Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCCN=C=NCC.[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.[N:24]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=[C:25]=S.C(OCC)(=O)C>O1CCCC1>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=[C:25]1[NH:24][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(N=C=S)cc1
Reactant: COCCNc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCn1c(Nc2ccc(C(=O)OC)cc2)nc2ccccc21
Temperature: 25 °C
Yield: 68.9 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 791 mg) is added to a solution of N1-(2-methoxyethyl)benzene-1,2-diamine (311 mg, 1.87 mmol) and methyl 4-isothiocyanatobenzoate (328 mg, 1.70 mmol) in tetrahydrofuran. The reaction may be heated to reflux for 2 hr and cooled to room temperature. The mixture may be diluted in an appropriate solvent such as ethyl acetate, filtered and concentrated. The residue may be purified by any appropriate method, including Biotage column chromatography to give methyl 4-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-ylamino)benzoate (381 mg).
Reaction SMILES: Br.Br[C:3]1[CH:8]=[CH:7][N:6]=[N:5][CH:4]=1.[C:9]1(B2OC(C)(C)C(C)(C)O2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[C:9]1([C:3]2[CH:8]=[CH:7][N:6]=[N:5][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: Brc1ccnnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C1=C(c2ccnnc2)CCCC1
Yield: 89.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using 4-bromopyridazine hydrobromide (0.50 g, 2.09 mmol), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.43 g, 2.09 mmol), tetrakis(triphenylphosphine)palladium (0) (0.12 g, 0.10 mmol), cesium carbonate (1.50 g, 4.59 mmol), 1,4-dioxane (7.0 mL) and water (3.5 mL), to yield the title compound (301 mg, 99%) as a colorless solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9].S(Cl)(Cl)=O.C(N(CC)CC)C.O[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([O:10][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:9]
Reactant: OCCN1CCOCC1
Reactant: O=C(O)C1CC2C=CC1C2
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(OCCN1CCOCC1)C1CC2C=CC1C2
Yield: 75 %

Procedure:
Cyclopentadiene, which was obtained by thermolysis of dicyclopentadiene, was dissolved in a conventional organic solvent, and the solution was cooled to about −30° C. About 1 equiv. of cooled acryl acid was slowly added to the solution. The reaction mixture was stirred for about 10 hours, after which the reaction mixture was allowed to reach room temperature and stirred for additional 10 hours. The solvent was removed using a rotary evaporator, and 5-norbornene-2-carboxylic acid was obtained by vacuum distillation. About 1 mole of 5-norbornene-2-carboxylic acid and about 1 mole of thionyl chloride were slowly combined and agitated in a bath. The remaining or unreacted thionyl chloride was removed and about 1 mole of triethylamine and 4-(2-hydroxyethyl)morpholine were added to the mixture. The reaction mixture was extracted with ethyl acetate. And the organic layer was separated, dried over anhydrous MgSO4, and concentrated to provide the title compound represented by formula 1a in 75% yield.
Reaction SMILES: N[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([Br:13])=[C:6]([F:14])[C:3]=1[C:4]#[N:5].N(OC(C)(C)C)=O.O>O1CCCC1>[Br:13][C:7]1[C:6]([F:14])=[C:3]([CH:2]=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1c(N)c([N+](=O)[O-])cc(Br)c1F
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc([N+](=O)[O-])cc(Br)c1F
Temperature: 50 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a cooled (0° C.) solution of 2-amino-5-bromo-6-fluoro-3-nitro-benzonitrile (8.0 g, 30.8 mmol) in tetrahydrofuran (40 mL) was added tert-butyl nitrite (4.6 mL, 37 mmol) dropwise and stirred for 16 h at 50° C. The reaction mixture was treated with water and extracted with ethyl acetate. The organic fraction was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (2% to 10% ethyl acetate:hexanes) afforded 4.0 g (53%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.72 (dd, J=3.0, 2.7 Hz, 1H), 8.51 (dd, J=3.0, 2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([Cl:21])=[C:16]([OH:22])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]#[N:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([Cl:21])=[C:16]([O:22][CH2:24][C:25]#[N:26])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1c(Cl)ccc2c1c1ccccc1n2Cc1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1c(Cl)ccc2c1c1ccccc1n2Cc1ccccc1
Temperature: 85 °C
Reaction time: 12 h
Yield: 113.9 %

