Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([OH:9])=[O:8].[CH2:25](O)[CH3:26]>C(OCC)(=O)C.CO>[NH2:5][C@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([O:9][CH2:25][CH3:26])=[O:8]
Reactant: N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCO
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: -25 °C
Reaction time: 3 h

Procedure:
3.9 cm3 of thionyl chloride are added to a stirred suspension of 7.9 g of (2R)-2-amino-6-{[(benzyloxy)carbonyl]amino}hexanoic acid (Ns-CBZ-D-lysine) in 120 cm3 of anhydrous ethanol cooled to a temperature in the region of −25° C. The mixture is stirred for 3 hours at this temperature and is then allowed to warm to about 20° C. After leaving for 3 days, the reaction mass is concentrated under reduced pressure (5 kPa) at a temperature in the region of 0° C. The residue obtained is taken up in 200 cm3 of ethyl acetate and the resulting solution is washed with aqueous sodium carbonate solution and then with aqueous sodium chloride solution. The organic solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 7.4 g of ethyl (2R)-2-amino-6-{[(benzyloxy)-=carbonyl]amino}hexanoate are obtained in the form of a pale yellow oil. (αD20=−11.7±0.6 at a concentration of 0.5% in methanol).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1.CO/[CH:14]=[C:15](/[C:17](/[O:20][Si](C)(C)C)=[CH:18]/[CH3:19])\[CH3:16].CC(C(CC(C(C)(C)C)=O)=O)(C)C.CC(C(CC(C(C)(C)C)=O)=O)(C)C.CC(C(CC(C(C)(C)C)=O)=O)(C)C.[Eu]>>[CH3:19][CH:18]1[C:17](=[O:20])[C:15]([CH3:16])=[CH:14][O:8][CH:7]1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cn1ncc([N+](=O)[O-])c1C=O
Reactant: C/C=C(O[Si](C)(C)C)/C(C)=C/OC
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: [Eu]
Product: CC1=COC(c2c([N+](=O)[O-])cnn2C)C(C)C1=O
Temperature: 80 °C

Procedure:
To a solution of 2-methyl-4-nitro-pyrazole-3-carbaldehyde (487 mg, 3.14 mmol) in CDCl3 (12 mL) was added [(Z)-1-[(E)-2-methoxy-1-methyl-vinyl]prop-1-enoxy]-trimethylsilane (944 mg, 4.71 mmol) and Resolve-Al™ EuFOD (127 mg, 0.31 mmol). The reaction mixture was heated at 80° C. in a sealed tube for 18 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 3,5-dimethyl-2-(2-methyl-4-nitro-pyrazol-3-yl)-2,3-dihydropyran-4-one as a mixture of diastereomers as a yellow oil (829 mg). A solution of this oil (829 mg, 3.14 mmol) and cerium(III) chloride heptahydrate (4.8 g, 12.56 mmol) in MeOH (10 mL) was stirred at room temperature for 15 min. After cooling to 0° C., sodium borohydride (143 mg, 3.8 mmol) was added portionwise and the mixture was stirred at 0° C. for 1 hr. The reaction was quenched with 1 M aqueous HCl (10 mL) and extracted with EtOAc (50 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in MeOH (40 mL) and treated with tosic acid monohydrate (87 mg). The mixture was heated at reflux for 18 hr and concentrated under reduced pressure. The residue was dissolved in DCM (30 mL) and the organic layer was washed with aqueous NaHCO3 (2×20 mL), washed with brine (20 mL), passed through a phase separation cartridge and concentrated under reduced pressure to give 5-(6-methoxy-3,5-dimethyl-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-pyrazole as a yellow oil (558 mg, 51% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.15-7.98 (m, 1H), 5.90 (d, J=3.6 Hz) and 5.78 (d, J=3.2 Hz) (1H), 5.72 (d, J=5.6 Hz) and 5.64 (d, J=10.8 Hz) (1H), 4.80 and 4.76 (2s, 1H), 4.16 and 4.06 (2s, 3H), 3.42 and 3.40 (2s, 3H), 2.65-2.58 (m, 1H), 1.77 and 1.65 (2s, 3H), 0.90 (d, J=7.2 Hz) and 0.83 (d, J=7.2 Hz) (3H).
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+:12](CC)([O-])=[O:13].C=CCCCC>C(N(CC)CC)C>[CH3:1][C:2]1[CH2:10][CH:9]([CH2:8][CH2:7][CH2:3][CH3:4])[O:13][N:12]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C=CCCCC
Solvent: CCN(CC)CC
Product: CCCCC1CC(C)=NO1

