Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1[OH:26])[CH:8]=[CH:7]2.[CH3:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=1[NH2:30].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C1(C)C=CC=CC=1>[C:22]([C:14]1[CH:15]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:17]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([NH:30][C:29]4[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:28]=4[CH3:27])[CH:3]=[CH:4][CH:5]=3)[N:10]=2)[C:13]=1[OH:26])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(-c2ccc3cccc(Br)c3n2)c(O)c(C(C)(C)C)c1
Reactant: Cc1cccc(C)c1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1Nc1cccc2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(8-bromo-2-quinolinyl)-4,6-di-tert-butylphenol (3.3 g, 8 mmol), 2,6-dimethylaniline (1.2 mL, 10 mmol), Pd(dba)2 (0.036 g, 0.6 mmol), L=(N-[2′-(dicyclohexylphosphino)[1,1′-biphenyl]-2-yl]-N,N-dimethylamine) (0.05 g, 0.12 mmol), NaOtBu (0.36 g, 3.6 mmol), and toluene (8 mL) is stirred for 8 h under an argon atmosphere at 100° C. The mixture is then poured into water and extracted with benzene (3×50 mL). The combined organic phase is washed with water and brine, and is then concentrated. The residue is purified by column chromatography (silica gel 40, hexane/toluene 2:1). Yield: 2.17 g (60%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]([NH2:16])=[N:14][C:13]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12]2)[CH:8]=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:6]=1)(=O)=O.[OH-:31].[Na+]>CN(C=O)C>[NH2:16][C:15]1[N:11]([C:9]2[CH:8]=[C:7]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:6][C:5](=[O:31])[N:10]=2)[N:12]=[C:13]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=1
Reactant: [OH-]
Reactant: CS(=O)(=O)c1nc(Nc2ccccc2)cc(-n2nc(Nc3ccccc3)nc2N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(Nc2ccccc2)nn1-c1cc(Nc2ccccc2)[nH]c(=O)n1
Yield: 90 %

Procedure:
1-(2-Methanesulfonyl-6-phenylamino-pyrimidin-4-yl)-N3-phenyl-1H-[1,2,4]triazole-3,5-diamine (12 mg, 0.028 mMol) was stirred at ambient temperature in 500 uL of DMF with 200 uL of 1N NaOH for 2 hrs. The reaction was quenched with water and a precipitate allowed come out of solution. The filtrate was decanted off and the solid was resuspended with water, allowed to settle, and again decanted. The solid was transferred to a round bottom flask with acetonitrile and the solvents removed under reduced pressure. The resultant material, a beige yellow solid, resulted in 90% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:21]([C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22]>O1CCOCC1>[C:21]([C:24]1[CH:25]=[C:26]([S:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: N#CC=CS(=O)(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)O)c2)cc1
Reaction time: 8 h

Procedure:
2.1 g (0.01 mol) of 3-(4-aminobenzenesulfonyl) acrylonitrile are dissolved in 100 ml dioxane, and 2 ml of pyridine are added thereto. A solution of 2.21 g (0.01 mol) of 3-carboxybenzenesulfonyl chloride in 50 ml dioxane is added portionwise at room temperature and the reaction mixture is held overnight. After filtering and mixing the filtrate with about 4 volumes of water the mixture is left at room temperature for 5 days. White flocs separate which are recovered by filtration and dried, giving 3-[4-(3-carboxybenzenesulfonamido)-benzenesulfonyl]acrylonitrile: ##SPC30##
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[C:5]([CH3:9])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([CH3:9])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1
Reactant: COc1ccc(CSc2nc(C)c(CO)n2C)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(CSc2nc(C)c(C=O)n2C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1,4-dimethyl-5-hydroxymethyl-2-(4-methoxybenzylthio)imidazole (1 g, 4 mmoles) and manganese dioxide (1.3 g, 15 mmoles) in methylene chloride (50 ml) was stirred at 25° C. for 16 hours. The mixture was filtered and the filtrate concentrated in vacuo to give 1,4-dimethyl-5-formyl-2-(4-methoxybenzylthio)imidazole.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[C@@H:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33]([CH3:42])([CH3:41])[O:32][C:31]2=[O:43])[CH2:26][CH2:25]1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:41][C:33]1([CH3:42])[O:32][C:31](=[O:43])[N:30]([CH:27]2[CH2:26][CH2:25][C:24](=[O:23])[CH2:29][CH2:28]2)[C@H:34]1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC1(C)OC(=O)N(C2CCC(O)CC2)[C@H]1c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC1(C)OC(=O)N(C2CCC(=O)CC2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 64 %

