Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15]/[CH:16]=[C:17](\[CH3:29])/[CH2:18][CH2:19]/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22])\[CH3:13])P(OP([O-])([O-])=O)(=O)[O-].CC1[C@H]2C[C@]3(CC2)[C@@H](CC[C@H]2C(C)(C)CCC[C@@]23C)C=1>CCCCC>[CH3:22][C@@:21]12[C@:16]34[CH2:15][C@H:14]([CH2:29][C@@H:17]3[CH2:18][CH2:19][C@H:20]1[C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][CH2:23]2)[C:12](=[CH2:13])[CH2:11][CH2:10]4
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COP(=O)([O-])OP(=O)([O-])[O-]
Agent: CC1=C[C@@H]2CC[C@H]3C(C)(C)CCC[C@]3(C)[C@@]23CC[C@@H]1C3
Solvent: CCCCC
Product: C=C1CC[C@@]23C[C@@H]1C[C@@H]2CC[C@H]1C(C)(C)CCC[C@@]13C
Yield: 85 %

Procedure:
Chemicals. The preparations of (E,E,E)-geranylgeranyl diphosphate (GGPP), and ent- and syn-copalyl diphosphate (CPP), and syn-stemarene have been previously described. (Mohan et al. 1996). Stemodene standards were derived from a 1.5:1 mixture (ca. 5 mg) of synthetic racemic exo- and endo-stemodenes, kindly provided by Jim White. (White et al. 1994). This was fractionated by flash chromatography on a silica gel column (1 cm×10 cm) using pentane and the later eluting fractions (enriched for the exo isomer) were pooled and concentrated under nitrogen to yield ˜2 mg exo-stemodene (˜85% purity by GC analysis). Unless otherwise noted, chemicals were purchased from Fisher Scientific (Loughborough, Leicestershire, UK) and molecular biology reagents from Invitrogen (Carlsbad, Calif., USA).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]([OH:18])=O)[N:11]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1>C1COCC1>[CH3:19][N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[CH2:31][CH2:30][N:29]([C:16](=[O:18])[CH2:15][N:12]3[CH:13]=[CH:14][C:10]([NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])=[N:11]3)[CH2:28][CH2:27]2)[CH2:24][CH2:25]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: O=C(O)Cn1ccc(NC(=O)c2ccc(Cl)s2)n1
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(C(=O)Cn3ccc(NC(=O)c4ccc(Cl)s4)n3)CC2)CC1

Procedure:
Using general method A, using THF instead of DMF as solvent, {3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrazol-1-yl}-acetic acid (example 57.3) was reacted with 1-(N-methyl-4-piperidyl)-piperazine to give 5-chloro-thiophene-2-carboxylic acid (1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazol-3-yl)-amide. Off-white solid. MS 451.3 ([M+H]+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1
Temperature: 120 °C

Procedure:
A suspension of 3-nitrophenol (837 mg, 6.02 mmole), 1-chloro-3-[imidazo-1-yl]-propane (871 mg, 1 eq), K2CO3 (3.3 gm, 4 eq) and NaI (1.0 gm, 1.1 eq) in DMF was heated at 120° C. for 6 hr. After cooling to RT, the reaction was filtered and the filter cake was washed with DMF. The solvent was removed from the filtrate and the residue was chromatographed (radial chromatography; 4 mm silica gel plate that was eluted with a step gradient of DCM containing 0, 1, 2.5, 5, 7.5% MeOH) to afford 400 mg of 3-[3-imidazo-1-ylpropyloxy]]-nitrobenzene. This was treated with 10% palladium on charcoal (400 mg) in EtOH under a hydrogen atmosphere for 4 hr. Removal of the catalyst and the solvent left 3-[3-imidazo-1-ylpropyloxy]]-aniline was then coupled with 319A as described for 570 to afford 576 (HPLC retention time (YMC ODS S5 4.6×30 mm): 1.33 min). Beginning with 4-nitrophenol and 1-chloro-3-[imidazo-1-yl]-propane 577 (HPLC retention time (YMC ODS S5 4.6×30 mm): 1.42 min) was prepared in a similar manner as 576.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:21][OH:22]>CCOC(C)=O.O>[C:1]1([CH:7]2[CH2:10][C:9](=[N:21][OH:22])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccccc2)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: ON=C1CC(c2ccccc2)C1
Yield: 78.9 %

