Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:18](=O)[C:5]2[O:6][CH:7]=[CH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].C([O-])(O)=O.[Na+]>COCCOCCOC>[Br:1][C:2]1[S:18][C:5]2[O:6][C:7](=[S:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=S1C(Br)=CC2=C1OC=CN=C2c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Product: S=C1CN=C(c2ccccc2Cl)c2cc(Br)sc2O1
Temperature: 0 °C

Procedure:
(a) 0.1 Mol=35.8 gm of 7-bromo-5-(o-chlorophenyl)-thieno-[2,3-e]-4,1-oxazepinone were heated with 350 ml of diglyme, 24 gm of P2S5 and 19 gm of NaHCO3 for 30 minutes at 60° C. Subsequently, the reaction mixture was poured over about 1 liter of ice water, whereby a crystalline precipitate was formed, which was suction-filtered off, washed with water and dried. 37 gm=99% of theory of 7-bromo-5-(o-chlorophenyl)-thieno-[2,3-e]-4,1-oxazepine-2-thione were obtained M.p. from 200° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([C:20](O)=[O:21])=[CH:18][N:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)[N:16]=1.Cl.C([N:40]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([C:20]([NH2:40])=[O:21])=[CH:18][N:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][CH:29]=2)[N:16]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A mixture of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (0.75 g), 1H-1,2,3-benzotriazol-1-ol ammonia complex (0.26 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.33 g), and N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carbamide (0.70 g, yield 94%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from acetone-hexane. Melting point: 158–159° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][N:26]=[N+:27]=[N-:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCN=[N+]=[N-]
Yield: 107.4 %

Procedure:
To a solution of (2-hydroxyethyl)carbamic acid t-butyl ester (1.5 g, 6.2 mmol) in tetrahydrofuran (75 ml) were added diphenylphosphoryl azide (3.0 ml, 13.9 mmol), triphenylphosphine (3.7 g, 14.1 mmol), and a 40% solution of diethylazodicarboxylate in toluene (5.1 g, 13.9 mmol) in an ice bath under an atmosphere of nitrogen, and then the mixture was stirred for 4 hours under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (3:1) as the eluant to afford (2-azidoethyl)carbamic acid t-butyl ester (1.24 g, yield 72%) as a colorless and transparent syrup.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[C:4](=[O:7])[CH2:5]O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C>ClCCl>[Br:29][CH2:5][C:4]([N:3]([CH2:8][CH3:9])[CH2:1][CH3:2])=[O:7]
Reactant: CCN(CC)C(=O)CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)CBr
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Under a nitrogen atmosphere, N,N-diethyl-2-hydroxy-acetamide (42 mg, 0.320 mmol) was dissolved in dichloromethane (1.5 mL) and the mixture was cooled to 0° C. Triphenylphosphine (125.9 mg, 0.480 mmol) and N-bromosuccinimide (85.4 mg, 0.480 mmol) were added in order and the mixture was stirred at room temperature for 3.5 hours. The mixture was warmed to room temperature and 2-bromo-N,N-diethylacetamide was prepared in situ. To the mixture, solution of No. 5447725 (Compound G; 56 mg, 0.080 mmol) in dichloromethane (1.0 mL) was added dropwise under a nitrogen atmosphere. N,N-Diisopropylethylamine (69.7 μL, 0.40 mmol) was then added at room temperature, and the mixture was stirred under feflux for 14 hours. After completing the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated brine and dried over anhydrous sodium sulfate. After the organic layer was filtered and the solvent was distilled off, the residue was then purified by HPLC (water with 0.05% TFA-acetonitrile with 0.05% TFA) to obtain 31.2 mg (42% yield) of the triester form.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[CH:3]=1.[CH2:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:23]#[CH:24].C(N(CC)CC)C>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[C:2]([C:24]#[C:23][CH2:22][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[S:10][C:9]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(C#CCN4CCOCC4)sc23)c(F)c1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of bromide 42 (100 mg, 0.27 mmol) in THF (5 ml) was added 4-(prop-2-ynyl)morpholine (68 mg, 0.54 mmol) [H-W. Tsou, et. al. J. Med. Chem., 2001, 44, 2719-2734], triethylamine (68 mg, 0.67 mmol), CuI (5 mg, 0.03 mmol) and Pd(PPh3)2Cl2 (5.3 mg, 7.56 μmol). The reaction mixture was degassed with nitrogen and refluxed for 2 hrs, cooled to room temperature and adsorbed onto silica. Purification by column chromatography (eluent EtOAc) afforded the title compound 56 as a beige solid (88 mg, 79%). MS (m/z): 397.1 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([C:16]([OH:18])=O)[CH:7]=1)[CH3:4])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH:50]1[CH2:55][CH2:54][CH:53]([N:56]2[CH2:59][C:58]([CH2:82][C:83]#[N:84])([N:60]3[CH:64]=[C:63]([C:65]4[C:66]5[CH:73]=[CH:72][N:71](COCC[Si](C)(C)C)[C:67]=5[N:68]=[CH:69][N:70]=4)[CH:62]=[N:61]3)[CH2:57]2)[CH2:52][CH2:51]1>O1CCCC1>[CH2:1]([N:3]([CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[N:9]=[C:8]([C:16]([N:50]2[CH2:51][CH2:52][CH:53]([N:56]3[CH2:57][C:58]([CH2:82][C:83]#[N:84])([N:60]4[CH:64]=[C:63]([C:65]5[C:66]6[CH:73]=[CH:72][NH:71][C:67]=6[N:68]=[CH:69][N:70]=5)[CH:62]=[N:61]4)[CH2:59]3)[CH2:54][CH2:55]2)=[O:18])[CH:7]=1)[CH3:4])[CH3:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: CCN(C)Cc1cc(C(=O)O)nc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(C)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Reaction time: 1 h

