Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH3:6])([CH3:3])[CH3:2].C(N(P(OC)[Cl:18])C(C)C)(C)C>C1COCC1>[CH3:6][CH2:5][N:4]([CH:7]([CH3:9])[CH3:8])[CH:1]([CH3:3])[CH3:2].[ClH:18]
Reactant: COP(Cl)N(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
344 mg (0.5 mmole) of N6 -benzoyl-5'-O-dimethoxy-trityl-2'-O-methyl-adenosine (compound IIa) were dissolved in 2 ml of anhydrous THF, and the resulting solution was admixed with 362 μl (2 mmoles) of diisopropyl ethyl amine (DIPEA) with stirring under an argon atmosphere at room temperature. Then 300 μl (1.5 mmoles) of N,N-diisopropyl-amino-methoxy-chlorophosphine was added over 1 minute. After 5 minutes, DIPEA hydrochloride was formed as a white precipitate. Stirring was continued at room temperature and, after 45 minutes, the reaction mixture was analysed by a chromatography using silica gel 60 TLC (the mobile phase: n-hexane/acetone (1:1) containing 5% of triethyl amine) to confirm whether the spot of the starting material (Rf =0.52) had disappeared and the spot of the product (IIb2) (Rf =0.76) had appeared. After the confirmation of the latter spot, 20 ml of ethyl acetate was added to the reaction mixture under cooling with ice. Then the reaction mixture was washed twice with 15 ml of an ice-cooled saturated aqueous sodium bicarbonate solution, and then washed once with 15 ml of an ice-cooled saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate. After the sodium sulfate had been separated by a filtration, the filtrate was evaporated to dryness. The oily residue thus obtained was dried under reduced pressure, and dissolved in 2 ml of dichloromethane, and added dropwise with stirring to 200 ml of n-hexane which had been cooled to a temperature of -50° C., whereby a white precipitate was formed
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[C:18]([CH3:30])=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[C:18]([CH3:30])=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1
Reactant: Cc1nn(Cc2cccc(F)c2)cc1-c1c[nH]c2ncc(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn(Cc2cccc(F)c2)cc1-c1c[nH]c2ncc(-c3ccc(C4CCNCC4)c(F)c3)cc12
Yield: 21.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (140 mg, 0.239 mmol) was deprotected in TFA/DCM (5/1 mL) to afford 25 mg (17.48% yield) of the titled compound after purification by preparative HPLC along with one more isomer 1H NMR (CD3OD, 300 MHz): δ 8.70-8.60 (bs, 1H), 8.59 (s, 1H), 8.20 (s, 1H), 7.70 (s, 1H), 7.60-7.30 (m, 4H), 7.20-6.95 (m, 3H), 5.37 (s, 2H), 3.60-3.50 (m, 2H), 3.30-3.10 (m, 3H), 2.40 (s, 3H), 2.15-2.00 (m, 4H). MS: m/z=484.4 (M+1), HPLC: 98.76% in method B.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Oc1ccc2ncn(-c3cccc(Cl)c3Cl)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2,3-dichlorophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=280.0 [M+H]+.
Reaction SMILES: C1(C2CCCCCC=2)C[CH2:6][CH2:5][CH2:4][C:3](=[O:8])C=1.[Br:16]N1C(C)(C)C(=O)N(Br)C1=O.[CH3:27][C:28]([CH3:30])=[O:29]>O>[Br:16][CH:30]1[CH:28]([OH:29])[CH2:27][CH:4]2[CH:5]1[CH2:6][C:3]2=[O:8]
Reactant: CC(C)=O
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: O=C1C=C(C2=CCCCCC2)CCCC1
Solvent: O
Product: O=C1CC2C1CC(O)C2Br

