Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH3:30][O:31][C:32](=[O:41])[C@H:33]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH2:34].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:30][O:31][C:32](=[O:41])[C@H:33]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH:34][C:13](=[O:14])[CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(CC(Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To a suspension of 1.00 g of (±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid and 0.67 g of L-histidine methyl ester dihydrochloride in 8 ml of N,N-dimethylformamide were added 0.72 ml of diphenylphosphoryl azide and 1.27 ml of triethylamine under ice-cooling, and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform/methanol=15/1 by volume) to obtain 1.36 g of N-[(±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine methyl ester.
Reaction SMILES: [NH2:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1.N[C@H](C(O)=O)CCC(=O)N.N[C@H](C(O)=O)CC(=O)N.N[C@H](C(O)=O)CCCNC(=N)N.N(CC(O)=O)C>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@H](Cc1ccc(O)cc1)C(=O)O
Agent: CNCC(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: NC(=O)CC[C@H](N)C(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
DTyr 0.52; Gln 0.99; Asn 1.00; Arg 1.01; Gly 1.01 (Mca,Cys and Sar were not determined)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:28]C(=O)OC(C)(C)C)[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:19]=2)=[CH:2]1.Cl>ClCCl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:28])[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:19]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(/C=C/c2ccncc2)c1)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H](COc1cncc(/C=C/c2ccncc2)c1)Cc1c[nH]c2ccccc12
Reaction time: 2 h

Procedure:
A solution of Example 2B (603 mg, 1.28 mmol) in dichloromethane (20 mL) at room temperature was treated with 4N HCl in dioxane (5 mL), stirred for 2 hours, and concentrated. The residue was dissolved in water (1.5 mL) and freeze-dried to provide the desired product as the hydrochloride salt (610 mg, 99%). MS (DCI/NH3) m/e 371 (M+H)+, 1HNMR (CD3OD) δ 8.76 (d, J=6.8 Hz, 2H), 8.52 (d, J=1.4 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.16 (d, J=7.1 Hz, 2H), 7.86 (d, J=16.6 Hz, 1H), 7.77 (m, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.50 (d, J=16.6 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.28 (s, 1H), 7.13 (m, 1H), 7.03 (m, 1H), 4.39 (dd, J=3.4, 10.5 Hz, 1H), 4.25 (dd, J=5.4, 10.5 Hz, 1H), 4.00 (m, 1H), 3.30 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1)#[CH:2].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1>C(N(CC)CC)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=2)[CH:17]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: Brc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 70 °C
Yield: 70.7 %