Procedure:
After prestirring a mixture of 6-{[ethyl(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (40.1 mg, 0.152 mmol, from Step A), triethylamine (56.6 μL, 0.406 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (54.0 mg, 0.142 mmol) in tetrahydrofuran (1.1 mL) for 30 minutes, {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (50.0 mg, 0.101 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base) was added and the reaction stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was successively washed with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate, filtered and concentrated. The product was deprotected by stirring first in a 1:1 mixture of DCM:TFA for 1 hour, followed by evaporation and stirring with ethylenediamine (0.2 mL) in methanol (1 mL) until deprotection was complete. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product. Yield: 0.025 g (41%); LC-MS: 608.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.89 (s, 1H), 7.61 (d, 1H), 7.06 (d, 1H), 4.11-4.02 (m, 1H), 3.78-3.71 (m, 4H), 3.63-3.48 (m, 5H), 3.32-3.21 (m, 1H), 3.17-3.07 (m, 1H), 2.62-2.53 (m, 1H), 2.48 (q, 2H), 2.21 (s, 3H), 1.84-1.74 (m, 1H), 1.70-1.61 (m, 1H), 1.37-1.18 (m, 2H), 1.03 (t, 3H). 19F NMR (400 MHz, DMSO-d6): δ −69.45 (s, 3F).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][CH:20]([CH3:22])[CH3:21])[N:12]=3)=[CH:9][N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:20]([NH:19][C:13]1[N:12]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([NH:1][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:3]=3)[N:8]([S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=3)(=[O:24])=[O:25])[CH:9]=2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1)([CH3:21])[CH3:22]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(N)cnc32)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(Nc4ccccc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
4-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(isopropylamino)pyrimidine-5-carbonitrile (0.204 g, 0.455 mmol) in DCM (12 mL) was treated with phenylboronic acid (0.111 g, 0.910 mmol, 2.0 Eq), copper acetate (0.124 g, 0.682 mmol, 1.5 Eq), pyridine (0.074 mL, 0.910 mmol, 2.0 Eq) and 4 Angstrom molecular sieves (0.600 g) and the reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was quenched with 4M Ammonia in MeOH (12 mL) and filtered through a plug of celite whilst washing through with further DCM/MeOH. The combined washes were evaporated to dryness and purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/Petroleum Ether) to give the title compound as a yellow solid (85 mg, 36%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][C:6]1[N:14]2[C:9]([C:10]([OH:15])=[CH:11][CH:12]=[CH:13]2)=[C:8]([C:16](=[O:20])[C:17]([NH2:19])=[O:18])[C:7]=1[CH2:21]C>CCOC(C)=O.CCCCCC>[CH2:5]([C:6]1[N:14]2[C:9]([C:10]([OH:15])=[CH:11][CH:12]=[CH:13]2)=[C:8]([C:16](=[O:20])[C:17]([NH2:19])=[O:18])[C:7]=1[CH3:21])[C:4]1[CH:23]=[CH:24][CH:25]=[CH:2][CH:3]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c(O)cccn2c1Cc1cccc(Cl)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)C(N)=O)c2c(O)cccn2c1Cc1ccccc1
Yield: 88 %

