Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([N:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4](=[O:10])[NH:5][C:6]1=[O:9])[CH2:1][CH2:3][CH3:8]
Reactant: CCc1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1cc(CC)c(=O)[nH]c1=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solution of 5.6 g (40 mmol) of 5-ethyluracil in 60 ml of dimethylformamide, 5.5 g (40 mmol) of potassium carbonate and 2.3 ml (20 mmol) of n-iodobutane were added and stirred for 2 hours at 120° C. The reaction mixture was concentrated under reduced pressure and distributed between dichloromethane and aqueous solution of ammonium chloride, and the organic layer was concentrated under reduced pressure. The residue was adsorbed on a silica gel column and eluted with 30% ethyl acetate/hexane to obtain 2.7 g of 1-butyl-5-ethyluracil (Yield: 69%).
Reaction SMILES: C([N:5]1[N:9]=[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]2=[N:6]1)CC#C.C(N1C2C=CC=CC=2N=N1)CC#C>>[N:6]1[NH:5][N:9]=[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=12
Reactant: C#CCCn1nc2ccccc2n1
Agent: C#CCCn1nnc2ccccc21
Product: c1ccc2n[nH]nc2c1

Procedure:
The title compounds were prepared in accordance with the general method of Example 108(C), from 90 mg (0.53 mmol) of 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole and 1-(but-3-ynyl)-1H-benzo[d][1,2,3]triazole. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 10 mg (42 μmol, 8%) of 24-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange oil with a purity of 82%. Another fraction yielded after SCX column (DCM, DCM/MeOH 98:2, DCM/MeOH/NH4OH 95:4:1 to 94:4:2) 19 mg (76 μmol, 14%) of 1-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([N+]([O-])=O)[CH3:11])=[CH:5][CH:4]=1.Cl.[OH2:16]>C(Cl)(Cl)Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:16])[CH3:11])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=C(C)[N+](=O)[O-])cc1
Reactant: O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CSc1ccc(CC(C)=O)cc1
Reaction time: 4 h

Procedure:
A stirred mixture of crude 1-methylsulfanyl-4-(2-nitro-propenyl)-benzene (27a) (28.8 mmol) iron filings (6.25 g, 112 mmol) and ferric chloride hexahydrate (0.155 g, 0.57 mmol) in water (20 ml) is heated to reflux. Concentrated hydrochloric acid (10 ml) is added over 2 hours the reflux continued for 4 hours. After 18 hours at room temperature the reaction is diluted with water and chloroform. The mixture is filtered through celite and the organic extract is separated. The aqueous extract is extracted with chloroform and the combined organic extracts are dried (MgSO4). The solvent is removed and the residue is purified by chromatography on silica eluting with hexane-ethyl acetate (3:1) to afford the title compound (2.65 g).
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:30]=[C:29]2[C:6]([CH:7]([CH2:31][C:32](O)=[O:33])[CH2:8][C:9]32[CH2:14][CH2:13][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])[CH2:11][CH2:10]3)=[CH:5][CH:4]=1>O1CCOCC1>[F:2][C:3]1[CH:30]=[C:29]2[C:6]([CH:7]([CH2:31][C:32]([NH2:1])=[O:33])[CH2:8][C:9]32[CH2:10][CH2:11][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:26])([F:25])[F:27])[CH2:13][CH2:14]3)=[CH:5][CH:4]=1
Reactant: O=C(O)CC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(F)ccc21
Reactant: N
Solvent: C1COCCO1
Product: NC(=O)CC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(F)ccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 7 using 0.5 M NH3 in dioxane and (±)-(E)-2-(6-fluoro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid. LC-MS Method 1 tR=1.67, min, m/z=461.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])=[CH:18][CH:17]=1>>[CH3:24][C:22]([NH:25][C:26](=[O:28])[CH3:27])([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CC(=O)NC(C)(C)c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(4-fluorophenyl)piperazine instead of phenylpiperazine and N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as pale-brown crystals, m.p.=104.5-106° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:9]=[CH:8][C:7]=2[N:6]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:5]=1.[CH3:30]C(C)([O-])C.[Na+].CI>O>[CH3:30][O:1][CH2:2][CH2:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[N:9]=[CH:8][C:7]=2[N:6]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:5]=1
Reactant: CC(C)(C)[O-]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CCO)cn2COCC[Si](C)(C)C)c1=O
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCCc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To 5 ml of mixed solvent (dehydrated tetrahydrofuran:N,N-dimethylformamide=3:1 (V/V)) solution containing 1.29 g (2.93 mmol) of 3-(2-hydroxyethyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 57-(e) was added 0.56 g (5.83 mmol) of sodium tert-butoxide under room temperature, and the mixture was stirred at the same temperature for 2 hours. Then, 1.1 ml (17.7 mmol) of methyl iodide was added to the mixture, and the mixture was further stirred for 16-hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.18 g of the title compound as a slightly yellowish oil. (Yield: 89%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[NH3:12]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:12])([O-:3])=[O:2]
Reactant: N
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: CCO
Product: NCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 65 %