Procedure:
Add 1-ethynyl-3-methoxybenzene (0.56 g, 4.22 mmol) to a mixture of 3,5-dibromopyridine (1.00 g, 4.22 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.06 g, 0.08 mmol) and copper (I) iodide (0.03 g, 0.17 mmol) in triethylamine (8 mL) and heat at 70° C. for 2 h. Cool to room temperature, dilute with ethyl acetate and an aqueous saturated solution of ammonium chloride, and separate the layers. Wash the organic layer with an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify the resulting residue by silica gel chromatography, eluting with 2.5% ethanol in 50:50 chloroform/hexanes, to give the title compound (0.86 g, 71%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:22])[C:10]([C:19]([OH:21])=O)=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH2:35][CH2:36][CH2:37][OH:38]>CN(C)C=O>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:22])[C:10]([C:19]([NH:35][CH2:36][CH2:37][OH:38])=[O:21])=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: NCCO
Reactant: CCc1ccc2c(-c3cncc(C)c3)c(C(=O)O)c(C)nn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3cncc(C)c3)c(C(=O)NCCO)c(C)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid (70 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (68.2 mg) and 1-hydroxybenotriazole (48 mg) in dimethylformamide (2 mL) was added 2-aminoethanol (17.4 mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (50:1–10:1). The crude product was triturated with isopropylether to give 7-ethyl-N-(2-hydroxyethyl)-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxamide as a yellow powder (47 mg).
Reaction SMILES: [Cl:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][NH:5][C:6](=[O:31])[N:7]([C@H:9]([CH2:15][O:16][C:17](=[O:30])[NH:18][C:19]1[N:20]=[CH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([F:29])=[CH:24][CH:23]=2)[CH2:10][CH2:11][C:12](O)=[O:13])[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:61]([O:65][C:66]([N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1)=[O:67])([CH3:64])([CH3:63])[CH3:62].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][NH:5][C:6](=[O:31])[N:7]([C@H:9]([CH2:15][O:16][C:17](=[O:30])[NH:18][C:19]1[N:20]=[CH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([F:29])=[CH:24][CH:23]=2)[CH2:10][CH2:11][C:12]([N:71]1[CH2:72][CH2:73][N:68]([C:66]([O:65][C:61]([CH3:64])([CH3:62])[CH3:63])=[O:67])[CH2:69][CH2:70]1)=[O:13])[CH3:8]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)O)COC(=O)Nc1cc2cc(F)ccc2cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of (S)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)pentanoic acid (83 mg, 0.160 mmol, 1.0 equiv) in DMF (1 mL) were added HBTU (72 mg, 0.191 mmol, 1.2 equiv.), tert-butyl-1-piperazine carboxylate (59 mg, 0.320 mmol, 2.0 equiv.) and DIEA (83 μL, 0.480 mmol, 3.0 equiv.). The reaction mixture was stirred 1 h at RT and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-tert-butyl 4-(4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)pentanoyl)piperazine-1-carboxylate (61 mg, 55%). LRMS (M+H+) m/z 689.3.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]1[CH2:15][NH:14][CH2:13]1.Cl.[CH3:17][N:18]1[CH2:23][CH2:22][C:21]2([CH2:32][C:31]3[C:26](=[N:27][CH:28]=[C:29](/[CH:33]=[CH:34]/[C:35](O)=[O:36])[CH:30]=3)[NH:25][C:24]2=[O:38])[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:17][N:18]1[CH2:19][CH2:20][C:21]2([CH2:32][C:31]3[C:26](=[N:27][CH:28]=[C:29](/[CH:33]=[CH:34]/[C:35]([N:14]4[CH2:13][CH:12]([C:4]5[O:5][C:6]6[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=6[C:3]=5[CH3:2])[CH2:15]4)=[O:36])[CH:30]=3)[NH:25][C:24]2=[O:38])[CH2:22][CH2:23]1
Reactant: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)O)cnc1NC2=O
Reactant: Cc1c(C2CNC2)oc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C2CN(C(=O)/C=C/c3cnc4c(c3)CC3(CCN(C)CC3)C(=O)N4)C2)oc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.7 %

Procedure:
To a solution of 3-(3-methylbenzofuran-2-yl)azetidine hydrochloride (21.7 mg, 0.097 mmol) and (E)-3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylic acid hydrochloride (22.0 mg, 0.065 mmol) in DMF (3 mL) were added EDCI.HCl (18.9 mg, 0.099 mmol), HOAt (13.9 mg, 0.102 mmol) and N,N-diisopropylethylamine (57 μL, 0.333 mmol). The reaction was stirred at rt for 20 h., after which the mixture was partitioned between DCM and H2O. The layers were separated and the aqueous layer extracted with DCM (3×). The combined organic layers were washed with brine (3×), dried over Na2SO4 and concentrated and the residue was purified by flash chromatography (DCM/MeOH, 5%→20%). The product (10.6 mg, 35%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][NH:4][C:5]1[C:10]([C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][N:8]=[C:7]([C:20]#[N:21])[N:6]=1.[Cl:24][CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[Cl:24][CH2:25][CH2:26][CH2:27][S:28]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:12]#[C:11][C:10]2[C:5]([NH:4][CH2:3][C:2]([CH3:23])([CH3:22])[CH3:1])=[N:6][C:7]([C:20]#[N:21])=[N:8][CH:9]=2)[CH2:15][CH2:16]1)(=[O:30])=[O:29]
Reactant: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1CCNCC1
Reactant: O=S(=O)(Cl)CCCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1CCN(S(=O)(=O)CCCCl)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 51 %