Procedure:
A reactor was charged with 20.0 parts phthalic anhydride, 20.9 parts nitroethane, 34.0 parts 1-hexene and heated to reflux. Then, 13.8 parts of triethylamine was slowly added over a one hour period. The mixture was refluxed for 20 hours. The product mixture was vacuum fractionally distilled to provide 3-methyl-5-butylisoxazoline in good yields.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:42]2[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][CH2:51][OH:52])=[C:44]([O:53][CH3:54])[N:43]=2)=[CH:24]\[C@@H:25]2[N:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=3[O:39][CH3:40])[C:28](=[O:41])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].O>C(Cl)(Cl)Cl>[CH3:8][S:9]([O:52][CH2:51][CH2:50][CH2:49][CH2:48][C:45]1[C:44]([O:53][CH3:54])=[N:43][C:42](/[C:23](/[C:20]2[CH:21]=[CH:22][C:17]([C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:18][CH:19]=2)=[CH:24]/[C@H:25]2[CH2:26][CH2:27][C:28](=[O:41])[N:29]2[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=2[O:39][CH3:40])=[CH:47][CH:46]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCO)c(OC)n2)c(OC)c1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCOS(C)(=O)=O)c(OC)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (50 μL) and methanesulfonyl chloride (25 μL) were added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(4-hydroxybutyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (144 mg) in chloroform (2 mL), and the mixture was stirred at room temperature for three hours. Triethylamine (50 μL) and methanesulfonyl chloride (25 μL) were further added thereto and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)butyl methanesulfonate as a crude product. 2 M dimethylamine (solution in methanol) (3 mL) was added to 4-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)butyl methanesulfonate, and the mixture was stirred at room temperature for 17 hours. The solvent was evaporated from the reaction solution and then water was added, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0→4:1) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-[4-(dimethylamino)butyl]-6-methoxypyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]#[C:13]Br.C(N(CC)CC)C>CC(C)=O>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[C:13]#[N:12]
Reactant: N#CBr
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N#CN1C(=O)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
To a 25 mL round-bottomed flask was added phthalimide (1.47 g, 10.0 mmol), cyanogen bromide (1.27 g, 12.0 mmol), and 10 mL of reagent grade acetone. The resulting mixture was cooled using an ice/salt bath while triethylamine (1.8 mL, 12.8 mmol) was added dropwise over a 2 minute period. After 15 minutes, the mixture was transferred to a separatory funnel and partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, dried (MgSO4), and filtered. The solution was decolorized with activated charcoal, and concentrated to give a brown solid. This material was recrystallized from ethyl acetate to give 1.32 g (77%) of a brown crystalline solid, mp 189°-191° C. (reported in Zh. Org. Khim. 1977, 13, 968 as 190° C.): IR (nujol) 2258 (nitrile), 1755 (carbonyl) cm-1 ; 1H NMR (200 MHz, DMSO) δ 8.05-8.15 (m, 4); 13C NMR (50 MHz, DMSO) δ 162.61, 136.35, 130.76, 125.03, 102.86.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH:29]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:30]([O:32]C)=[O:31])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.O>C1COCC1>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH:29]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:30]([OH:32])=[O:31])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Reaction time: 2.5 h
Yield: 94 %