Procedure:
To 1 g of bicycloheptenone (III) dissolved in the mixture of 20 ml of acetone and 5 ml of water, 1.5 g of 1,3-dibromo-5,5-dimethyl-hydantoin was added in portions under constant stirring. After 16 hours at room temperature the solvent was evaporated under reduced pressure. The residue was dissolved in 10 ml of water and extracted several times with dichloromethane. Obtained organic extracts were washed with brine, dried over magnesium sulfate and evaporated. A residuum in the form of a yellow oil was then separated by silica-gel column chromatography with solvent mixture of 20% ethyl acetate in light petroleum to obtain 2-bromo-3-hydroxybicyclo[3.2.0]heptan-6-one] (IV) (U.S. Pat. No. 4,272,629).
Reaction SMILES: Cl.[C:2]([N:5]1[C@@H:11]([CH3:12])[C@H:10]([NH2:13])[C:9](=[O:14])[N:8]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[O:26][CH3:27])[C:7]2[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:6]1=2)(=[O:4])[CH3:3].[C:34]([N:41]([CH3:47])[C@H:42]([C:44](O)=[O:45])[CH3:43])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:2]([N:5]1[C@@H:11]([CH3:12])[C@H:10]([NH:13][C:44](=[O:45])[C@@H:42]([N:41]([CH3:47])[C:34](=[O:35])[O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[CH3:43])[C:9](=[O:14])[N:8]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[O:26][CH3:27])[C:7]2[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:6]1=2)(=[O:4])[CH3:3]
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](N)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a 0° C. solution of (3S,4S)-5-acetyl-3-amino-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (216 mg, 465 μmol) in DMF (1.55 ml) was added Boc-N-methyl-L-alanine (104 mg, 511 μmol), N,N-diisopropylethylamine (322 μl, 1.86 mmol), and HBTU (194 mg, 511 μmol). The reaction was stirred at rt for 30 min, then diluted with H2O and the solids were collected by vacuum filtration, taken up in EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (255 mg, 89%) as a white solid. MS m/z 636 (MNa)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[C@@H:15]([NH:16]C(=O)OC(C)(C)C)[CH2:14][C@@H:13]([N:24]2[CH2:31][C:30]3[C:26](=[N:27][N:28]([S:32]([CH:35]4[CH2:37][CH2:36]4)(=[O:34])=[O:33])[CH:29]=3)[CH2:25]2)[CH2:12][O:11]1.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[C@@H:15]([NH2:16])[CH2:14][C@@H:13]([N:24]2[CH2:31][C:30]3[C:26](=[N:27][N:28]([S:32]([CH:35]4[CH2:37][CH2:36]4)(=[O:34])=[O:33])[CH:29]=3)[CH2:25]2)[CH2:12][O:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CC4)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CC4)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 1.5 h

Procedure:
A solution of the product obtained in Step A above (74 mg, 0.14 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated to give the title compound. 1H NMR (500 MHz, CD3OD): δ 1.18-1.24 (m, 2H); 1.35-1.40 (m, 2H); 2.12 (q, 1H, J=12 Hz); 2.79-2.86 (m, 1H); 2.92-2.98 (m, 1H); 3.64 (td, 1H, J=12, 6 Hz); 3.79 (t, 1H, J=12 Hz); 3.90-3.98 (m, 1H); 4.48-4.54 (m, 1H); 4.57-4.72 (m, 5H); 7.25-7.32 (m, 1H); 7.46-7.53 (m, 1H); 8.08 (s, 1H). LC-MS: 443.04 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@@H:16]([CH3:17])[C:15](=[O:18])[C:12]3([CH2:14][CH2:13]3)[C:11]2=[O:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:20][Mg]Br.O1CCCC1>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@@H:16]([CH3:17])[C@:15]([OH:18])([CH3:20])[C:12]3([CH2:14][CH2:13]3)[C:11]2=[O:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[Mg]Br
Reactant: C[C@H]1C(=O)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1N(c2ccc(C#N)c(Cl)c2)C(=O)C2(CC2)[C@]1(C)O
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-4-[(6S)-6-methyl-4,7-dioxo-5-azaspiro[2.4]hept-5-yl]benzonitrile (35 mg) in tetrahydrofuran (6.0 mL) was added dropwise 1 mol/L-methylmagnesium bromide/tetrahydrofuran solution (1.3 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[CH:32]1([C:35]([CH:43]2[CH2:45][CH2:44]2)=[N:36][S@@:37]([C:39]([CH3:42])([CH3:41])[CH3:40])=[O:38])[CH2:34][CH2:33]1.C(O)(=O)C>O1CCCC1>[CH:43]1([C:35]([CH:32]2[CH2:34][CH2:33]2)([C:19]2[S:20][C:16]([C:14]3[CH:13]=[C:12]([NH:21][C:22]4[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH:11]=[C:10]([CH3:9])[CH:15]=3)=[CH:17][N:18]=2)[NH:36][S@@:37]([C:39]([CH3:41])([CH3:42])[CH3:40])=[O:38])[CH2:45][CH2:44]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: CC(C)(C)[S@@](=O)N=C(C1CC1)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(N[S@](=O)C(C)(C)C)(C3CC3)C3CC3)s2)c1
Reaction time: 0.67 h
Yield: 76.3 %