Procedure:
3-Nitrobenzyl bromide (10 g, 46.3 mmol) was dissolved in ethanol (200 ml) and stirred at room temperature A solution of conc.NH3 (aq) (200 ml) in ethanol (300 ml) was added dropwise to the reaction over 30 minutes. The reaction was stirred for 18 h at room temperature before evaporating to dryness. Water (350 ml) was added to the residue and the solution was washed with EtOAc (2×200 ml). The aqueous layer was basified with 1M NaOH and extracted with EtOAc (2×200 ml). The organic extracts of the basic layer were combined, dried (Na2SO4) and evaporated to dryness. The product was obtained as an orange oil (4.6 g, 65% yield). LCMS purity 100%, m/z 153 [M++H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[C:26]3[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[C:26]3[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)cccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc2c(C(=O)NCC3CCNCC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
To a solution of 4-{[(2-isopropyl-1H-benzoimidazole-4-carbonyl)amino]methyl}-piperidine-1-carboxylic acid tert-butyl ester (10.8 g, 27.0 mmol) dissolved in dichloromethane (50 mL) at 0° C. was slowly added trifluoroacetic acid (50 mL) in 5 mL portions. The solution was allowed to warm to room temperature, stirred for an additional 20 minutes then evaporated in vacuo. Excess trifluoroacetic acid was removed by co-evaporation with toluene. The residue was then dissolved in a minimal volume of dichloromethane and slowly added to diethyl ether (1 L) at 0° C. The resulting slurry was stirred for 2 h at room temperature then filtered to afford the bis-trifluoroacetate salt of the title compound as a light brown solid (12.7 g, 24.0 mmol, 89%). (m/z): [M+H]+ calcd for C17H24N4O 301.21; found 301.5. Retention time (anal. HPLC: 2-50% MeCN/H2O over 6 min)=1.65 min. 1H NMR (300 MHz, MeOD-d3): δ (ppm) 1.59 (d, 6H), 1.60 (m, 1H), 2.03 (m, 2H), 2.04 (m, 1H), 3.00 (m, 2H), 3.43 (m, 2H), 3.45 (m, 2H), 3.63 (septet, 1H), 7.63 (t, 1H), 7.90 (d, 1H), 7.96 (d, 1H), 9.04 (t, 1H).
Reaction SMILES: C(Cl)(Cl)=O.[NH2:5][C:6]1[CH:10]=[C:9]([Cl:11])[S:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=S)(=[O:14])=[O:13].C(N(CC)CC)C>O1CCCC1>[Cl:11][C:9]1[S:8][C:7]2[S:12](=[O:14])(=[O:13])[N:15]=[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])[NH:5][C:6]=2[CH:10]=1
Reactant: CC(C)NC(=S)NS(=O)(=O)c1sc(Cl)cc1N
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Temperature: 0 °C
Yield: 92.9 %