Procedure:
A mixture of 9-benzyl-3-chloro-9H-carbazol-4-ol (0.227 g, 0.739 mmol), bromoacetonitrile (0.177 g, 1.48 mmol), potassium carbonate (0.204 g, 1.48 mmol), and DMF (2 mL) is heated at 85° C. for 4 h, then allowed to cool and stir at room temperature for 12 h. Additional bromoacetonitrile (0.177 g) and potassium carbonate (0.204 g) are added and the mixture is heated again at 85° C. for 2 h. After cooling, the mixture is combined with that from another experiment run in the same manner (starting with 0.15 g of 9-benzyl-3-chloro-9H-carbazol-4-ol) and the combined mixtures are partitioned between ethyl acetate-aq. ammonium chloride/brine and brine. The organic layer is dried over magnesium sulfate and concentrated to dryness. Chromatography on silica gel (55 mL) using ethyl acetate-hexane (10/90) gave 0.292 g of [(9-benzyl-3-chloro-9H-carbazol-4-yl)oxy]acetonitrile as a clear liquid. 1H NMR (CDCl3) δ5.07, 5.50, 7.11, 7.15, 7.25-7.47, 7.50, 8.34.
Reaction SMILES: [C:1]([NH:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[NH2:27][CH2:26][CH2:25][NH:24][C:1](=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCN
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
tert-Butyl 2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylcarbamate (600 mg, 1.27 mmol) was taken up in 2 mL of EtOAc along with 2 mL of saturated HCl in EtOAc at 0° C. The resulting reaction mixture was stirred at room temperature for 2 h. Saturated aqueous Na2CO3 was added to adjust the pH=8. The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure to afford 470 mg of the (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-aminoethyl)docosa-4,7,10,13,16,19-hexaenamide (98% yield).
Reaction SMILES: [Cl-:1].C([N:4]1[CH:8]=[C:7]2[S:9][C:10]([CH2:12][NH3+:13])=[CH:11][C:6]2=[N:5]1)C.[CH2:14](N1C2C=C(C(OC)=O)SC=2C=N1)[CH3:15].Cl.S1C2C=CN=CC=2C=C1CN>>[Cl-:1].[CH2:14]([N:5]1[C:6]2[CH:11]=[C:10]([CH2:12][NH2:13])[S:9][C:7]=2[CH:8]=[N:4]1)[CH3:15]
Reactant: CCn1cc2sc(C[NH3+])cc2n1
Reactant: CCn1ncc2sc(C(=O)OC)cc21
Agent: Cl
Agent: NCc1cc2cnccc2s1
Agent: [Cl-]
Product: CCn1ncc2sc(CN)cc21

Procedure:
Intermediate G′ was prepared from methyl 1-ethyl-1H-thieno[3,2-c]pyrazole-5-carboxylate (G′-3) following similar procedures for synthesizing intermediate D from D-2, as described above. MS (m/z): 182 (M+1)+.
Reaction SMILES: [K].[NH:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Br:9][CH2:10][CH2:11][CH2:12]Br>CN(C)C=O>[Br:9][CH2:10][CH2:11][CH2:12][N:4]1[C:5](=[O:7])[CH2:6][NH:2][C:3]1=[O:8]
Reactant: O=C1CNC(=O)N1
Reactant: BrCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1CNC(=O)N1CCCBr