Procedure:
In a similar manner as described in step 2 of Example 12, the title compound was prepared from methyl 2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate (0.186 g, 0.355 mmol), prepared in the previous step, and 1N NaOH (0.53 mL, 0.53 mmol) in 2:2:1 THF:MeOH:water (25 mL). The starting material required heating to dissolve in the THF (10 mL). After the solution was clear, MeOH (10 mL) was added followed by the water (5 mL). The reaction was complete after 2.5 hours. The solids were isolated by filtration to give 2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid as a beige solid (0.17 g, 94%), mp 194–196° C. (dec). Elemental Analysis for C35H27NO3.0.23 H2O Calc'd: C, 81.83; H, 5.39; N, 2.73. Found: C, 81.07; H, 5.44; N, 2.56.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1Br.C(N(CC)CC)C.N>CN(C)C=O.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>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:23][CH2:22][CH:17]2[CH2:16][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1OCC1CCCCC1
Reactant: C#CC1CCN(Cc2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C(#CC1CCN(Cc2ccccc2)CC1)c1ccccc1OCC1CCCCC1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 13.7 %

Procedure:
1.19 g of 1-benzyl-4-ethynylpiperidine was dissolved in 20 ml of N,N-dimethylformamide, 1.774 g of (2-cyclohexylmethyloxy)bromobenzene, 114 mg of cuprous iodide, 0.92 ml of triethylamine and 347 mg of tetrakis(triphenylphosphine)palladium were added thereto, and the mixture was stirred at 100° C. for 3.5 hours under anitrogen atmosphere. Ice-water and a diluted ammonia were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After filtering through alumina and silica gel, the solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to give 316 mg of the title compound as a slight yellow oil.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[NH:28]([CH3:43])[C@H:29]([C:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32]>C(Cl)(Cl)Cl.O>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([N:28]([CH3:43])[C@H:29]([C:34]([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:35])[CH2:30][CH:31]([CH3:32])[CH3:33])=[O:6])[CH3:3]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN[C@@H](CC(C)C)C(=O)Cc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H](C(=O)Cc1ccccc1)N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: -20 °C

Procedure:
18.9 g (100 m mol) Boc-(D)-Ala-OH are dissolved in 250 ml chloroform and cooled with stirring to -20° C. 23.1 ml (21.2 g=210 m mol) N-methylmorpholine and 12.2 ml (12.0 g=100 m mol) pivaloyl chloride are then added and the whole stirred for 2 hours, still at -20° C. Anhydride formation is followed by means of IR control. When anhydride formation is complete 23.5 g (100 m mol) H-MeLeu-Bzl dissolved in 50 ml chloroform are added dropwise to the obtained reaction mixture at -20° C. and over a period of 5 minutes. Formation of the dipeptide is followed using thin-layer chromatography and IR-spectrometry. After 19 hours no further anhydride can be detected. The obtained reaction solution is poured onto 300 ml water and diluted with 300 ml chloroform. The organic phase is separated, washed with 100 ml water, dried over sodium sulphate, filtered and the solvent carefully evaporated off at max. 40° C. The obtained residue is recrystallised from hexane to yield the title compound: rotation, [α]D25 =-35.3° C. (c=1.05 m chloroform; M.P.=81° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:13]([F:12])([F:22])[F:23])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)cnc1Cl
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Br)cnc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 140 °C
Yield: 24.3 %