Procedure:
To a solution of lithium diisopropylamide (1.8 M, 2.12 mL, 3.81 mmol) in tetrahydrofuran (5 mL) at −78° C. was added a solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 24, 564 mg, 1.68 mmol) in tetrahydrofuran (5 mL) over 8 minutes. After 40 minutes, a solution of (R)—N-(dicyclopropylmethylidene)-2-methylpropane-2-sulfinamide (0.325 g, 1.52 mmol) in tetrahydrofuran (4 mL) was added all at once. After 90 minutes, acetic acid (0.275 mL) was added and the reaction mixture was partitioned between ethyl acetate (45 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The layers were separated and the organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the crude material using silica gel flash chromatography (ethyl acetate/hexanes) yielded (R)—N-{dicyclopropyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-methylpropane-2-sulfinamide (638.6 mg, 1.16 mmol, 76% yield) as a yellow film. MS ESI: [M+H]+ m/z 550.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:22]1[CH2:23][CH2:24][CH2:25][C:20]([OH:26])([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:21]1)=[O:5]
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1cc(F)ccc1F
Product: COc1cccc(C2(O)CCCN(C(=O)c3cc(F)ccc3F)C2)c1

Procedure:
The compound of Example 5 was prepared according to the general preparation protocol A from 2,5-difluorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[C:8]=1[NH:16][C:17](=[O:38])[CH2:18][N:19]1[C:23](=[O:24])[C:22]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:21]([C:30]2[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=2)[C:20]1=[O:37])([CH3:6])[CH3:5]>O1CCCC1.C(OCC)(=O)C.[Cu](I)I.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>[C:1]([C:33]1[CH:34]=[CH:35][C:30]([N:21]2[C:22]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:23](=[O:24])[N:19]([CH2:18][C:17]([NH:16][C:8]3[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:10][CH:11]=[CH:12][C:7]=3[CH:4]([CH3:6])[CH3:5])=[O:38])[C:20]2=[O:37])=[CH:31][CH:32]=1)#[N:2]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CN1C(=O)N(c2ccc(I)cc2)C2(CCCCC2)C1=O
Reactant: [C-]#N
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1C(=O)N(c2ccc(C#N)cc2)C2(CCCCC2)C1=O
Temperature: 80 °C

Procedure:
38 mg (0.58 mmol, 2 eq.) of potassium cyanide and 5.5 mg (0.029 mmol, 0.1 eq.) of copper iodide are added to 170 mg (0.29 mmol, 1 eq.) of N-(2,6-diisopropyl-phenyl)-2-[1-(4-iodo-phenyl)-2,4-dioxo-1,3-diaza-spiro[4.5]dec-3-yl]acetamide in 10 ml of tetrahydrofuran. The reaction medium is degassed with nitrogen for 20 minutes, and 17 mg (0.015 μmol, 0.05 eq.) of tetrakis(triphenylphosphine)palladium are added. The medium is heated at 80° C. for 6 hours. The medium is cooled to room temperature and diluted with ethyl acetate, and then filtered through Celite. The filtrate is washed with water. The organic phases are combined. They are dried over sodium sulfate. The solvents are evaporated off and the residue is precipitated from dichloromethane and heptane. The product 2-[1-(4-cyanophenyl)-2,4-dioxo-1,3-diaza-spiro[4.5]dec-3-yl]-N-(2,6-diisopropylphenyl)acetamide is obtained in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[CH2:5][C:6]([CH3:14])([CH3:13])[O:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CC(C)=O>[CH2:24]([O:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4](=[O:15])[CH2:5][C:6]([CH3:13])([CH3:14])[O:7]2)=[C:2]([OH:1])[CH:11]=1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: CC1(C)CC(=O)c2c(O)cc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(O)c2c(c1)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.5 %