Procedure:
A yellow slurry of 3-phenylcyclobutanone (1.09 g, 7.44 mmol), MeOH (33.8 mL), water (3.38 mL), potassium carbonate (2.26 g, 16.4 mmol), and hydroxylamine hydrochloride (1.14 g, 16.4 mmol) was heated at 50° C. for 14 hours. The mixture was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (0-50% EtOAc/hexanes, gradient elution) to provide the title compound (947 mg, 5.87 mmol, 79% yield). MS (DCI) M/Z 162 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([NH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:4][C:3]1=2.[BH4-].[Na+].O>CO>[OH:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([NH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)CCCC2O

Procedure:
To a solution of N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (1.00 g, 4.94 mmol) in methanol (20 mL) at 0° C. is added sodium borohydride (0.50 g, 7.41 mmol). The reaction is stirred for 1.5 hours, whereupon water is added and the volatiles are removed in vacuo. The mixture is extracted with dichloromethane and the organic phase is dried over sodium sulfate, filtered, and concentrated to give N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide, which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([O:19][CH3:20])=[O:18])=[C:15](O)[C:10]=3[C:9]3[CH2:23][O:24][CH2:25][CH2:26][C:8]2=3)=[CH:4][CH:3]=1.CCN(CC)CC.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+].[CH3:56][C:57]1[CH:62]=[CH:61][C:60](B(O)O)=[CH:59][CH:58]=1.C([O-])([O-])=O.[Na+].[Na+].[NH4+].[Cl-]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:60]4[CH:61]=[CH:62][C:57]([CH3:56])=[CH:58][CH:59]=4)[C:10]=3[C:9]3[CH2:23][O:24][CH2:25][CH2:26][C:8]2=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(O)c2c3c(n(Cc4ccc(F)cc4)c2c(=O)n1C)CCOC3
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccc(C)cc2)c2c3c(n(Cc4ccc(F)cc4)c2c(=O)n1C)CCOC3
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 13.2 %

Procedure:
An ice cold solution of methyl 5-(4-fluorobenzyl)-9-hydroxy-7-methyl-6-oxo-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylate (2.54 g, 6.57 mmol) and Et3N (4.56 ml, 32.9 mmol) in DCM (40 mL) was treated with Tf2O (2.221 ml, 13.15 mmol). After 15 min, the reaction mixture was poured into sat. aq. NaHCO3 and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was dissolved in 1,4-Dioxane (21.74 ml)/Water (4.35 ml), treated with 4-methylphenyl boronic acid (1.251 g, 9.20 mmol) and Na2CO3 (2.091 g, 19.72 mmol) and then degassed with N2 for 5 min. Pd(PPh3)4 (0.759 g, 0.657 mmol) was added and the reaction mixture was warmed to 80° C. After 2 h, the reaction mixture was poured into sat. aq. NH4Cl and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. the residue was loaded onto celite and purified by ISCO (0-50% EtOAc-hexanes) to afford methyl 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylate (400 mg, 0.869 mmol, 13.21% yield) as a yellow foam. 1H NMR (400 MHz, CHLOROFORM-d)=7.17 (d, 6H), 7.03-6.96 (m, 2H), 5.83 (s, 2H), 3.96 (s, 2H), 3.86 (t, J=5.6 Hz, 2H), 3.60 (s, 3H), 3.56 (s, 3H), 2.64 (t, J=5.5 Hz, 2H), 2.40 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:22]OC)[CH:10]=1)=[O:5])[CH3:2].B(Br)(Br)[Br:26]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:22][Br:26])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2sc(-c3ccccc3)nc2COC)n[nH]1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2sc(-c3ccccc3)nc2CBr)n[nH]1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 36 %