Procedure:
A mixture of 5-bromo-2-chloronicotinic acid (2.36 g, 10 mmol), 4-trifluoromethoxyphenol (2.14 g, 12 mmol) and K2CO3 (4.14 g, 30 mmol) in DMF (30 mL) was heated at 140° C. for 24 h. After cooling to room temperature the mixture was diluted with water (150 mL) and the pH was adjusted to 6 with acetic acid. The mixture was extracted with EtOAc (3×50 mL) and the combined organic extracts were dried (MgSO4) and evaporated to give an oil. This was triturated with water to give a sticky solid which was filtered and washed with water and then pentane. The resulting beige solid was suspended in further pentane, sonicated, filtered and dried in vacuo at 60° C. to give the product (0.92 g, 24%) as a beige solid; (δH (CDCl3, 300 MHz) 7.19 (2H, m), 7.28 (2H, m), 8.35 (1H, s), 8.58 (1H, s); MS m/z (TS+) 378, 380 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]2[CH:6]=[C:7]3[C:14](=O)[NH:13][CH2:12][C@@H:11]([CH3:16])[N:8]3[C:9]=2[CH:10]=1>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]2[CH:6]=[C:7]3[CH2:14][NH:13][CH2:12][C@@H:11]([CH3:16])[N:8]3[C:9]=2[CH:10]=1
Reactant: C[C@@H]1CNC(=O)c2cc3cc(Cl)c(Cl)cc3n21
Solvent: Cc1ccccc1
Product: C[C@@H]1CNCc2cc3cc(Cl)c(Cl)cc3n21
Product: Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
(R)-7,8-Dichloro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one was suspended in toluene and the mixture heated to reflux to remove traces of water. The mixture was cooled to 0° C. (ice-bath) before the addition, via syringe, of borane in tetrahydrofuran. The mixture was stirred 15 min at 0° C., and heated to reflux. After 4 h, the mixture was cooled and excess borane destroyed by the slow addition of a 10% sodium carbonate solution (10 ml). The phases were separated, the aqueous phase extracted with ethyl acetate (2×25 ml), the combined organic phases washed with brine, dried over magnesium sulfate and evaporated. The resulting oil was dissolved in ethyl acetate (5 ml) and a solution of HCl in ethyl acetate added dropwise. The product precipitated out of solution after a short while. It was filtered, washed with a small amount of ethyl acetate and dried to afford the title compound as a white solid (yield 65%).ISP-MS: m/e 255.0 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[I:9]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([I:9])=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Cl)ccn1
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(I)cn1
Temperature: 80 °C
Yield: 66.8 %

Procedure:
4-Chloropyridin-2-amine (0.142 g, 1.10 mmol) and N-iodosuccinimide (0.273 g, 1.22 mmol) were combined in 1.5 mL of acetic acid. The solution was sonicated briefly and then heated to 80° C. After 1 hour the solution was cooled to room temperature and then concentrated under vacuum. After adjusting the pH to ˜ 8/9 with aqueous ammonia, a light brown solid was collected by filtration. The solid was purified on a 12 g Combiflash column eluting with a gradient of DCM to 5% methanol/0.25% NH4OH (˜28% in water)/DCM. The fractions containing the product were combined and concentrated under vacuum to give 4-chloro-5-iodopyridin-2-amine (187 mg, 67%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.20 (1 H, s), 6.69 (1 H, s), 6.40 (2 H, s); LCMS-ESI (POS), M/Z, M+1: Found 254.9.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:10]=1)=[O:8])C.O.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36](S(O)(=O)=O)=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH2:43]([N:6]1[CH:5]=[CH:4][C:13]2=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:11]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:10]=[C:9]2[C:7]1=[O:8])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(CNC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1)OCC
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2ccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
A mixture of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (2,2-diethoxyethyl)-amide (I-1A-1a; 528 mg, 0.92 mmol) and p-toluenesulfonic acid monohydrate (175 mg, 0.92 mmol) in toluene (5 ml) was heated to reflux in round bottom flask fitted with a Dean-Stark condenser. After 1 hour, the reaction was cooled to room temperature, and then extracted from saturated aqueous sodium bicarbonate with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), a concentrated, in vacuo. The crude material (0.49 g) was purified on a Biotage™ Flash 40S column using 10-20-40% ethyl acetate in hexanes as eluant to afford I-1A-1b as a solid (69 mg, 16%): +ES MS (M+1) 480.1; 1H NMR (500 MHz, CD2Cl2) δ 7.50 (d, J=1.5 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.42 (dd, J=8.3, 2.1 Hz, 1H), 7.38-7.27 (m, 7H), 7.18 (d, J=8.7 Hz, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.42 (d, J=7.5 Hz, 1H), 5.21 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([Br:31])[C:28](=[O:32])[N:27]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)C.C(Cl)(Cl)[Cl:44].CO>>[ClH:44].[Br:31][C:29]1[C:28](=[O:32])[N:27]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[CH:30]=1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(Br)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Solvent: CO
Solvent: CCOCC
Product: Cl
Product: O=c1c(Br)cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reaction time: 18 h