Procedure:
2.81 g of 5,7-dihydroxy-2,2-dimethyl-4-oxochromane was dissolved in 60 ml of acetone. Thereafter, 2.05 g of potassium carbonate and 1.80 g of allyl bromide were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 24 hours. Thereafter, 0.20 g of potassium carbonate and 0.18 g of allyl bromide were further added to the reaction solution, and the obtained mixture was then stirred at room temperature for 10 hours. Thereafter, 0.20 g of potassium carbonate and 0.18 g of allyl bromide were further added to the reaction solution, and the obtained mixture was then stirred at room temperature for 14 hours. Thereafter, 0.20 g of potassium carbonate and 0.18 g of allyl bromide were further added to the reaction solution, and the obtained mixture was then stirred at room temperature for 7 hours. The reaction solution was concentrated under a reduced pressure, and the residue was diluted with ethyl acetate. The resultant product was washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 2.90 g of the subject compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]2[CH2:20][CH:19]3[N:21]([CH3:22])[CH:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:9][CH:8]=1)(=O)=O.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:22][N:21]1[CH:19]2[CH2:18][CH2:17][CH:16]1[CH2:15][CH:14]([S:13][C:10]1[CH:11]=[CH:12][C:7]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:8][CH:9]=1)[CH2:20]2
Reactant: OB(O)c1ccccc1
Reactant: CN1C2CCC1CC(Sc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1C2CCC1CC(Sc1ccc(-c3ccccc3)cc1)C2
Temperature: 90 °C

Procedure:
To a mixture of 4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl trifluoromethanesulfonate (0.4 g) and phenylboronic acid (0.25 g) in DMF (5 ml) were added triethylamine (0.58 ml) followed by dichlorobis(triphenylphosphine) palladium (II) (0.04 g). The solution was heated at 90° C. for 4 hours, cooled to room temperature and diluted with ethyl acetate. This was washed with saturated aqueous sodium hydrogen carbonate solution, then brine, dried (MgSO4), filtered and evaporated. Partial clean up was achieved using preparative LC-MS. The mixture was stirred with aqueous sodium hydroxide solution (0.5M) to hydrolyse residual triflate to the phenol. The product was extracted into ethyl acetate, still however contaminated with some of the phenol. The material was loaded onto a PE-AX column and eluted with methanol with the final clean up by preparative LC-MS to yield [1,1 ′-biphenyl]4-yl 8-methyl-8-azabicyclo[3.2. 1]oct-3-yl sulfide.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:10]=[C:11]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[C:25]=3[S:36]([NH2:39])(=[O:38])=[O:37])[CH:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[CH3:15])C1C=CC=CC=1.Cl>CCO.[OH-].[OH-].[Pd+2]>[CH3:15][C:14]1[CH:13]=[CH:12][C:11]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]([F:34])([F:35])[F:33])[C:25]=3[S:36]([NH2:39])(=[O:38])=[O:37])[CH:20]=[CH:19][N:18]=2)=[CH:10][C:9]=1[NH:8][CH3:1]
Reactant: Cc1ccc(Nc2nccc(Nc3cccc(OCC(F)(F)F)c3S(N)(=O)=O)n2)cc1N(C)Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CNc1cc(Nc2nccc(Nc3cccc(OCC(F)(F)F)c3S(N)(=O)=O)n2)ccc1C
Reaction time: 0.5 h

Procedure:
A suspension of 44 mg 20% Pd(OH)2 on charcoal in EtOH (10 mL) is treated with H2 under vigorous stirring. To this 2-{2-[3-(benzyl-methyl-amino)-4-methyl-phenylamino]-pyrimidine-4-ylamino}-6-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide (28 mg, 0.049 mmol) and 0.1 mL of 1M HCl are added (final volume ca. 20 mL). After stirring for 30 min under H2 the catalyst is removed by filtration and the residue of the filtrate, neutralized with ammonia, is purified by chromatography (silica gel, CH2Cl2/CH3OH 95:5), yielding the title compound. 1H-NMR (400 MHz, DMSO-d6): 1.95 (s, CH3—C(4″)); 2.59 (d, J=5, NHCH3); 4.83 (q, J=5, NHCH3); 4.90 (q, J=9.4, OCH2CF3); 6.15 (d, J=6, H—C(5′)); 6.72 (d, J=2, H—C(2″)); 6.75 (d, J=8.5, H—C(5″)); 6.9 (dd, J=8.5 and 2, H—C(6″)); 6.93 (d, J=8.5, H—C(5)); 6.8-7.5 (b, SO2NH2); 7.4 (t, J=8.5, H—C(4)); 8.03 (d, J=6, H—C(6′)); 8.23 (d, J=8.5, H—C(3)); 8.95 (s, NH); 9.0-10.1 (b, NH).
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[CH2:19]([NH2:22])[CH2:20][CH3:21]>>[CH2:19]([NH:22][C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:20][CH3:21]
Reactant: CC[K]
Reactant: CCCN
Reactant: O=C(O)C1OC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: CCCNC(=O)C1OC1C(=O)OCC
Yield: 75.4 %