Procedure:
To a solution of 4-(2,2-dimethyl-propylamino)-5-(3-piperazin-1-yl-prop-1-ynyl)-pyrimidine-2-carbonitrile (0.16 mmol) in CH2Cl2 (5 ml), 3-chloropropanesulfonyl chloride (0.192 mmol) and triethylamine (0.192 mmol) are added at 0° C. The reaction mixture is stirred at room temperature for 14 h and then saturated aqueous solution of ammonium chloride is added to the reaction mixture. The mixture is extracted with two 50 ml portions of AcOEt. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum. The purification of the residue by silica gel column chromatography affords 37 mg of title compound in 51% yield. Rf=0.33 (AcOEt only)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:12][O:13][CH3:14])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH:4]([CH2:12][O:13][CH3:14])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:8][CH:7]=1
Reactant: COCC(COC)Oc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COCC(COC)Oc1ccc(S(=O)(=O)Cl)cc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
(2-Methoxy-1-methoxymethyl-ethoxy)-benzene (1.0 g) was dissolved in 10 mL of chloroform and the solution was cooled to −30° C. Chlorosulfonic acid (1 mL) was added dropwise while maintaining the temperature of the mixture below −20° C. Stirring was continued in succession for one hour at −20° C., for one hour at 5° C. and for 30 minutes at room temperature. The mixture was poured on ice, the organic layer washed with cold water, dried (sodium sulfate) and concentrated yielding 0.8 g of 4-(2-methoxy-1-methoxymethyl-ethoxy)-benzenesulfonyl chloride as an oil. EI-MS: 294 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:12]([CH3:14])[CH3:13])=[CH:8][C:9]=2[CH3:11])[S:4][C:3]=1[C:15]([NH2:17])=[O:16].[NH:18]1C=CN=[CH:19]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CCOC(C)=O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:12]3[CH:13]=[CH:19][N:18]=[CH:14]3)=[CH:8][C:9]=2[CH3:11])[S:4][C:3]=1[C:15]([NH2:17])=[O:16]
Reactant: c1c[nH]cn1
Reactant: Cc1cc(N(C)C)nc2sc(C(N)=O)c(N)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-n2ccnc2)nc2sc(C(N)=O)c(N)c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To a solution of 20 mg (0.067 mmol) of starting 4-methylpyridine triflate intermediate (see Example 2) in 1.2 mL of 1,4-dioxane was added 9.2 mg of imidazole. The resulting mixture was stirred for 2 h at 80° C. After that time 0.5 mL of 2M solution of sodium carbonate was added. The stirring was continued overnight at 100° C. The reaction mixture was then cooled to room temperature, diluted with EtOAc, dried with sodium sulfate and concentrated. The crude product was chromatographed (preparative TLC on silica gel eluting with 10% MeOH/methylene chloride, Rf=0.56) to afford 3.7 mg of product, which was further purified by HPLC (reverse phase—solvent system: isocratic 60% water/acetonitrile providing 2.7 mg (14.7%) of the title compound.
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[O:5]=[CH:6][C@@H:7]([CH2:9][OH:10])[OH:8].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>ClCCl>[CH2-:1][C:2]([CH3:4])=[O:3].[S:18]([O:5][CH2:6][C@H:7]([OH:8])[CH2:9][OH:10])([CH3:21])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=C[C@H](O)CO
Agent: [CH2-]C(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H](O)CO