Procedure:
Dess-Martin periodinane (500 mL, 0.3 M in DCM, 0.15 mol) was added over 15 minutes to an ice-cooled solution of (S)-3-(4-hydroxycyclohexyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (39.5 g, 0.136 mol) in DCM (1 L). The resulting mixture was stirred at room temperature under nitrogen for 22.5 hours. Saturated aqueous Na2S2O3 (300 mL) and saturated aqueous NaHCO3 (300 mL) were added, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, washed with brine (300 mL), dried, filtered and concentrated. The resulting residue was purified by column chromatography (eluting with 100% DCM to DCM/MeOH=100:1) to afford (S)-5,5-dimethyl-3-(4-oxocyclohexyl)-4-phenyloxazolidin-2-one (25 g, 64%). 1H NMR (300 MHz, d6-DMSO) δ ppm 7.45-7.20 (m, 5H), 4.67 (s, 1H), 4.0-3.90 (m, 1H), 2.60-2.35 (m, 2H), 2.25-1.95 (m, 4H), 1.85-1.70 (m, 1H), 1.55-1.40 (m, 1H), 1.47 (s, 3H), 0.80 (s, 3H). m/z (ESI) 288 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCCc1ccc(O)cc1
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc(O)cc4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and tyramine, m.p. 129-131° C. MS [(+)ESI, m/z]: 554 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.CCOC(C)=O>[N:13]([CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cccc2cnccc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cccc2cnccc12
Reaction time: 3 h

Procedure:
To a solution of 0.0415 g (0.23 mmol) 16 in 3 mL DMF was added 0.0169 g (0.26 mmol) sodium azide. After a 3 h, an additional 0.0033g (0.05 mmol) portion of sodium azide was added. After 24 h at room temperature, the reaction mixture was diluted with 50 mL EtOAc and washed with 20 mL brine. The aqueous layer was extracted with 10 mL EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (10×175 mm silica gel, linear gradient 5-20% EtOAc:hexane) produced 17. 1H NMR (CDCl3, 400 MHz) δ 9.318 (s, 1H, ArH); 8.637 (d, 1H, J=6.10 Hz, ArH); 8.010 (d, 1H, J=7.94 Hz, ArH); 7.822 (d, 1H, J=6.10 Hz, ArH); 7.713 (d, 1H, J=7.02 Hz, ArH); 7.617 (dd, 1H, J=7.17, 8.09 Hz, ArH); 4.774 (s, 1H, ArH); MS (Electrospray): m/z 185.0 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:40][N:14]4[CH2:15][CH2:16][N:17]([C:19](=[O:39])[CH:20]([NH:31]C(=O)OC(C)(C)C)[C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C1(C2N=CC(O[C@H]3CN4CCN(C(=O)C(NC(=O)OC(C)(C)C)C5C=CC(C(F)(F)F)=CC=5)C[C@@H]4C3)=NC=2)CC1>>[NH2:31][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=1)[C:19]([N:17]1[CH2:16][CH2:15][N:14]2[CH2:40][C@H:11]([O:10][C:7]3[CH:6]=[N:5][C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][N:8]=3)[CH2:12][C@H:13]2[CH2:18]1)=[O:39]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)OC(=O)NC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1ccc(C(F)(F)F)cc1
Product: NC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure described for Example 206, substituting the product from Example 180 for the product from Example 181. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.76-1.04 (m, 4 H) 1.91-4.91 (m, 12 H) 5.27-5.61 (m, 1 H) 5.65-5.96 (m, 1 H) 7.65-8.01 (m, 4 H) 8.06-8.22 (m, 2 H) 8.67-8.99 (m, 3 H) 11.27-11.94 (m, 1 H); MS (APCI) m/z 462 (M+H)+.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[CH3:13][C@@H:14]1[CH2:23][CH2:22][CH2:21][C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[C@@H:15]1[C:24](=[O:26])C.C(=O)C.Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCCC1>[CH3:13][C@@H:14]1[CH2:23][CH2:22][CH2:21][C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[C@@H:15]1[C:24](=[O:26])/[CH:7]=[CH:5]/[CH3:6]
Reactant: CC(C)NC(C)C
Reactant: CC(=O)[C@@H]1[C@H](C)CCCC12CCCC2
Agent: CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C/C=C/C(=O)[C@@H]1[C@H](C)CCCC12CCCC2
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 33 %