Procedure:
(3-(m-Chlorobenzyl)-2-ethyl-8-hydroxyindolizin-1-yl)glyoxylamide 36h. Mp, 144-146° C. (AcOEt-hexane). 88% Yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.Br[CH:14]([CH2:27][CH3:28])[C:15]([NH:17][C:18]([CH3:26])([CH3:25])[C:19]#[C:20][CH2:21][CH2:22][CH2:23][Cl:24])=[O:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:14]([CH2:27][CH3:28])[C:15]([NH:17][C:18]([CH3:26])([CH3:25])[C:19]#[C:20][CH2:21][CH2:22][CH2:23][Cl:24])=[O:16])=[CH:7][CH:6]=2
Reactant: Oc1ccc2ncc(Br)cc2c1
Reactant: CCC(Br)C(=O)NC(C)(C)C#CCCCCl
Product: CCC(Oc1ccc2ncc(Br)cc2c1)C(=O)NC(C)(C)C#CCCCCl

Procedure:
In a similar procedure to Example 6 Stage 2, 3-bromo-6-hydroxyquinoline was reacted with 2-bromo-N-(1-chloro-6-methylhept-4-yn-6-yl) butyramide to give 2-(3-bromo-6-quinolinyloxy)-N-(1-chloro-6-methylhept-4-yn-6-yl) butyramide as a colourless oil. 1H NMR (CDCl3) δ: 1.04-1.10(3H, t); 1.60(6H, s); 1.86-1.94(2H, m); 2.00-2.06(2H, m); 2.32-2.36(2H, t); 3.60-3.64(2H, t); 4.56(1H, t); 6.34(1H, s); 7.02 (1H, m); 7.42-7.46(1H, dd); 8.03 (1H, d); 8.22(1H, s); 8.78(1H, s).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:5]=[N:4][NH:3]1.O.NN>CO>[NH2:9][CH2:8][C:7]1[C:2](=[O:1])[NH:3][N:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccn[nH]c1=O
Agent: NN
Solvent: O
Solvent: CO
Product: NCc1ccn[nH]c1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-[(3-Oxo-2,3-dihydropyridazin-4-yl)methyl]isoindoline-1,3-dione (255 mg, 1.00 mmol) in methanol (2 mL) was mixed with hydrazine monohydrate (250 mg, 5.00 mmol) at room temperature and stirred at 60° C. for 3 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure repeatedly to give a crude reaction product containing the desired product, which was used for the next step.
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].[N+:7]([C:10]1[CH:27]=[CH:26][C:13]([CH2:14][CH:15]([C:21](=O)[CH2:22][CH2:23][CH3:24])[C:16](OCC)=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(O)C>[CH2:22]([C:21]1[N:6]=[C:3]([CH3:4])[N:5]=[C:16]([OH:17])[C:15]=1[CH2:14][C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:27][CH:26]=1)[CH2:23][CH3:24]
Reactant: CCCC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Reactant: CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCc1nc(C)nc(O)c1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.6 %

Procedure:
3.5 g of sodium are dissolved in 175 ml of ethanol. 9.5 g of acetamidine hydrochloride are added to this solution and the mixture is stirred for 5 minutes at room temperature. 20 g of ethyl 2-(4-nitrobenzyl)-3-oxohexanoate, prepared in Example 3, are then added and the mixture is stirred for 4 days at room temperature. The solvents are then evaporated off under vacuum and the residue is taken up with hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and then evaporated under vacuum to give an oily residue which crystallises in an acetone/ether mixture. The crystals are drained and dried and give 10.9 g of 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of crystals of melting point 200° C.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[CH:18]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9](O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]1([CH2:33][O:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN1CCOCC1.N1C2C(=NC=CC=2)N(O)N=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[C@H:18]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9]([NH:35][O:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)N1CCOCC1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.9 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-[5-(4-morpholinylcarbonyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-oxobutanoic acid (212 mg, 0.58 mmol) in dichloromethane (DCM) (10 ml) was added O-(phenylmethyl)hydroxylamine (93 mg, 0.75 mmol), 4-methylmorpholine (0.17 ml, 1.5 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (79 mg, 0.58 mmol), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (133 mg, 0.70 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 5 hours. The reaction mixture was then washed with water (15 mL) and NaHCO3 solution (15 mL×3), and concentrated to provide the crude product as a mixture of diastereomers. This mixture was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (3R)-3-(cyclopentyl methyl)-4-[(5S)-5-(4-morpholinylcarbonyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-oxo-N-[(phenylmethyl)oxy]butanamide (57 mg, 21% yield). MS: 472 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:23]3[NH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH2:14][CH2:13][NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC([O-:28])(C)C.[K+].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:23]3[NH:22][C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15](=[O:28])[C:14]=3[CH2:13][NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1OC
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2NCc3c2[nH]c2ccccc2c3=O)cc1OC