Procedure:
A −78° C. solution of the above-prepared 5-(4-methoxymethyl-2-phenyl-thiazol-5-yl)-2H-pyrazole-3-carboxylic acid ethyl ester (1.5 g, 4.37 mmole, 1.0 eq) in dry CH2Cl2 (20 ml) was treated with a solution of 1.0M BBr3 in CH2Cl2 (5.24 ml, 5.24 mmole, 1.2 eq) and the mixture stirred at −78° C. for 45 minutes, then allowed to warm to room temperature and stirred for one hour. The reaction mixture was quenched by adding saturated NaHCO3, stirred for 30 minutes then extracted twice with CH2Cl2. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow solid. Silica gel chromatography using a gradient elution of (3:2)-(1:1) hexanes-ethyl acetate provided 610 mg (36%) of the title compound as an off white solid. 1H NMR(CDCl3): δ 1.4 (t, 3H), 4.4 (q, 2H), 4.9 (s, 2H), 7.2 (s, 1H), 7.4 (m, 3H), 7.95 (m, 2H), 11.1 (bs, 1H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8](Cl)[N:7]=1>C(O)CCC>[CH:1]1([NH:4][C:8]2[N:7]=[C:6]([Cl:5])[N:14]=[C:13]3[C:9]=2[NH:10][CH:11]=[N:12]3)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: Clc1nc(NC2CC2)c2[nH]cnc2n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Cyclopropylamine (6.65 g, 0.116M) and N,N-dfisopropylethylamine (20.8 ml, 0.116M) is added to a suspension of 2,6-dichloropurine (20 g,0.106M) in n-butanol (200 ml). The mixture is stirred at 60° C. for 20 hours. The mixture is cooled and the precipitate isolated by filtration, washed with n-butanol and dried under vacuum to give 6-cyclopropylamino-2-chloropurine; ES+ (M+1) 209.5; mp 249.7° C. dec.
Reaction SMILES: [C:1]([NH:5][C:6]([CH2:8][N:9]1[C:13]([CH2:14][N:15]=[N+]=[N-])=[C:12]([CH3:18])[N:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([NH:5][C:6]([CH2:8][N:9]1[C:13]([CH2:14][NH2:15])=[C:12]([CH3:18])[N:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncn(CC(=O)NC(C)(C)C)c1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ncn(CC(=O)NC(C)(C)C)c1CN

Procedure:
A solution of 1-t-butylaminocarbonylmethyl-4-methyl-5-azidomethylimidazole (1.27 g, 5.4 mmol) and 10% Pd/C (700 mg) in ethyl acetate (100 ml) was hydrogenated at atmospheric pressure for 5 h. The catalyst was removed by filtration through Celite and the solvents removed in vacuo to give the title compound. 1H NMR (CDCl3) d 1.27 (s, 9 H), 2.23 (s, 3 H), 3.83 (s, 2 H), 4.50 (s, 2 H), 7.08 (br s, 1 H), 7.46 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.ClCCl>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:1])[CH:3]=[O:4]
Reactant: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
In a 250 mL round bottom flask was charged 2-methyl-2-(4-nitrophenyl)propan-1-ol (3.86 g, 19.8 mmol), anhydrous dichloromethane (75 mL), 4-methylmorpholine N-oxide (3.47 g, 29.7 mmol), and 4 Å molecular sieves (9.8 g). TPAP (tetrapropylammonium perruthenate) (346 mg, 0.98 mmol) was added in one portion and the reaction was stirred at ambient temperature for 16 h. Upon completion of the reaction the material was filtered through a pad of silica and concentrated in vacuo. The material was purified by flash chromatography eluting with a gradient of 20% ethyl actetate/hexanes to 30% ethyl actetate/hexanes to give 2-methyl-2-(4-nitrophenyl)propanal (2.11 g, 55.1%).
Reaction SMILES: C(O[C:4]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=O)C.[OH2:17]>>[C:7]1(=[O:16])[N:6]([CH2:4][CH2:4][NH:6][CH2:7][CH2:8][OH:17])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Product: O=C1c2ccccc2C(=O)N1CCNCCO
Reaction time: 2 h