Procedure:
At −60° C., a solution of diisopropylamine (4.1 ml, 28.8 mmol) in tetrahydrofuran (30 ml) was treated with n-butyl lithium (18 ml, 1.6M in hexane, 28.8 mmol). The resulting solution was stirred at −30° C. for 20 min., cooled to −70° C., and treated with a solution of crude 1-(rel-(6R,7R)-7-methylspiro[4.5]decan-6-yl)ethanone (4.3 g, 22 mmol) in tetrahydrofuran (10 ml). The resulting solution was stirred 45 min. at −70° C., and treated within 15 min. with a solution of acetaldehyde (5 ml, 88.5 mmol) in tetrahydrofuran (10 ml). After 2 h stirring, the reaction mixture was poured into 2N aqueous HCl and ice (150 ml) and extracted twice with MTBE (100 ml). The combined organic phases were washed with water (50 ml), with a saturated aqueous NaCl solution (100 ml), dried (MgSO4), and concentrated. The crude product (5.5 g) was dissolved in toluene (60 ml). The resulting solution was treated with para-toluene sulfonic acid monohydrate (0.5 g, 2.8 mmol) and heated at 60° C. for 1.5 h. The reaction mixture was cooled, poured into a cold saturated aqueous solution of NaHCO3 (100 ml) and the aqueous phase was extracted with MTBE (80 ml). The combined organic phases were washed with a saturated aqueous NaCl solution (80 ml), dried (MgSO4) and concentrated. FC (SiO2, hexane/MTBE 30:1) of the crude product (5.5 g) gave (E)-1-(rel-(6R,7R)-7-methylspiro[4.5]decan-6-yl)but-2-en-1-one (1.6 g, 33%). Boiling point: 100° C. (0.07 mbar).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH:9]=O)[CH:5]=[N:4]1)[CH3:2].Cl.Cl.[Cl:13][C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][N:19]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Cl:13][C:14]1[C:15]([N:20]2[CH2:21][CH2:22][N:23]([CH2:9][C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=3[CH3:8])[CH2:24][CH2:25]2)=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: CCn1ncc(C=O)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCn1ncc(CN2CCN(c3nccnc3Cl)CC2)c1C
Yield: 88.6 %

Procedure:
Dissolve 1-ethyl-5-methyl-1H-pyrazole-4-carbaldehyde (2.92 g, 21.1 mmol) in 1,2-dichloroethane (184 mL). Add 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (4.97 g, 18.3 mmol), triethylamine (5.9 mL, 42.3 mmol), sodium triacetoxyborohydride (6.72 g, 31.7 mmol) and acetic acid (1.98 mL) and stir at room temperature for 18 hr. Add aq. saturated sodium bicarbonate and extract four times with DCM. Dry combined organic layers (magnesium sulfate), filter, concentrate, and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes then 10:90 to 20:80 methanol:ethyl acetate) to give 3′-chloro-4-(1-ethyl-5-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (5.2 g, 88%). MS (ES): m/z=321 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7](OC)([C:9]2[S:10][C:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)=[C:12]([CH3:14])[CH:13]=2)[C@H:6]([OH:27])[C@@H:5]([OH:28])[C@@H:4]1[OH:29].C([SiH](CC)CC)C.B(F)(F)F>C(Cl)Cl.C(#N)C>[OH:1][CH2:2][C@@H:3]1[C@@H:4]([OH:29])[C@H:5]([OH:28])[C@@H:6]([OH:27])[C@H:7]([C:9]2[S:10][C:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)=[C:12]([CH3:14])[CH:13]=2)[O:8]1
Reactant: CCCc1ccc(Cc2sc(C3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc2C)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: ClCCl
Product: CCCc1ccc(Cc2sc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc2C)cc1
Temperature: -45 °C
Yield: 37 %