Procedure:
A solution of 2(S)-glycerol-2,3-acetonide (109 g), obtained from mannitol-1,2:5,6-diacetonide via D-glyceraldehyde acetonide using the method described by LeCocq et al., Biochem., 3, 976 (1964), in 1 L dry dichloromethane was cooled to -35° with stirring. Triethylamine (140 ml) was added followed by the dropwise addition of mesyl chloride (71 ml) over 10 minutes while maintaining the reaction between -35° and -25°. The cooling bath was removed and after 45 minutes, 250 ml 1N hydrochloric acid was added. The layers were separated and the dichloromethane solution was washed in turn with 250 ml portions of water (1×), 1N sodium hydroxide (1×) and water (1×). The aqueous layers were dried over sodium sulfate and evaporated to give 172.1 g of (2R)-3-mesyloxy-1,2-propanediol acetonide as a pale yellow oil.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][N:7]([C:9](=[O:26])[CH2:10][P:11]([O:23]CC)([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[C@H:6]([C:27]([O:29][CH3:30])=[O:28])[CH2:5]1)=[N+:2]=[N-:3].Br[Si](C)(C)C>ClCCl>[N:1]([CH:4]1[CH2:8][N:7]([C:9](=[O:26])[CH2:10][P:11]([OH:23])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[C@H:6]([C:27]([O:29][CH3:30])=[O:28])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC(N=[N+]=[N-])C[C@H]1C(=O)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC(N=[N+]=[N-])CN1C(=O)CP(=O)(O)CCCCc1ccccc1
Reaction time: 19 h
Yield: 90.2 %

Procedure:
(S)-4-Azido-1-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline, methyl ester (1.60 g), dry dichloromethane and bromotrimethylsilane (0.85 g) are stirred under argon at room temperature. After 19 hours, an additional equivalent of bromotrimethylsilane is added and stirring is continued for 2 hours. Excess bromotrimethylsilane and dichloromethane is removed in vacuo and the residue is treated with ethyl acetate/water and stirred for 15 minutes. The layers are separated and the ethyl acetate layer is extracted with saturated sodium bicarbonate. The aqueous extracts are acidified to pH 1.0 with concentrated hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, brine, dried over sodium sulfate, and the solvent stripped to yield 1.35 g of the title compound as an oil.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[N-:15]=[N+:16]=[N-:17].[Na+].O.C(=O)(O)[O-].[Na+]>CN(C=O)C.[I-].[Na+]>[N:15]([CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.2 %

Procedure:
To a solution of 45.3 g (172 mmol) of 4-bromo-1-t-butoxycarbonylpiperidine in 750 mL of DMF was added 22.3 g (343 mmol) of sodium azide and 2.5 g (17 mmol) of sodium iodide. The reaction was stirred at rt for 24 h and then at 60° C. for 4 h. The mixture was poured into water containing 20 mL of sodium bicarbonate and extracted twice with 1:1 ether:hexanes. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 5-10% ethyl acetate in hexanes to afford 39 g of title compound having a trace of elimination byproduct.
Reaction SMILES: ClC1C=C(C2C=C(C(N3CCNC(=O)C3)=O)O[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)C=CC=1.Br[C:30]1[CH:31]=[C:32]([C:42]([N:44]2[CH2:49][CH2:48][NH:47][C:46](=[O:50])[CH2:45]2)=[O:43])[O:33][C:34]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1>>[Cl:41][C:37]1[CH:36]=[C:35]([C:34]2[O:33][C:32]([C:42]([N:44]3[CH2:49][CH2:48][NH:47][C:46](=[O:50])[CH2:45]3)=[O:43])=[CH:31][C:30]=2[C:17]2[CH:16]=[C:15]([CH3:19])[CH:14]=[C:13]([CH3:12])[CH:18]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)o2)CCN1
Reactant: Cc1cccc(-c2oc(C(=O)N3CCNC(=O)C3)cc2-c2cccc(Cl)c2)c1
Product: Cc1cc(C)cc(-c2cc(C(=O)N3CCNC(=O)C3)oc2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 18 starting with the compound from Example 27A. 15.0 mg (28% of theory) of the title compound are obtained.
Reaction SMILES: C(#N)C.C(=O)([O-])[O-].[K+].[K+].[C:10]([N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])(OCC)=O.Cl.N[C@@H:28]1[C:33](C)([CH3:34])[CH2:32][CH2:31][C@H:30]([OH:36])[CH2:29]1>O>[OH:36][C@@H:30]1[CH2:31][C@H:10]([N:15]2[C:16](=[O:25])[C:17]3[C:18](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:20])[C:33]([CH3:34])([CH3:32])[CH2:28][CH2:29]1
Reactant: CC1(C)CC[C@H](O)C[C@@H]1N
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CC[C@H](O)C[C@@H]1N1C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 52.3 %

