Standard workup gave 2.7 g of crude product which was purified via silica gel chromatography using a ISCO Companion instrument, yielding 1.69 g of purified product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=O.[ClH:18].Cl.[O:20]([CH2:22][CH2:23][NH2:24])[NH2:21].N1C=CC=CC=1>C(O)C>[ClH:18].[NH2:24][CH2:23][CH2:22][O:20][N:21]=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCCCC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COCCCCC(=NOCCN)c1ccc([N+](=O)[O-])cc1

Procedure:
5.35 Mmol (1.27 g) of 5-methoxy-4'-nitrovalerophenone (melting point 64.5°-65.5° C.), 5.35 mmol (0.80 g) of 2-aminoxyethylamine dihydrochloride and 0.34 ml of pyridine were refluxed for 2 hours in 5 ml of absolute ethanol. After evaporating the reaction mixture to dryness in vacuo, 25 ml of water and 10 ml of 2 N sodium hydroxide solution were added and extracted with 25 and 10 ml, respectively, of methylene chloride. The extracts were dried over sodium sulphate and then evaporated to dryness in vacuo. Toluene was added another two times to the resulting base which was evaporated in vacuo. The residue was dissolved in absolute ethanol and an equimolar quantity of alcoholic hydrochloric acid was added. After the addition of diethyl ether, the title compound crystallized. Melting point 121.5°-122.5° C.