Procedure:
To a solution of crude (3R,4S,5S,6R)-6-(hydroxymethyl)-2-methoxy-2-(4-methyl-5-(4-propylbenzyl)thiophen-2-yl)tetrahydro-2H-pyran-3,4,5-triol (50) in DCM (11.8 mL) and ACN (11.8 mL) was added triethylsilane (0.786 mL, 4.90 mmol) followed by BF3 etherate (0.611 mL, 4.90 mmol) under nitrogen atmosphere at −60° C. The reaction temperature was maintained −60 to −30° C. for 2 hours. The reaction was quenched with a saturated NaHCO3 solution (20 mL), and then extracted with EtOAc (50 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by prep HPLC (C18) to provide the title compound 51 (391 mg, 0.996 mmol, 37%).
Reaction SMILES: CS(O[CH:6]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[C-:25]#[N:26].[Na+].O>CS(C)=O>[C:25]([CH:6]([CH2:16][NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][NH:8][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])#[N:26]
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCC(C#N)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a stirred solution of 2-[(tert-butoxycarbonyl)amino]-1-{[(tert-butoxycarbonyl)amino]methyl}ethyl methanesulfonate (10 g) in dimethyl sulfoxide (100 ml) was added sodium cyanide (2 g) at room temperature and the whole mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residual oil was purified by column chromatography on silica gel (ethyl acetate:hexane=1:5) to give di-tert-butyl (2-cyano-1,3-propanediyl)biscarbamate (4.04 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([N+:22]([O-])=O)[CH:16]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:27]([O-])=O.[Cl-].[NH4+]>CCO.C1COCC1.O.[Fe]>[NH2:27][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:2]=1[Cl:1])[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([NH2:22])[CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cc(CN(Cc2ccc(Cl)c([N+](=O)[O-])c2)c2ccccc2)ccc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(CN(Cc2ccc(Cl)c(N)c2)c2ccccc2)ccc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of product from Example 148C (0.304 g, 0.703 mmol) in EtOH (10 mL), THF (10 mL) and H2O (2.5 mL) was added iron powder (0.393 g, 7.03 mmol), followed by addition of ammonium chloride (0.188 g, 3.52 mmol). The resulting mixture was stirred at 90° C. for 2 hrs and then filtered through celite and washed with ethanol. The filtrate was concentrated in vacuo, and the residue was partitioned between CH2Cl2 and H2O, and the organic layer was dried over anhydrous Na2SO4. The drying agent was filtered off, and solvent was removed in vacuo to give a crude product that was purified by column chromatography on silica gel using a solvent gradient 0-0.1% MeOH in CH2Cl2 to afford the title compound (0.259 gm, 99%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].OO.C([OH:16])C>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][N+:4]([O-:16])=[CH:3][C:2]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCO
Reactant: CCOC(=O)c1cnccn1
Agent: OO
Solvent: CC(=O)O
Product: CCOC(=O)c1c[n+]([O-])ccn1

Procedure:
Compound 26--Ethyl pyrazine carboxylate-4-oxide 3.4 g hydrogen peroxide (30%) was added in three portions over a period of 1 hour to a solution of 3.06 g of ethyl pyrazine carboxylate (prepared as above) in 15 ml of glacial acetic acid at 65° C. After stirring for 16 hours another 3.4 g hydrogen peroxide were added and the solution was stirred for 48 additional hours. The volume of the mixture was reduced, 30 ml of ethanol were added and the solution was filtered. The liquid was evaporated and the residue purified on silica gel with toluene/ethyl acetate to give 0.5 g (14.80) of white ethyl pyrazinecarboxylate-4-oxide; m.pt. 128° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[C:25]1([CH:35]=O)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH:22][CH2:35][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([Br:12])=[CH:10][CH:11]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1N
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1NCc1cccc2ccccc12

Procedure:
(S)-3-(4-Bromo-phenyl)-2-{5-chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester was prepared from (S)-2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (2.5 g, 6.07 mmol) and 1-naphthaldehyde (2.0 g, 13.3 mmol) according to Procedure G, except for the following: after completion of the reaction, 100 mL of DCM was added and the organic washed with saturated sodium bicarbonate, dried over sodium sulfate, and evaporated. The crude material was purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:23]=[CH:24][CH:25]=[N:26]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([NH:26][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=2)[CH2:23][CH2:24]1
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1I
Reaction time: 18 h
Yield: 81.7 %

Procedure:
3-Iodo-4-methylbenzoic acid (5 g, 19.1 mmol) and HATU (8.71 g, 22.9 mmol) in DMF (25 ml) were stirred at room temperature for 10 minutes. HOBT (2.58 g, 19.1 mmol), cyclopropylamine (1.37 g, 22.9 mmol) and DIPEA (2.5 ml, 57.3 mmol) were added and stirring continued for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (100 ml) and aqueous sodium carbonate (1M, 75 ml). The aqueous layer was extracted with DCM (50 ml) and the combined organic phases washed with brine (75 ml) and dried (magnesium sulphate). The solution was absorbed onto silica and purified by chromatography on silica eluting with ethyl acetate/cyclohexane (1:3). The product fractions were reduced to dryness under vacuum to give N-cyclopropyl-3-iodo-4-methylbenzamide (4.7 g, 82%). LCMS: retention time 3.09 min, MH+302.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:23]([CH:28]=O)=[CH:24][CH:25]=[CH:26][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2Cl)CC1

Procedure:
69 mg of the target compound (0.18 mmol, 21.7%) was obtained using 1-(2-methoxyphenyl)piperazine (311 mg, 1.62 mmol), 2′-chlorobiphenyl-2-carbaldehyde (175 mg, 0.81 mmol) and NaBH(OAc)3 (523 mg, 2.43 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:35]([OH:37])=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(OCC3C=CC=CC=3)=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:35]([OH:37])=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-Nε-benzyloxycarbonyl-L-lysine (502 mg, 1.00 mmol) was dissolved in TFA/CH2Cl2 (3 mL/3 mL) and stirred at room temperature for 1 h. The volatiles were removed in vacuo to afford the title compound quantitatively as a white solid.