Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21](C(NN)=O)[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[N:29]([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[NH2:29][C:21]1[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][C:12]([OH:14])=[O:13])[O:23][N:22]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)NN)no1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A solution of tert-butyl(3R)-6-cyclohexyl-3-[3-(hydrazinocarbonyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 71) (1.06 g, 2.76 mmol) in glacial AcOH (10 ml) was treated with 2M HCl (10 ml) and stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0° C. before being treated with a solution of NaNO2 (278 mg, in 5 ml H2O) making sure the temperature never rose above 5° C. The reaction mixture was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature before being heated at 85° C. until the evolution of gas a finished. The reaction mixture was neutralised with sat. Na2CO3 solution and extracted with EtOAc. The organic extract was washed with brine and the solvent removed under reduced pressure. The residue was treated with TFA (4 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue azeotroped from toluene (×3) and DCM (×3) to afford the title compound as a foam (390 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:19])[CH2:14][O:13][CH2:12][C:11](N(N=O)C)=[N:10]2)=[CH:5][CH:4]=1.CN(C)C=O.CC(C)([O-])C.[K+].[N+:31]([CH3:34])([O-:33])=[O:32]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:19])[CH2:14][O:13][CH2:12]/[C:11](=[CH:34]/[N+:31]([O-:33])=[O:32])/[NH:10]2)=[CH:7][CH:8]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C2(C)COCC(N(C)N=O)=N2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(C)COC/C(=C/[N+](=O)[O-])N2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 100 mmol of [5-(4-methoxyphenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-N-nitroso-N-methylamine, 200 ml of N,N-dimethylformamide, 50 ml of nitromethane and 115 mmol of potassium tert-butoxide is stirred at room temperature for 15 minutes. It is quenched by adding 20 ml of glacial acetic acid and diluted with dichloromethane and water. The organic phase is separated off, washed with water, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]([NH:6][NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=1)=O.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]1[N:38]([C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)=[N:7][N:6]=1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Cl)ccc2Cl)cc1
Reactant: COc1ccc(N)cc1
Solvent: Clc1ccccc1Cl
Solvent: ClP(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Cl)ccc3Cl)n2-c2ccc(OC)cc2)cc1
Temperature: 180 °C
Yield: 33.9 %