Procedure:
Phosgene (1.14 ml, 20% in toluene) was added dropwise to a solution of N-(3-amino-5-chloro-2-thienylsulfonyl)-N'-isopropylthiourea (0.63 g, 2.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry tetrahydrofuran (10 ml) with stirring at 0° C. The mixture was stirred for 1 h at 0° C., and evaporated to dryness. The residue was triturated with water, and the precipitate was isolated by filtration, washed with water and dried affording 0.52 g (93%) of the title compound.
Reaction SMILES: FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.[NH:16]1[CH:23]=[N:22][C:20]([NH2:21])=[N:19][C:17]1=[O:18].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.Cl[C:37]1([O:43][C@H:42]([CH:44](C(C2C=CC(C)=CC=2)=O)[OH:45])[C@@:40](C(C2C=CC(C)=CC=2)=O)([OH:41])[CH2:39]1)O.C[O-].[Na+]>C(#N)C.CO>[CH2:39]1[C@H:37]([N:16]2[C:17](=[O:18])[N:19]=[C:20]([NH2:21])[N:22]=[CH:23]2)[O:43][C@H:42]([CH2:44][OH:45])[C@H:40]1[OH:41]
Reactant: Cc1ccc(C(=O)C(O)[C@H]2OC(O)(Cl)C[C@@]2(O)C(=O)c2ccc(C)cc2)cc1
Reactant: Nc1nc[nH]c(=O)n1
Agent: C[O-]
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CO
Product: Nc1ncn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.8 %

Procedure:
34 mL of BSTFA are added to a suspension of 6.4 g of azacytosine in 300 mL of acetonitrile. The mixture is brought to 50° C. and it is stirred for 90 minutes. It is cooled to ambient temperature, 6.3 mL of trimethylsilyltriflate and 11.1 g of 1-chloro-3,5-di-p-toluoyl-2-deoxy-D-ribofuranose are added to the solution, in about ten minutes. It is stirred for 140 minutes, 400 mL of methanol are added controlling the temperature in an ice bath. Concentration is carried out at low pressure until a viscous residue is obtained, 400 mL of methanol are added, it is heated to 50° C. and 36 mL of 30% solution of sodium methylate in methanol are added. It is stirred for 1 hour, it is cooled to 0° C., it is stirred to complete precipitation and the solid is filtered by washing it on the filter with methanol. 2.3 g of decitabine with HPLC purity (UV 254 nm) of 99.2% are obtained after drying at low pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2.[CH3:23]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.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>[CH3:13][O:12][C:10]1[CH:11]=[C:2]([CH3:23])[CH:3]=[C:4]2[C:9]=1[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Br)cc(OC)c2OC1C(F)(F)F
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(C)cc(OC)c2OC1C(F)(F)F
Temperature: 90 °C
Yield: 69.3 %