Procedure:
10.4 g (0.1 mol) of N,N-(2-hydroxyethyl),ethyl amine and 22 g (0.1 mol) of N-ethoxycarbonyl phthalimide were dissolved in 50 ml of H2O and stirred for 2 hours. The reaction mixture was lyophilized and the solid product washed with methanol (40 ml). The remaining white solid (Compound 14) was collected and dried.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23](O)=[O:24])=[CH:19][CH:18]=2)=[O:14])[CH:3]=1.Cl.CN.F[B-](F)(F)F.[N:36]1(OC(N(C)C)=[N+](C)C)[C:40]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(#N)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]([NH:36][CH3:40])=[O:24])=[CH:26][CH:27]=2)=[O:14])[CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOc1nc(C(=O)NCc2ccc(OCC(=O)O)cc2)cc(N)c1C#N
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1nc(C(=O)NCc2ccc(OCC(=O)NC)cc2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of Example 188B (19 mg, 0.05 mmol), methylamine HCl salt (7 mg, 0.1 mmol) in N,N-dimethylformamide (500 μL) was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (18 mg, 0.055 mmol), followed by N,N-diisopropylethylamine (44 μL). The reaction mixture was stirred at ambient temperature for 1 hr. It was diluted with 1 mL acetonitrile and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to provide the titled compound as white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.95 (t, J=6.4 Hz, 1H), 8.00-7.94 (m, 1H), 7.29 (bs, 2H), 7.23 (d, J=8.9 Hz, 2H), 7.07 (s, 1H), 6.91 (d, J=8.9 Hz, 2H), 4.49 (q, J=7.1 Hz, 2H), 4.42 (s, 2H), 4.40 (d, J=6.4 Hz, 2H), 2.65 (d, J=4.6 Hz, 3H), 1.31 (t, J=7.1 Hz, 3H). MS (m/e) 384 (M+H)+.
Reaction SMILES: C(C1CCCC1=[O:11])CCCC.[OH-:12].[Li+].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:15][CH3:16]>>[OH:12][OH:11].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:15][CH3:16]
Reactant: [OH-]
Reactant: CCCCCC1CCCC1=O
Agent: [Li+]
Solvent: CCOC(=O)CC
Product: OO
Temperature: 100 °C
Yield: 70 %

Procedure:
In a three-necked 250 ml flask equipped with a magnetic stirrer and a reflux condenser were introduced 31 g of 2-pentyl cyclopentanone (0.2 mole), 31 g of anhydrous ethyl propionate, and 0.048 g (1 mol %) of anhydrous lithium hydroxide. The mixture was brought to reflux at ca. 100° C. Then 57.5 g (0.22 mole) of an anhydrous 13% w/w hydrogen peroxide solution in ethyl propionate, obtained from extraction of a 70% aqueous H2O2 solution by ethyl propionate, were slowly added over 4 h in the reactor while maintaining the reflux 2 h after the end of the introduction. The reaction mixture was then washed with 10% water to remove the non converted H202, and finally distilled to recover the solvent.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[F:4][C:5]([F:12])([F:11])[CH2:6][CH2:7][C:8](Cl)=[O:9].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:4][C:5]([F:12])([F:11])[CH2:6][CH2:7][C:8]([N:2]([CH3:1])[NH2:3])=[O:9]
Reactant: O=C(Cl)CCC(F)(F)F
Reactant: CNN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(N)C(=O)CCC(F)(F)F
Temperature: 0 °C

Procedure:
To a stirred solution of methylhydrazine (7.81 g, 169 mmol) in CH2Cl2 (150 mL) cooled to 0° C. was added over 2 hours 4,4,4-trifluorobutanoyl chloride (2.72 g, 16.94 mmol, 0.3 M solution in CH2Cl2) via a syringe pump. After the addition the reaction was stirred at 0° C. for −1 h and then was allowed to warm to ambient temperature. After an additional hour of stirring at ambient temperature, the reaction mixture was poured into a—saturated aqueous solution of Na2CO3 (400 mL). The organic layer was—separated and the—aqueous solution was extracted with additional CH2Cl2 (1×150 mL). The —CH2Cl2 layers—were—combined, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a yellow liquid: 1H NMR (400 MHz, CDCl3) major rotomer δ 3.77 (s, 2H), 3.20 (s, 3H), 2.93-2.85 (m, 2H), 2.48-2.33 (m, 2H); 13C NMR (101 MHz, CDCl3) major rotomer δ 172.81, 127.22 (q, J=276.0 Hz), 29.55 (q, J=29.4 Hz), 25.70 (q, J=3.0 Hz); 19F NMR (376 MHz, CDCl3) major rotomer δ—66.69.
Reaction SMILES: O.O.O.[Br:4]([O-])(=O)=O.[Na+].[Cl:9][C:10]1[C:18]2[O:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][C:14]=2[CH:13]=[C:12]([C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[O:25])[C:11]=1[Cl:32]>O.C(O)(=O)C>[Cl:9][C:10]1[C:18]2[O:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][C:14]=2[CH:13]=[C:12]([C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][C:27]=2[Br:4])=[O:25])[C:11]=1[Cl:32]
Reactant: CCOC(=O)C1Oc2cc(C(=O)c3ccnn3C)c(Cl)c(Cl)c2O1
Reactant: [O-][Br+2]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1Oc2cc(C(=O)c3c(Br)cnn3C)c(Cl)c(Cl)c2O1
Reaction time: 15 h
Yield: 41.2 %