Procedure:
Into a 1 L round-bottomed flask fitted with a mechanical stirrer, reflux condenser and nitrogen inlet were introduced 2,5-dichloro-N′-[4-(octyloxy)benzoyl]benzohydrazide (40 g, 0.09146 mole, 1 equivalent), p-anisidine (67.60 g, 0.5487 mole, 6 equivalents) and 300 mL 1,2-dichlorobenzene. Mechanical stirring resulted in partial solvation of the solids. Phosphorus trichloride (12.56 g, 0.0146 mole, 1 equivalent) was added and the contents of the flask heated at 180° C. for 12 hrs. The solvent was distilled off under a light vacuum and the residue transferred to a 2 L flask with 1 L of a 1:1 acetone/heptane mixture. The solid material was filtered off and dissolved in acetone. Enough heptane was added to precipitate a purple-colored oily sludge. Heptane dilution of a test sample of the acetone/heptane layer ensured that the oily sludge had been completely precipitated. The acetone/heptane layer was decanted off and diluted further with a large excess of heptane to precipitate a white solid. This was filtered off, dissolved in acetone and re-precipitated with heptane. Filtration and drying gave 3-(2,5-dichlorophenyl)-4-(4-methoxyphenyl)-5-[4-(octyloxy)phenyl]-4H-1,2,4-triazole (16.25 g, 34% yield).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12](Cl)[C:13]3[N:14]([C:16](=[O:23])[N:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:18]=3)[CH:15]=2)[CH:5]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>C1COCC1.CCOC(C)=O>[C:19]([N:17]1[C:16](=[O:23])[N:14]2[CH:15]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:25])[N:11]=[C:12]([NH:29][CH:26]([CH3:28])[CH3:27])[C:13]2=[N:18]1)([CH3:21])([CH3:20])[CH3:22]
Reactant: COC(=O)c1cccc(-c2cn3c(=O)n(C(C)(C)C)nc3c(Cl)n2)c1
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Nc1nc(-c2cccc(C(=O)O)c2)cn2c(=O)n(C(C)(C)C)nc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 580 mg of 3-(2-tert-butyl-8-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-benzoic acid methyl ester and 944 mg of isopropylamine in THF (8.0 mL) was stirred at ambient temperature. After 72 h, the reaction was diluted with EtOAc and washed with water followed by sat. sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated to an orange semi-solid. This material was dissolved in 1,4-dioxane (6.0 mL) and 2N KOH (1.0 mL) was added. This mixture was heated at reflux for 16 h, cooled to ambient temperature and the solvent removed. The residue was dissolved in water and the pH adjusted to 3 with 2N HCl prior to extraction with 9:1 chloroform/MeOH (3×). The organic extracts were washed with sat. sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to leave 3-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-benzoic acid as a yellow solid. MS (M+H+)=370.4.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)(F)F)c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (97 mg, 0.161 mmol) in DCM (7 ml) was added TFA (3 ml) and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate and the organic layer was separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (45 mg, 0.095 mmol, 59% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.82 (s, 1H), 7.69 (s, 1H), 7.47-7.53 (m, 2H), 7.35-7.42 (m, 2H), 4.63 (s, 2H). LC-MS (ES+) m/z 473.07, [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]([CH2:17][CH2:18][CH3:19])[C:12]([O:14]CC)=[O:13])[N:4]=1>CO.[OH-].[Na+]>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]([CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])[N:6]=1
Reactant: CCCC(C(=O)OCC)c1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.2 g (8 mmol) ethyl 2-(4,6-dimethoxypyrimidin-2-yl)pentanoate in 20 ml methanol and 3 ml 5N caustic soda was stirred overnight at room temperature. The mixture was concentrated and the residue dissolved in 10 ml water, extracted with 50 ml ethyl acetate and the aqueous phase acidified with 2N hydrochloric acid until it was pH 5. The aqueous phase was extracted three times with ether, the combined phases were dried over magnesium sulphate and concentrated.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:30]=[CH:29][C:13]3[N:14]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=5)[N:17]=[C:15]4[S:16][C:12]=3[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.[H][H]>[Ni].C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:30]=[CH:29][C:13]3[N:14]4[CH:19]=[C:18]([C:20]5[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=5)[N:17]=[C:15]4[S:16][C:12]=3[CH:11]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1

Procedure:
Intermediate 3 is dissolved into Methanol and THF and placed in a Hydrogenator. Raney Nickel is added and the vessel is pressurized with Hydrogen and stirred for >24 hrs. The reaction mixture is concentrated to a thick paste and diluted with Methyl tert-butyl ether. The resulting solids are filtered and washed with Methyl tert-butyl ether and dried under vacuum to give Intermediate 4.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CCN(CC)CC.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(Cl)Cl>[N:21]1([S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a suspension of 4-acetylbenzenesulfonyl chloride (5.5 g, 25 mmol) in CH2Cl2 (75 mL) and Et3N (2 equiv, 7.0 mL, 50 mmol) was added morpholine (1.5 equiv, 3.3 mL, 38 mmol) dropwise. The mixture was stirred at room temperature for 30 min. The mixture was then diluted with CH2Cl2 (100 mL) and washed with 5% HCl (2×50 mL), water (50 mL), and then brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to afford crude 1-[4-(morpholine-4-sulfonyl)phenyl]ethanone (2) (4.78 g, 18 mmol, 71%): HPLC Retention Time; 5.82 min. (Method B) M+1, 270.0.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>C1(C)C=CC=CC=1.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>[CH:12]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2ncccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2ncccc2n1
Temperature: 140 °C
Yield: 57.1 %