Procedure:
1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (1.854 g, 6.04 mmol) (prepared as in Example 11) and KOt-Bu (1.14 g, 10.15 mmol) were stirred in DMF (60 mL) at room temperature for 10 min. Oxygen was bubbled through the solution for 1 h. The reaction mixture was neutralized with 1N HCl solution (10.15 mL, 10.15 mmol) and the water removed in vacuo as an azeotrope with toluene. Silica gel (˜5 g) was added to the residual DMF solution, followed by diethyl ether (600 mL), which resulted in precipitation of the product onto the silica gel. The diethyl ether was decanted and the silica gel was washed with diethyl ether (2×100 mL). After the solvent was decanted and any remaining trace amounts evaporated, the residue was purified by column chromatograph (silica gel; EtOH:EtOAc=1:9) to yield the product as a bright yellow solid. The product was recrystallized from methanol.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5]1
Reactant: CCOC(=O)c1n[nH]c(C)n1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C)n(Cc2cccc(Br)c2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
To a solution of ethyl 5-methyl-1H-1,2,4-triazole-3-carboxylate (1.0 g, 6.44 mmol) and 1-bromo-3-(bromomethyl)benzene (1.77 g, 7.08 mmol) in THF (32 mL), K2CO3 (1.78 g, 12.88 mmol) was added. The mixture was stirred at 50° C. for 18 h then filtered. The filtrate was concentrated under reduced pressure and the crude product was purified on a Biotage pre-packed silica gel column with a gradient of 12% to 100% EtOAc:Hexanes to afford ethyl 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carboxylate (1.25 g, 60%) as a viscous oil. MS (ES+) C13H14BrN3O2 requires: 323, 325. found: 324, 326 [M+H]+(1:1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH3:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH2:15][S:16][CH2:17][CH2:18][NH2:19].[CH3:20][N:21]=[C:22]=[S:23]>O>[CH3:20][NH:21][C:22]([NH:19][CH2:18][CH2:17][S:16][CH2:15][C:14]1[NH:13][CH:12]=[N:11][C:10]=1[CH3:9])=[S:23]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNC(=S)NCCSCc1[nH]cnc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(i) Potassium carbonate (7.75 g.) was added to a solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (14.6 g.) in water (120 ml.). The solution was stirred at room temperature for 15 minutes and methyl isothiocyanate (5.15 g.) was added. After heating under reflux for 30 minutes, the solution was slowly cooled to 5°. The product (13.1 g.) was collected and recrystallised from water to give N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea, m.p. 150°-152°.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)(C)C>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl
Temperature: 120 °C

Procedure:
2,4-dichloro-5,7-difluoro-3-methylquinoline (4.90 g, 10.0 mmol), tert-butyl piperazine-1-carboxylate (3.70 g, 20.0 mmol) and triethylamine (2.80 mL, 20.0 mmol) were slurried in isopropyl alcohol (40 mL) and heated at 120° C. for 12 h. The reaction was then allowed to cool to rt and concentrated to dryness. The crude product was then purified by column chromatography (silica gel, 0 to 20% EtOAc:hexane) to give tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate. Mass Spectrum (ESI) m/e=398.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH2:30]([N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH3:31]>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:44]3[CH2:45][CH2:46][N:41]([C:33]4[N:32]([CH2:30][CH3:31])[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=4)[CH2:42][CH2:43]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: CCn1c(N2CCNCC2)nc2ccccc21
Product: CCn1c(N2CCN(CCCCC3(C(=O)NCc4ccc(F)cc4)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 1-ethyl-2-piperazin-1-yl-1H-benzimidazole.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1[N:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: O=C1CNCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CN(c2c(F)cc([N+](=O)[O-])cc2F)CN1
Temperature: 25 °C

Procedure:
A solution of 4-imidazolidinone (9.5 g, 110.5 mmol), 3,4,5-trifluoronitrobenzene (1 eq) and diisopropyl ethylamine (28.6 mL, 165 mmol) in dry DMF (80 mL) was heated to 60° C. overnight under argon. The reaction mixture was allowed to cool to room temperature and ice pieces were added. The solid formed was filtered and washed with water. The solid was air dried to yield the nitro compound as yellow crystals.