Procedure:
The potassium salt of 2,4-imidazolinedione (hydantoin; 5.5 g, 0.04 mole; prepared as in Example 44) was reacted with 1,3-dibromopropane (14.3 ml, 0.14 mole) in 50 ml of dimethylformamide for 16 hours at room temperature and then for 2 hours at reflux. The reaction mixture was filtered, evaporated to dryness, and the residue recrystallized from isopropyl alcohol (950 mg, m.p. 103°-106° C., m/e 222/220).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([N:21]5[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23][CH2:22]5)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=[C:4]2[CH:3]=1.[CH2:36](N(CC)CC)[CH3:37]>C1COCC1.CC(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:36]([C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([N:21]5[CH2:22][CH2:23][CH:24]([CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33])[CH2:25][CH2:26]5)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=[C:4]2[CH:3]=1)=[CH2:37]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(I)ccn45)nc23)CC1
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=Cc1ccn2c(-c3ccc4cccc(N5CCC(CNC(=O)OC(C)(C)C)CC5)c4n3)nnc2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To tert-butyl (1-(2-(7-iodo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (91 mg, 0.16 mmol) in THF/IPA (2/1 mL) was added C2H3BF3K (31 mg, 0.23 mmol), PdCl2(dppf) dichloromethane adduct (13 mg, 0.016 mmol) and triethylamine (24 mg, 0.23 mmol). The reaction was stirred for 2 hours, and then heated at 60° C. overnight. The reaction was cooled to ambient temperature and concentrated. The crude material was purified by silica gel chromatography (20:1 Hexane/EtOAc) to provide the final product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[CH:17]=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1.C(OC(=O)C)C>C1COCC1>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:16][CH2:17][CH2:8]1
Reactant: O=c1cnc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)NCCN2
Temperature: 0 °C
Yield: 66 %

Procedure:
Basically, a 500 ml, three-necked flask was charged with lithium aluminum hydride (300 ml, lM in THF, 300 mmol) under an inert atmosphere. To the lithium aluminum hydride was added 2-keto-1,2-dihydroquinoxaline (22 g, 0.15 mol) in dry THF (100 ml) in small portions to prevent a sharp rise of temperature. After the addition was complete, the mixture was heated at the refluxing temperature of THF for 4 hours. The excess lithium aluminum hydride was decomposed by a slow addition of ethylacetate (10 ml) at room temperature. The resulting mixture was dropped slowly into ice water and extracted with diethyl ether. The diethyl ether solution was dried over anhydrous MgSO4, filtered and the solvent evaporated to give a yellow solid. The solid was recrystallized in hexane to give 1,2,3,4-tetrahydroquinoxaline in 66% yield.
Reaction SMILES: [Br:1]Br.[CH:3]1[C:13]2[C:12](=[O:14])[CH2:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:11]1[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[CH2:8][C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[C:12]1=[O:14]
Reactant: BrBr
Reactant: O=C1Cc2ccccc2Cc2ccccc21
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2Cc2ccccc2C1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.34 ml of bromine in 10 ml of carbon tetrachloride was added to a solution of 5 g of 10,11-dihydro-[5H]-dibenzo (a,d) cycloheptene-11-one in 60 ml of carbon tetrachloride cooled to 0° C and after stirring for 30 minutes at room temperature, the insolubles were filtered off. The filtrate was distilled to dryness under reduced pressure to obtain 6.6 g of raw product which was crystallized from methanol to obtain 10-bromo-10,11-dihydro-[5H]-dibenzo (a,d) cycloheptene-11-one melting at 82°-84° C. The product was identical to that described by Rigaudy et al [Bull. Soc. Chim., 1959, p. 638].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[CH:8]=[C:9]([S:14](Cl)(=[O:16])=[O:15])[CH:10]=[C:11]([Cl:13])[CH:12]=1>O1CCOCC1>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][S:14]([C:9]1[CH:8]=[C:7]([Cl:6])[CH:12]=[C:11]([Cl:13])[CH:10]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: NCCCN
Solvent: C1COCCO1
Product: NCCCNS(=O)(=O)c1cc(Cl)cc(Cl)c1
Yield: 29.2 %