Procedure:
Following the procedure of Example 1, monoethyl potassium epoxysuccinate (1.98 g) was successively treated with oxalyl chloride (1.5 g) and n-propylamine (1.2 g) to give 1.5 g of ethyl N-propyl-2,3-epoxysuccinamate (Compound No. 16) as colorless needles melting at 58° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[C:21](Cl)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20])(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reaction time: 16 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2'-fluorophenyl)-2H-1,4-benzodiazepin-2-one (50 mg, 0.186 mmol) was suspended in methylene chloride (1 ml). Cinnamoyl chloride (34.5 mg, 0.207 mol) was added to the methylene chloride mixture. The pH of the stirred mixture was adjusted to ~9 with 50 μl of triethylamine. After stirring for 16 hours the mixture was filtered. The product in the filtrate was purified by prep TLC. The product band was collected by washing the silica containing the product, with 80:20:2 CMW. The solvent was evaporated and the residue was dissolved in methanol, placed in a small vial and evaporated. Yield 16.6 mg.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=3[CH3:29])=[O:20])[C@H:13]3[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][CH2:34][C@H:12]3[C:11]=2[C:10]=1[Cl:42]>>[ClH:8].[Cl:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=3[CH3:29])=[O:20])[C@H:13]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34][C@H:12]3[C:11]=2[C:10]=1[Cl:42]
Reactant: Cc1cccc(NC(=O)CN2c3ccc(Cl)c(Cl)c3[C@@H]3CCN(C(=O)OC(C)(C)C)CC[C@@H]32)c1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(NC(=O)CN2c3ccc(Cl)c(Cl)c3[C@@H]3CCNCC[C@@H]32)c1C
Product: Cl

Procedure:
TFA (0.60 mL, 7.7 mmol) was added to a solution of tert-butyl (5aS*,10bS*)-9,10-dichloro-6-{2-[(2,3-dimethylphenyl)amino]-2-oxoethyl }-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.20 g, 0.39 mmol) in CH2CI2 (7 mL). The reaction was quenched with 10% aqueous NaOH (5 mL) after 2.5 h and extracted with CH2Cl2 (3×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude yellow foam (0.15 g) was purified via column chromatography (Biotage, 40S) with CH2Cl2/MeOH/NH4OH (976:21:3) followed by the preparation of the hydrochloride salt to give 67 mg (38%) of an off white solid: mp 238.5-241.0° C.; 1H NMR (DMSO, 300 MHz) δ 9.60 (s, 1H), 8.92 (br s, 2H), 7.30 (d, J=8.4 Hz, 1H), 7.13 (m, 1H), 7.03 (m, 2H), 6.54 (d, J=8.7 Hz, 1H), 4.24 (m, 1H), 4.16 (d, J=17.1 Hz, 1H), 3.87 (d, J=17.1 Hz, 1H), 3.71 (m, 1H), 3.35 (m, 2H 3.08 (m, 3H), 2.34 (m, 1H), 2.24 (m, 3H), 2.12 (m, 5H); IR (diffuse reflectance) 2969, 2955, 2938, 2823, 2796, 2772, 2755, 2727, 1676, 1527, 1464, 1285, 1274, 806, 787 cm−1; MS (EI) m/z 417 (M+), 419, 226, 120, 106, 105, 9, 77, 76, 56; HRMS (FAB) calcd for C22H25CL2N3O+H 418.1453, found 418.1439.