Procedure:
4-[6-(6-Bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 0.46 mmol) prepared as in Example 2 was dissolved in 1:1 chloroform/methanol (15 ml), to which was added diethyl ether (25 ml). The solution was purged with anhydrous hydrogen chloride gas and stoppered for 18 hours. The resulting white solid was filtered, washed with diethyl ether and dried in vacuo at 60° C. to give 6-bromo-8-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride as a pale yellow solid (0.254 g). MS (APCI); M++1: Calc, 470.12, Found, 470.0. Analyses for C21H24BrN2O.1.25 H2O.2.2HCl: Calc'd: C, 44.01; H, 5.05; N, 17.11, Cl (ionic), 13.61; H2O, 3.93. Found: C, 43.74; H, 5.07; N, 16.78; Cl (ionic), 13.73 ; H2O, 3.81
Reaction SMILES: [N: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][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[C:21]1(CCC[Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:32]1C[O:35][CH2:34][CH2:33]1>>[C:21]1([CH:17]([C:16]2[CH:19]=[CH:20][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:14][CH:15]=2)[CH2:32][CH2:33][CH2:34][OH:35])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: Br[Mg]CCCc1ccccc1
Product: OCCCC(c1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of the aldehyde from Step I, (1.34 g) in THF at 0° was added dropwise the 3-phenylpropylmagnesium bromide (1.1 mol. equiv., from above). After 30 mins, the reaction was quenched by the addition of 25% aqueous NH4OAc solution. The mixture was then extracted with ethyl acetate (x2), the organic phase was washed with brine (x2), dried and evaporated under reduced pressure. The title compound was obtained after recrystallization from ethyl acetate/hexane, m.p. 118°-119°.
Reaction SMILES: [CH2:1]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[NH:4]C[CH2:2]1.[CH2:10](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.BrCC(OCC1C=CC=CC=1)=O>C1COCC1>[NH2:4][C@H:5]([C:7]([OH:9])=[O:8])[C@H:6]([CH2:1][CH3:2])[CH3:10]
Reactant: O=C(O)[C@@H]1CCCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: O=C(CBr)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 318.4 %

Procedure:
Using the procedure described in Example 5 and Example 17, L-homoproline-L-isoleucine benzylamide (43 mg, 0.13 mmol), was treated with triethylamine (91 uL, 0.65 mmol, 1.5 eq), and benzyl 2-bromoacetate (41 uL, 0.26 mmol, 2.0 eq) in THF (2.5 mL). Purification by HPLC provided 54.3 mg of L-isoleucine, N-[1-(2-(carbobenzyloxymethylene)-2-oxoethyl)-L-homoprolyl] benzylamide.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]([O-])=[O:15].[Na+].S(=O)(=O)(O)O>ClC=C(Cl)Cl>[N:14]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:15]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC=C(Cl)Cl
Product: O=NN(c1ccccc1)c1ccccc1

Procedure:
210 g of 20% diphenylamine solution in trichloroethylene, 59 g of 38% sodium nitrite aqueous solution and 150 g of 20% sulfuric acid are simultaneously fed, under stirring, (Re = 8-10×103) at 17°-20° C. for about 7-10 min into a 500 ml reactor equipped with a cooling jacket, a thermometer and an agitator; this is followed by another stirring for about 5-8 min. The stirring is discontinued after said period of time has elapsed; complete layer separation of the organic and aqueous phases takes place during 15-20 min. 217 g of organic phase containing 48.4 g of N-nitrosodiphenylamine and 0.42 g of diphenylamine are obtained. Diphenylamine conversion degree is 99%; N-nitrosodiphenylamine yield, 99.3% in terms of converted diphenylamine.