Procedure:
2-chloro-1,5-naphthyridine (10-1) (35 g, 213 mmol) in toluene (420 mL) was treated with tributyl(vinyl)stannane (101 g, 93.4 mL, 319 mmol) and tetrakis(triphenylphosphine)palladium (36.9 g, 31.9 mmol). The mixture was heated at 140° C. under microwave irradiation for 20 min, then cooled and concentrated in vacuo. The residue was purified by silica gel flash column chromatography, eluting with 0-100% EtOAc/heptane. The fractions containing the desired product (10-2) were pooled, and after solvent removal in vacuo, 19 g (57%) of the product were obtained. LC/MS: m/z (M+H)=157.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](/[N:8]=[CH:9]/[C:10]2[O:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[O:28][C:27](=[O:29])[NH:26][N:25]=2)[CH2:20][CH2:19]1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[O:28][C:27](=[O:29])[NH:26][N:25]=2)[CH2:22][CH2:23]1
Reactant: O=c1[nH]nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)o1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]nc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3F)CC2)o1
Yield: 80.8 %

Procedure:
5-[1-(2-Fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9e, 0.40 g, 1 mmol) on reduction with sodiumcyano borohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 5-[1-(2-fluoro-4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (10e, 326 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].[H][H]>[Pd].C(O)C>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: CC(O)C#Cc1nc(N)c2ncn(C)c2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(O)CCc1nc(N)c2ncn(C)c2n1

Procedure:
4-(6-Amino-9-methyl-9H-purin-2-yl)but-3-yn-2-ol (1.5 g, 6.88 mmol) was placed in an autoclave with ethanol (30 ml) and palladium 10% on graphite (0.350 g, 20% in weight) was added. The mixture was stirred overnight under 4 atm of hydrogen at 50° C. The catalyst was filtered off through Celite and the resulting solution was evaporated under reduced pressure, to give a residue that was used without any further purification.
Reaction SMILES: Br[C:2]1[C:3]([C:13]#[N:14])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>C1(C)C=CC=CC=1.CCO.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]([C:13]#[N:14])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)c(C#N)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccccc2Cl)c(C#N)c([N+](=O)[O-])c1
Yield: 100 %

Procedure:
5-Bromo-4-cyano-3-nitroanisole [prepared by the method of Harrison et al, J. Chem. Soc. C, 1769 (1966)] (250 mg, 0.86 mmol) and 2-chlorophenylboronic acid (150 mg, 0.96 mmol) were dissolved in a mixture of toluene (10 ml), EtOH (5.6 ml), and 1N aqueous sodium carbonate (1.7 ml). The solution was placed under a nitrogen atmosphere and tetrakis(triphenylphosphine)palladium (30 mg, 0.03 mmol) added. After refluxing for 3 h, the solvent was removed from the reaction mixture under reduced pressure. The residue was partitioned between H2O (50 ml) and EtOAc (50 ml) and the EtOAc layer washed with H2O (2×50 ml), and dried over MgSO4. Following removal of the solvent, the crude material was purified on silica gel, eluting with hexane/ether (1/1, v/v). This gave the subtitle compound as a colourless gum (252 mg, 100%). Rf 0.38 (hexane/ether 1:1, v/v). MS m/z 306 and 308 (MNH4+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C@@H:19]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:33])[CH3:32])[C:18]2=[O:43])=[CH:12][CH:11]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C@@H:19]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:33])[CH3:32])[C:18]2=[O:43])=[CH:14][CH:15]=1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3[N+](=O)[O-])cc2)C1=O)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Yield: 89.9 %

Procedure:
A solution of 7.79 g (13.23 mmol) of the intermediate obtained in Step A in 200 mL of methanol containing 0.9 g of 5% palladium on carbon was hydrogenated at 40 psi. When the uptake of hydrogen was complete, the catalyst was removed by filtration through Celite. The filtrate was concentrated under vacuum to yield 6.6 g (11.9 mmol, 90%) of product. FAB-MS: calculated for C33H4N4O4 556; found 557(M+H). 1H NMR (400 MHz, CDCl3): 1.32 (s, 6H), 1.39 (s, 9H), 1.87 (m, 1H), 2.51 (dd, 1H), 2.59 (m, 1H), 4.51 (m, 1H), 4.89 (d, 1H), 5.15 (d, 1H), 5.32 (br s, 1H), 6.71 (d, 1H), 6.81 (s, 1H), 7.21 (m, 10H).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.O.[C:20]([O:24][C:25](=[O:34])[N:26]([CH3:33])[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:20]([O:24][C:25](=[O:34])[N:26]([CH:27]1[CH2:28][CH2:29][N:30]([CH2:2][C:3]2[S:11][C:10]3[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:8][C:7]([Cl:18])=[N:6][C:5]=3[CH:4]=2)[CH2:31][CH2:32]1)[CH3:33])([CH3:23])([CH3:21])[CH3:22]
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (85 mg, 0.244 mmol) in DMF (2 mL) were added water (13 μL), methyl-piperidin-4-yl-carbamic acid tert-butyl ester (105 mg, 0.489 mmol) and cesium carbonate (159 mg, 0.489 mmol). The resulting mixture was stirred at RT for 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resultant residue was purified by column chromatography to give the title compound as a pale brown solid (73 mg, 62%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12]1)=[O:10].[C:20]([S:23][CH2:24][CH2:25][C:26](Cl)=[O:27])(=[O:22])[CH3:21]>C(Cl)Cl>[CH3:7][O:8][C:9]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[C:26](=[O:27])[CH2:25][CH2:24][S:23][C:20](=[O:22])[CH3:21])=[O:10]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: COC(=O)C1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C1Cc2ccccc2N1C(=O)CCSC(C)=O