Procedure:
A solution of 1.53 g of sodium bromate trihydrate in 5 ml of water is added to a solution of 2.0 g of ethyl 4,5-dichloro-6-(1-methyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylate in 20 ml of acetic acid at room temperature. The mixture is stirred at the same temperature for 15 hours. The reaction mixture is concentrated under reduced pressure to remove acetic acid. The residue is neutralized by addition of an aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane-ethyl acetate) to give 1.0 g of ethyl 4,5-dichloro-6-(1-methyl-4-bromo-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylate as an oil.
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20]([NH:22][CH3:23])=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C.[OH:31][CH:32]1[CH2:37][CH2:36][CH:35]([C:38]([NH:40][NH2:41])=O)[CH2:34][CH2:33]1>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20]3[N:22]([CH3:23])[C:38]([CH:35]4[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]4)=[N:40][N:41]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: NNC(=O)C1CCC(O)CC1
Reactant: CNC(=O)C1(c2ccc(Cl)cc2)CC1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1c(C2CCC(O)CC2)nnc1C1(c2ccc(Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Methyl trifluoromethanesulfonate (53.9 μL, 0.491 mmol) was added to 1-(4-chlorophenyl)-N-methylcyclopropanecarboxamide (100.0 mg, 0.48 mmol). The resulting reaction mixture was stirred at 60° C. for 30 min. To the reaction mixture were then added toluene (2.0 mL), triethylamine (68.6 μL, 0.492 mmol) and 4-hydroxycyclohexanecarbo-hydrazide (38 mg, 0.24 mmol). The resulting mixture was stirred for 3 h at 60° C. and an additional 1 h. at 110° C. The mixture was then cooled to room temperature (about 25° C.). After cooling, the reaction mixture was concentrated to provide a residue. The residue was purified by Prep-HPLC to afford the desired products (cis- and trans-two isomers). Isomer I: LCMS: (M+H)+=332.2/334.2; isomer II: LCMS: (M+H)+=332.1/334.1.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:23][C@@H:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26]>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][C:25](=[O:26])[CH:24]([OH:23])[CH:28]([CH3:30])[CH3:29])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(C)[C@H](O)C(=O)O
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC(=O)C(O)C(C)C)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (S)-2-hydroxy-3-methyl-butyric acid to afford the title compound:
Reaction SMILES: [OH:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[C:5]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([C:31](=[O:43])[CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[CH:4][CH:3]=1.Cl.CO.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[C:5]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:31](=[O:43])[CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCNCCc2ccc(O)c3[nH]c(=O)sc23)C(=O)CCOCCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: O=C(CCOCCc1ccccc1)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-{(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)[3-(2-phenylethoxy)propanoyl]amino}piperidine-1-carboxylate (Example 11c), 0.050 g) was stirred with 4N hydrogen chloride in dioxan (1.3 mL). After 15 minutes, methanol (1 mL) was added and the reaction mixture was stirred at room temperature overnight. Ether (5 mL) was added to give a white precipitate. The precipitate was allowed to settle, before decanting off the liquid. The residue was concentrated in vacuo, azeotroping with ether to give the title compound as a white solid (0.030 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH3:15][S:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>C(O)CC>[CH3:15][S:16][C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1)=[CH:18][N+:19]([O-:21])=[O:20]
Reactant: COC(=O)C/C=C/c1ccc(N)cc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCCO
Product: COC(=O)C/C=C/c1ccc(NC(=C[N+](=O)[O-])SC)cc1
Yield: 85.5 %

Procedure:
7.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate was dissolved in 120 ml of n-propanol, followed by the addition of 30.28 g of 1,1-bis(methylthio)-2-nitroethylene. The obtained mixture was heated under reflux for 3 hours and distilled ro remove the solvent. The residue was purified by silica gel column chromatography (solvent: dichloromethane). The obtained solid was washed with ethyl ether to obtain 9.65 g of the title compound as a yellow powder (yield: 86%).