Procedure:
Acetonitrile (5 ml), potassium carbonate (3.1 mmol, 423 mg) and N-carboethoxyphthalimide (3.1 mmol, 670 mg) were added to a solution of cis-3-amino-4,4-dimethylcyclohexanol hydrochloride (500 mg, 2.8 mmol) in water (10 ml), and the resulting mixture was stirred as it was for 2 hours. The crystals precipitated were collected by filtration and then recrystallized from chloroform-diethyl ether to obtain cis-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione (400 mg, 53%, containing about 10% of trans isomer) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[C:15](=[O:16])[CH2:14][C@@H:13]([CH:17]=[O:18])[CH2:12]2)[CH3:10])=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si](C)(C)[C:39]([F:42])([F:41])[F:40]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:12][C@H:13]([CH:17]([OH:18])[C:39]([F:42])([F:41])[F:40])[CH2:14][C:15]2=[O:16])[CH3:10])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc([C@@H](C)N2C[C@H](C=O)CC2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Product: COc1ccc([C@@H](C)N2C[C@H](C(O)C(F)(F)F)CC2=O)cc1
Temperature: -60 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-5-oxopyrrolidine-3-carbaldehyde 1.07 (7 g, 28.31 mmol, 1.00 equiv) in toluene (100 mL), trimethyl(trifluoromethyl)silane (2.9 mL), followed by the addition of tetrabutylammonium fluoride (1 mol/L in tetrahydrofuran) (1.53 mL) dropwise with stirring at −60° C. The resulting solution was stirred overnight at room temperature, quenched by the addition of 100 mL of water/ice and extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane: methanol (200:1-80:1) to afford (4R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-4-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one. The diastereomers were separated by chiral HPLC (CHIRALPAK IC), and the later eluting diastereomer was collected to afford (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one 1.29. This compound is the earlier diastereomer under RP-HPLC conditions (Gemini column, water/acetonitrile/TFA).
Reaction SMILES: C[O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.[O-:18][C:19]#[N:20].[K+].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:19]([NH2:20])=[O:18])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH2:4]1
Reactant: N#C[O-]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
22.3 g (0.1 moles) of 10-methoxy-5H-dibenz(b,f)azepine prepared according to U.S. Pat. No. 27,622 are dissolved in 150 ml of toluene. 8.92 g (0.11 moles) of potassium cyanate and 10.8 g (0.11 moles) of 96% sulfuric acid are added. The mixture is heated between 40° and 50° C. stirring vigorously for 24 hours. When the analytical control detects a starting product content<2%, 50 ml of water are dropped into the mixture, which is stirred and the phases are separated. The organic phase is evaporated to dryness under vacuum and taken up into 100 ml of 10% sulfuric acid. The mixture is refluxed for 2-3 hours, cooled at room temperature and pump-filtered, washing with water; then it is recrystallized from dimethylacetamide (50 ml), filtered through charcoal washing the precipitate on the filter with acetone, and dried under vacuum. The product is identified by IR, NMR and mass spectroscopies.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:5])=[O:4].Br[CH2:27][CH3:28]>>[F:25][C:2]([F:24])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH2:27][CH3:28])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:4])=[O:5]
Reactant: CCCN(CCC)C1Cc2cc(O)c(OS(=O)(=O)C(F)(F)F)cc2C1
Reactant: CCBr
Product: CCCN(CCC)C1Cc2cc(OCC)c(OS(=O)(=O)C(F)(F)F)cc2C1

Procedure:
Using procedure 38, 2-(dipropylamino)-2,3-dihydro-6-hydroxy-1H-inden-5-yl trifluoromethanesulfonate (69, 1.9 g, 5 mmol) was treated with bromoethane (2.2 g, 20 mmol). Chromatographic purification yielded pure product 73 as a oil which was converted into the HCl salt and crystallized from EtOAc/hexane to give a white solid (mp 181-182 ° C.)