Procedure:
A mixture of ethyl 6-bromo-8-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.40 g, 1.05 mmole), trimethylboroxine (0.33 g, 2.63 mmole), Pd(PPh3)4 (0.13 g, 0.11 mmole) and K2CO3 (0.58 g, 4.20 mmole) in anhydrous DMF (5.0 mL) was heated to 90° C. under a dry N2 atmosphere for 18 hrs. The contents were poured into 2.4 N HCl (20 ml) and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil which was subject to flash chromatography (silica gel) and eluted with 10% EtOAc/ hexanes to give a light yellow oil (0.23 g, 70%): GCMS m/z 316.0 (M+). 1H NMR (CDCl3/400 MHz) 7.64 (s, 1H), 6.74 (s, 1H), 6.63 (s, 1H), 5.70 (q, 1H, J=7.0 Hz), 4.28 (m, 2H), 3.85 (s, 3H), 2.26 (s, 3H), 1.32 (m, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:42][CH:43]1[CH2:48][CH2:47][O:46][C:44]1=[O:45]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:42][CH:43]3[CH2:48][CH2:47][O:46][C:44]3=[O:45])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCOC1=O
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Agent: Br
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)NC3CCOC3=O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and α-Amino-γ-butyrolactone hydrobromide (36 mg, 0.2 mmole) were processed as in Examples 213A and 224B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ8.95 (s, 1 H), 8.31 (d, 1 H), 7.26 (m, 6 H), 7.18 (m, 3 H), 7.04 (m, 1 H), 6.97 (m, 2 H), 6.88 (m, 4 H), 4.53 (dd, 1 H), 4.34 (t, 1 H), 4.20 (m, 1 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 3.17 (s, 3 H), 2.91 (s, 3 H), 2.55 (t, 2 H), 2.39 (m, 2 H), 2.13 (t, 2 H), 1.67-1.90 (m, 2 H); MS (APCI+) m/z 642 (M+H)+.
Reaction SMILES: N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1)=O)CC1C2C(=CC=CC=2)NC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:62][C@H:63]([C:71](O)=O)[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.[NH2:74][N:75]1[CH2:81][C:79](=[O:80])[NH:78][C:76]1=[O:77]>CN(C)C=O>[NH2:62][CH:63]([CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)[CH:71]=[N:74][N:75]1[CH2:81][C:79](=[O:80])[NH:78][C:76]1=[O:77]
Reactant: NN1CC(=O)NC1=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Solvent: CN(C)C=O
Product: NC(C=NN1CC(=O)NC1=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Z-Trp-Trp-OH (0.1 mmol), 1-Hydroxybenzotriazolhydrate (0.1 mmol), and TBTU (0.1 mmol) were dissolved in dry dimethylformamide and stirred at r.t. After a few minutes Phe-Aminohydantoin (0.11 mmol) solved in dimethylformamide was added in portions and the reaction was allowed to reach room temperature over 18 hours. The solvent was removed and the residue was redissolved in ethyl acetate. The solution was washed with 1 mol/l HCl, and with 10% Na2CO3 and then dried over MgSO4. The reaction was filtered and the solvent was removed in vaccuo. The compound was purified by preparative HPLC.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[I:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1>C(O)(=O)C>[I:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][N:21]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:19])=[CH:16][CH:15]=1
Reactant: NNC(=O)c1ccc(I)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(I)cc1
Temperature: 100 °C
Yield: 83 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-iodobenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 430 mg of the title compound (83%) as a yellow solid in 98.7% purity by HPLC (Rt: 6.19, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]#[C:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1CCN(CCCc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Yield: 62.2 %

Procedure:
A mixture of 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.057 g, 0.12 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.036 g, 63%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79 (m, 2H), 2.22-2.60 (m, 13H), 2.66 (t, 2H), 4.20 (s, 2H), 4.76 (s, 2H), 7.08-7.38 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:19]([O:25][CH2:26]Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>CC(C)=O.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6]1[C:11]([C:12]([O:14][CH2:26][O:25][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Cc1c(Cl)cccc1Nc1ncccc1C(=O)O
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1c(Cl)cccc1Nc1ncccc1C(=O)OCOC(=O)C(C)(C)C
Yield: 77.4 %