Procedure:
To the mixture of 7.8 g of powdered potassium carbonate, 5.0 g of indoline-2-carboxylic acid methyl ester and 50 ml of methylene chloride, 4.7 g of 3-acetylthiopropanoyl chloride [Helv. Chim. Acta 40, 2148 (1957)] in 10 ml of methylene chloride are added at room temperature. After 1 hour the mixture is diluted with 100 ml of methylene chloride and washed with 50 ml of water, 50 ml of 1N hydrochloric acid and 50 ml of saturated aqueous sodium bicarbonate. The organic layer is dried and evaporated, to give the 1-(3-acetylthiopropanoyl)-indoline-2-carboxylic acid methyl ester as an oil, showing IR-bands at 1710, 1690 and 1640 cm-1.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].Cl.[NH2:31][OH:32].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:32][NH:31][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:17])=[O:18])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound (12d) (125 mg, 0.276 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (191 mg, 2.76 mmol) and a freshly prepared solution of sodium methoxide in methanol (95 mg, 4.14 mmol of sodium dissolved in 1 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13d as a solid. HPLC: =92% (Rt=14.16 min).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.Cl.[NH2:10][C@H:11]([C:15]([NH2:17])=[O:16])[CH2:12][CH2:13][CH3:14].[OH-].[Na+]>CO>[OH:16][C:15]1[C:11]([CH2:12][CH2:13][CH3:14])=[N:10][C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[N:17]=1
Reactant: O=C1CCCCC1=O
Reactant: CCC[C@H](N)C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc2c(nc1O)CCCC2
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
1,2-cyclohexanedione (5.4 g, 48 mM) was added all at once to a methanol solution (80 ml) of norvalineamide hydrochloride (6.1 g, 40 mM) at -30° C., and aqueous 12.5N NaOH (8 ml) was added dropwise thereto. The reaction mixture was stirred at -30° C. for 30 mins., cooling was removed, and the mixture stirred to room temperature for 3 hours. Conc. hydrochloric aicd (10 ml) was added to the reaction mixture under ice-cooling, sodium bicarbonate (8 g) was added after 10 mins., the methanol then being distilled off in vacuo. The residue was extracted with chloroform, and the extract washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product as colorless crystals (3.8 g., yield: 50%, m.p.: 131°-133° C.).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:18][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:16])([F:17])[F:1])=[CH:10][CH:11]=1
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Yield: 105.8 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-p-tolylpropan-2-ol (387 mmol, 100 g) was dissolved in carbon tetrachloride (400 mL) and N-bromosuccinimide (387 mmol, 68.9 g) was added in one portion followed by 2,2′-azobis(isobutyronitrile) (0.387 mmol, 0.064 g). The reaction was stirred at reflux for 4 hours, filtered through dicalite and the filtrate was evaporated to leave crude oil. The crude oil was triturated with diethyl ether, the solid obtained was filtered off and the filtrate taken to dryness (3 times) to yield the title compound as an oil (138 g). 1H NMR (CDCl3, 400 MHz): δ 4.49 (2H, s), 7.49 (2H, d), 7.69 (2H, d)