Procedure:
1,3-Diaminopropane (6 g, 81.5 mmol) was dissolved in 45 ml of 1,4-dioxane, and at 15-20° C. a solution of 3,5-dichlorobenzenesulfonyl chloride (2 g, 8.15 mmol) in 5 ml of 1,4-dioxane was slowly added over 3 hours under stirring. Stirring was continued at RT. After 30 hours the formed precipitate was filtered off and the filtrate concentrated in vacuo. The residue was distributed between ethyl acetate and water. The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated in vacuo to yield 2.0 g of crude material. 750 mg of this material was purified by HPLC to yield 675 mg of the title compound as TFA salt (MS=283.0 (M+H)+). 200 mg of this product was dissolved in ethyl acetate and treated with 5 ml of diluted potassium carbonate solution. The organic layer was separated, dried, filtered, and concentrated in vacuo to yield the TFA free title amine.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:11]([C:12](=[O:23])[CH:13]([NH:15]C(=O)OC(C)(C)C)[CH3:14])[N:10]=[C:9]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[S:8]1)=[N+:2]=[N-:3].Cl>CCO>[NH2:15][CH:13]([CH3:14])[C:12]([N:11]1[N:10]=[C:9]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[S:8][C:7]1([CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:23]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(N)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
tert-Butyl 1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-1-oxopropan-2-ylcarbamate (70 mg, 0.131 mmol) was dissolved in 7.0 mL of EtOH. HCl (0.65 mL, 0.659 mmol) was then added and the reaction stirred at 23° C. for 4 hours. The reaction was then concentrated and purified by chromatography (2-10% MeOH/DCM), yielding the product (54 mg, 95%) as a yellow oil. MS ESI (+) m/z 431 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ7.69 (m, 1H), 7.53 (d, 2H, J=8 Hz), 7.42 (t, 2H, J=7 Hz), 7.34 (m, 3H), 4.91 (m, 3H), 3.21 (m, 1H), 3.17 (m, 2H), 2.68 (m, 1H), 2.19 (m, 1 H), 1.99 (m, 1H), 1.73 (d, 1.5 H, J=8 Hz), 1.64 (d, 1.5 H, J=8 Hz).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]([OH:23])=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[NH2:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:36][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH3:35])[NH:26][C:21](=[O:23])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:25])([F:1])[F:24])[CH:4]=3)=[CH:13][CH:12]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 28 (30 mg, 0.085 mmol), tert-butyl 2-amino-2-methylpropanoate (15.0 mg, 0.088 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.01-1.16 (m, 2 H), 1.26-1.31 (m, 6 H), 1.3-5 (s, 9 H), 1.40-1.53 (m, 2 H), 1.68-1.77 (m, 1 H), 1.77-1.90 (m, 4 H), 1.93-2.02 (m, 2 H), 8.01 (s, 1 H), 13.98 (s, 1 H): MS (ESI) min 494 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.[NH2:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15].C(=O)=O.CC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:8]=[C:7]1[NH:9][C:2]([C:1]([NH:12][CH:13]([CH:14]([CH3:16])[CH3:15])[C:17]([OH:19])=[O:18])=[O:10])=[CH:3][C:4](=[O:5])[NH:6]1
Reactant: O=C(Cl)c1cc(=O)[nH]c(=O)[nH]1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)C(NC(=O)c1cc(=O)[nH]c(=O)[nH]1)C(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the orotoyl chloride solution, 6.56 g (56 mmol) of Valine is suspended, with stirring, in 50 mL of dry DCM. To this suspension a catalytic amount (˜0.1 mmol) of DMAP is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of about −15° C. When the target temperature is reached the drop wise addition of orotoyl chloride is commenced. Addition of orotoyl chloride continues, with constant cooling and stirring, until all of the orotoyl chloride is added, after which the reaction is allowed to warm to room temperature with constant agitation. The solution is then filtered to remove any remaining Valine and the volatile DCM is removed from the filtrate under reduced pressure, the remainder is then purified by flash chromatography (ethyl acetate/hexanes; 1/6), yielding 2-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-3-methylbutanoic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13]
Reactant: CC(C)N1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 130 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (1.35 g, 7.8 mmol), 1-isopropyl-piperazine (2.0 g, 15.6 mmol) and anhydrous potassium carbonate (1.18 g, 8.6 mmol) in N,N-dimethylacetamide (2.5 ml) was stirred at 130° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured onto cold water and stirred vigorously for 3 h. The resulting brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting brown solid was slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 5-(4-Isopropyl-piperazin-1-yl)-2-nitro-phenylamine (1.1 g, 53%) and used in the next step without further purification.
Reaction SMILES: [CH3:1][Mg]I.Br[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2.O>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2
Reactant: C[Mg]I
Reactant: Brc1cccc2cnccc12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1cccc2cnccc12