Procedure:
To a stirred mixture of 2-(3'-chloro-2'-methylanilino)-pyridine-3-carboxylic acid (26.3 g) in 400 ml of acetone, triethylamine (20.5 ml) was added. Thereafter pivaloyloxymethyl chloride (15 ml) was poured into the mixture and then it was refluxed 4 hours. Subsequently, the reaction mixture was cooled to 15°-20° C. poured into previously cooled distilled water (3000 ml) and maintained at 5°-7° C. for 4 hours. The cake was filtered by suction and the formed compound dried at 25°-35° C. under vacuum to obtain a yield of 77.4% (29.2 g) of pivaloyloxymethyl 2-(3'-chloro-2'-methylanilino)-pyridine-3-carboxylate, m.p.: 91° C.-92° C.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:6][CH2:5][NH:4][CH2:3]1.[O:22]1[CH2:25][C:24](=O)[CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[C:18]([F:21])([F:19])[F:20])[CH2:6][CH2:5][N:4]([CH:24]2[CH2:25][O:22][CH2:23]2)[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(O[C@@H]2CCNC[C@H]2F)c(C(F)(F)F)c1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(O[C@@H]2CCN(C3COC3)C[C@H]2F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of (3R,4R)-3-fluoro-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine (1.3 g, 1.0 eq, 4.3 mmol) and oxetan-3-one (0.43 g, 1.4 eq, 6.0 mmol) in 1,2-dichloroethane (50 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.6 g, 1.8 eq, 7.7 mmol) was added in portions to the above solution and the heterogeneous mixture was stirred at room temperature overnight. Work-up and purification of the crude mixture used the same conditions as Example 88 above for Compound 120, and gave the product in 66% yield.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:5]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6][C:7]=1[CH3:8])#[N:2].[CH2:19]([N:22]=[C:23]=[S:24])[CH2:20][CH3:21]>>[C:1]([C:3]1[C:4]([S:15]([NH:18][C:23]([NH:22][CH2:19][CH2:20][CH3:21])=[S:24])(=[O:16])=[O:17])=[C:5]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6][C:7]=1[CH3:8])#[N:2]
Reactant: CCOC(=O)Nc1sc(C)c(C#N)c1S(N)(=O)=O
Reactant: CCCN=C=S
Product: CCCNC(=S)NS(=O)(=O)c1c(NC(=O)OCC)sc(C)c1C#N

Procedure:
The title compound was prepared from 4-cyano-2-ethoxycarbonylamino-5-methyl-thiophene-3-sulfonamide and propyl isothiocyanate in analogy with the synthesis described in Example 1-d; m.p. 167-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8](=[O:20])[NH:9][C:10]3[C:15]([C:16]=2[CH3:17])=[C:14]([OH:18])[CH:13]=[CH:12][C:11]=3[Cl:19])=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:31])[CH2:29][O:18][C:14]1[CH:13]=[CH:12][C:11]([Cl:19])=[C:10]2[C:15]=1[C:16]([CH3:17])=[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:22][CH:21]=1)[C:8](=[O:20])[NH:9]2)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1c(Cc2ccc(Br)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Product: Cc1c(Cc2ccc(Br)cc2)c(=O)[nH]c2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 7a using 3-(4-bromobenzyl)-8-chloro-5-hydroxy-4-methyl-1H-quinolin-2-one and bromoacetic acid tert-butyl ester.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].Br[CH2:13][C:14]#[N:15]>O1CCOCC1>[C:14]([CH2:13][S:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[NH2:3])#[N:15]
Reactant: N#CCBr
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#CCSC[C@H](N)C(=O)O
Reaction time: 18 h

Procedure:
A 360 mL aqueous solution of commercially available (Aldrich) L-cysteine hydrochloride monohydrate (60.0 g, 341.7 mole) and sodium hydroxide (27.33 g, 683.4 mole), at room temperature, is treated with a solution of bromoacetonitrile (44.5 g, 370.6 mmole) in 130 mL of dioxane over 30 minutes. The reaction is stirred for 18 hours, during which time a thick precipitate will form. The solid is filtered off, washed with diethyl ether (100 mL) and dried under high vacuum at 40° C. to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>[OH-].[OH-].[Pd+2]>[CH3:3][C:2]([CH3:26])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Yield: 79.7 %

Procedure:
Prepared analogously to Example A3f) from 1-(1,1-dimethyl-ethoxycarbonyl)-4-[1-(phenylmethyl)-4-piperidinyl]piperazine by hydrogenolysis, but using Pearlman's catalyst instead of palladium/charcoal, in a yield of 79.7% of theory.