Procedure:
A 3M solution of methyl magnesium iodide in ether (50 ml, 0.15 mol) was added dropwise to a stirred, ice-cooled solution of 5-bromoisoquinoline (21 g, 0.10 mol), obtained by the method described in J. Org. Chem., 1904, 29, 329, and [l,3-bis(diphenylphosphino)-propane]nickel(II) chloride (400 mg, 0.7 mmol) in anhydrous ether and the reaction mixture heated under reflux for 5 days, allowed to cool, then poured into water (500 ml). The organic phase was separated, combined with ether extracts of the aqueous phase, washed with saturated brine, dried (MgSO4) and evaporated under reduced pressure to yield an oil, chromatography of which on silica gel, using a 5-50% ether in hexane elution gradient, provided the required product (8.4 g). Rf 0.40 (SS 8), m/e 144 (M+H)+. Found: C,79.57; H,6.26; N,8.61. C10H9N; 0.27 CH3CO2CH2 CH3 requires C,79.70; H,6.74; N,8.39%.
Reaction SMILES: [CH:1]([O:4][CH2:5][C@@H:6]([OH:9])[CH2:7][OH:8])([CH3:3])[CH3:2].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:10]([O:8][CH2:7][C@H:6]([OH:9])[CH2:5][O:4][CH:1]([CH3:3])[CH3:2])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)OC[C@@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC[C@@H](O)CO[Si](C)(C)C(C)(C)C

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 34 step iii) using (2S)-3-isopropoxypropane-1,2-diol (0.80 g) (the product from step (ii) in DCM (10 mL), tert-butyldimethylsilyl chloride (1.59 g), triethylamine (1.43 mL) and 4-(dimethylamino)pyridine (50 mg) at 0° C. to give the subtitle compound as a clear, colourless oil. Yield: 1.86 g
Reaction SMILES: [N:1]([C@@H:4]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C@H:5]1[O:10][C:8](=[O:9])[C@H:7]([CH:11]([CH3:13])[CH3:12])[CH2:6]1)=[N+:2]=[N-:3]>C(N)CCC>[CH2:4]([NH:1][C:8](=[O:9])[C@H:7]([CH:11]([CH3:13])[CH3:12])[CH2:6][C@H:5]([OH:10])[C@@H:4]([N:1]=[N+:2]=[N-:3])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:5][CH2:6][CH3:7]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)N=[N+]=[N-])OC1=O
Solvent: CCCCN
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)N=[N+]=[N-])C(C)C

Procedure:
24.9 g (0.09 mol) of 5(S)-azido-6-cyclohexyl-2(S)-isopropyl-4(S)-hexanolide in 250 ml of n-butylamine are boiled under reflux for 10 hours. After evaporating off the solvent, the residue is recrystallised from hexane: m.p. 100°-100.5°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:29])[C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[CH:18]=1.COC[C@@H]1[C@@H](C=O)[C@@]1(C)C1C=C(C(C)C)C=C(C(C)C)C=1>>[CH3:1][O:2][CH2:3][C@@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@:5]1([CH3:29])[C:17]1[CH:18]=[C:19]([CH:26]([CH3:27])[CH3:28])[CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: COC[C@@H]1[C@@H](C=O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CCOC(=O)/C=C(C)/C=C/[C@@H]1[C@@H](COC)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 73 %

Procedure:
Following a procedure similar to that for the preparation of Compound 24 but using Intermediate 48a as the starting material afforded the title compound (14 mg, 73% yield) as a white solid: