Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from Step A was taken up in 100 mL of methylene chloride and cooled in an ice bath. To the solution was added 7.6 mL of benzyl chloroformate and after 5 min 20 mL of DIPEA was added dropwise over 5 min. After stirring at r.t. for 3 h, the reaction was poured into water containing 50 mL of 2N HCl and was extracted twice with methylene chloride. The organics were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to give a solid. This was triturated with hot 5% ethyl acetate in hexanes, cooled, filtered and air dried to afford 16.5 g of title compound as an off white solid. T.l.c. (30% ethyl acetate in hexanes) Rf =0.75
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=2)[CH:8]=[C:7]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:6]=1)(=O)=O.[C:24]([NH:27][C:28]1[CH:33]=[CH:32]C(S)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>C(O)(C)(C)C>[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:1]([S:2][C:5]2[N:10]=[C:9]([NH:11][C:12]3[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=3)[CH:8]=[C:7]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:6]=2)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: Cc1cc(Nc2cc(N3CCOCC3)nc(S(C)(=O)=O)n2)[nH]n1
Solvent: CC(C)(C)O
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(N3CCOCC3)n2)cc1
Temperature: 25 °C

Procedure:
The above-prepared [2-methylsulfonyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (178 mg, 0.52 mmol) and 4-acetamidothiophenol (176 mg, 1.05 mmol) are refluxed in tert-butanol (5 mL) over 20 h. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography to give the desired product [2-(4-acetamidophenylsulfanyl)-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:11]OC)[C:7]([O:9][CH3:10])=[O:8].C(O)=O>CO.O.[Zn]>[NH2:11][CH:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CON=C(C(=O)OC)c1ccco1
Agent: [Zn]
Solvent: CO
Solvent: O
Solvent: O=CO
Product: COC(=O)C(N)c1ccco1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
To a magnetically stirred solution of methyl 2-(furan-2-yl)-2-(methoxyimino)acetate (17.50 g, 96 mmol) in 300 mL of MeOH was added 200 mL of a solution of 50% formic acid in water. The reaction mixture was cooled to 0° C. (ice bath) and zinc dust (18.74 g, 287 mmol) was added. After stirring at room temperature for 18 hr, the reaction mixture was filtered through a plug of Celite and the plug was washed with MeOH. Solvent was removed on the rotary evaporator and the yellow residue was dissolved in 50 mL of water, basified to pH 10 with a saturated solution of Na2CO3 and extracted with 3×100 mL of EtOAc. After drying (MgSO4) the organic extracts, solvent removal gave 10.2 g of methyl 2-amino-2-(furan-2-yl)acetate as an orange liquid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:41]([C:43]1[C:48]([CH3:49])=[CH:47][C:46](/[CH:50]=[CH:51]/[C:52]([O:54][CH3:55])=[O:53])=[CH:45][C:44]=1[CH3:56])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:55][O:54][C:52](/[CH:51]=[CH:50]/[C:46]1[CH:45]=[C:44]([CH3:56])[C:43](/[CH:41]=[CH:2]/[C:3]2[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[CH:5][C:4]=2[N+:19]([O-:21])=[O:20])=[C:48]([CH3:49])[CH:47]=1)=[O:53]
Reactant: COC(=O)/C=C/c1cc(C)c(C=O)c(C)c1
Reactant: O=C(OCc1ccccc1)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cc(C)c(/C=C/c2ccc(C(=O)OCc3ccccc3)cc2[N+](=O)[O-])c(C)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of benzyl 4-bromomethyl-3-nitrobenzoate (2.06 g, 5.88 mmol) and triphenylphosphine (1.54 g, 5.87 mmol) in DMF (10 mL) was heated at 100° C. for 1 h. To this solution was added methyl (E)-3-(4-formyl-3,5-dimethylphenyl)-acrylate (1.28 g., 5.86 mmol) and potassium carbonate (1.63 g, 11.8 mmol) and the mixture was heated and stirred at 100° C. for 18 h. The reaction was poured into ethyl acetate and extracted with water once and brine.five times. The organic layer was dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography using a 0-40% gradient of heptane/ethyl acetate to give benzyl 4-{(E)-2-[4-((E)-2-methoxycarbonylvinyl)-2,6-dimethylphenyl]-vinyl}-3-nitrobenzoate.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[O:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[NH4+].[Cl-].O.[C:19](OCC)(=[O:21])[CH3:20]>>[O:21]1[CH2:19][CH2:20][O:11][CH:15]1[CH2:14][CH2:13][CH2:12][C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)C(=O)CCCC1OCCO1
Temperature: -60 °C
Reaction time: 1.5 h

Procedure:
A 1 L 3-necked round bottom flask was equipped with a nitrogen line, overhead stirrer, and thermocouple. Under a nitrogen atmosphere, the flask was charged with diethyl oxalate (73.85 g) and tetrahydrofuran (250 mL). The solution was cooled to −60° C., and the liquid portion of the Grignard reagent was added to the cooled diethyl oxalate solution via cannula to maintain the temperature below −55° C. The Grignard preparation flask was washed with tetrahydrofuran (3×20 mL), and the resulting wash was added via cannula. The addition was complete after 1.5 hours, and the reaction was stirred for about 2 hours at −60° C. to −55° C. The cold reaction mixture was immediately poured into a mixture consisting of NH4Cl (32.1 g), water (100 mL), ice (200 g) and ethyl acetate (300 mL). The layers were separated and the aqueous layer was extracted again with ethyl acetate (2×300 mL). The combined organic layers were dried over magnesium sulfate and concentrated to afford 87 g (79 M % yield) of 5-(1,3-dioxolan-2-yl)-2-oxo-pentanoic acid, ethyl ester as a thick liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][CH2:48][CH:49]([OH:61])[CH2:50][N:51]1[CH2:60][CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:52]1[C:53]2[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:59][CH2:60][N:51]1[CH2:50][CH:49]([OH:61])[CH2:48][NH:47][C:17]([C:16]1[CH:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:22]=[CH:21][CH:20]=1)=[O:19]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.3 %

Procedure:
The solution of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (300 mg, 1.0 mmol) and HATU (381 mg, 1.0 mmol) in DCM (10 mL) was stirred at 25° C. for 30 min. Then 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (200 mg, 1.0 mmol) and DIPEA (259 mg, 2.00 mmol) was added and the resulting solution was stirred at 25° C. for 16 h. The solution was concentrated and the residue was purified by column chromatography to give the title product (140 mg, Yield 28.8%). LCMS (m/z): 495.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>CCOC(C)=O>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C#N)cc2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
To a suspension of Intermediate 14a (2.28 g, 9.49 mmol) in EtOAc (25 mL) and aq. NaOH solution (1M, 23.7 mL, 23.7 mmol) was added 2,2,2-trichloroethyl chloroformate (1.57 mL, 11.4 mmol) dropwise over 2 min. A precipitate formed which redissolved after 15 min, then the orange solution was stirred at RT for 90 min. 2,2,2-Trichloroethyl chloroformate (0.391 mL, 2.85 mmol) was added, and the orange mixture stirred at RT for 16 h. The layers were separated, and the aqueous extracted with EtOAc (25 mL). The combined organics were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave an orange-red oil. Recrystallisation from cyclohexane gave an off-white solid (3.12 g, 79%). LCMS (Method 3): Rt 4.46 min, m/z 415, 417 [MH+].
Reaction SMILES: CC[O:3][C:4](=[O:11])[C@@H:5]([CH2:7][C:8](O)=[O:9])[NH2:6].Cl.[NH2:13][OH:14].C(N(CC)CC)C>CO>[CH2:7]([C:8]([NH:13][OH:14])=[O:9])[CH:5]([NH2:6])[C:4]([OH:3])=[O:11]
Reactant: CCOC(=O)[C@H](N)CC(=O)O
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(CC(=O)NO)C(=O)O
Reaction time: 48 h
Yield: 50 %

Procedure:
0.1 mole of D-aspartic acid β-ethyl ester is dissolved in 200 ml of methanol, 0.2 mole of hydroxylamine hydrochloride is then added and the mixture is stirred until complete dissolution occurs. 0.4 mole of triethylamine is added and stirring is continued at room temperature for about 48 hr. The precipitate formed is collected on a filter. This crude product is recrystallized by dissolution in water, then diluted in absolute ethanol. This solution is kept at +4° C. for 12 hr. The crystals are filtered, washed with absolute ethanol and air-dried. This reaction yields 50 to 70% of D-Aspartic acid β-Hydroxamate.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[S:3]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[OH:37][C:29]1[CH:28]=[CH:27][C:26]([CH:24]([OH:25])[CH2:23][NH:22][CH:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:13]=[CH:14][C:9]([CH:8]=[C:4]4[S:3][C:2](=[NH:1])[NH:6][C:5]4=[O:7])=[CH:10][CH:11]=3)[CH2:16][CH2:17]2)=[CH:31][C:30]=1[NH:32][S:33]([CH3:36])(=[O:35])=[O:34]
Reactant: N=C1NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(=N)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Example 43) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp>210° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.80–2.00 (m, 2 H), 2.50–3.00 (m, 5 H), 2.92 (s, 3 H), 3.70–3.90 (m, 2 H), 4.47 (dd, J=7.9, 4.4 Hz, 1 H), 6.81 (d,J=8.3 Hz, 1 H), 6.90–7.10 (m, 3 H), 7.18 (d, J=2.0 Hz, 2 H), 7.39 (d, J=8.9 Hz, 2 H), 7.47 (s, 1 H); MS (ES) m/z: 532.0 (MH+); HRMS Calcd. for C24H30N5O5S2 (MH+): 532.1688. Found: 532.1672.
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16](F)=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[C:9]2[CH2:24][N:25]([C:29](=[O:39])[NH:30][C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:38])[C:26]([CH3:28])([CH3:27])[C:8]2=[N:7]1)=O)C.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C1COCC1>[Cl:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=1[NH:30][C:29]([N:25]1[CH2:24][C:9]2[C:8](=[N:7][NH:6][C:10]=2[NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([N:44]3[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]3)=[C:15]([NH2:20])[CH:14]=2)[C:26]1([CH3:27])[CH3:28])=[O:39]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1)CN(C(=O)Nc1c(Cl)cccc1Cl)C2(C)C
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)Nc3[nH]nc4c3CN(C(=O)Nc3c(Cl)cccc3Cl)C4(C)C)cc2N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
To a solution of 3-(3-Nitro-4-fluoro-benzoylamino)-5-(2,6-dichloro-phenylcarbamoyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (0.28 g, 0.48 mmol) in dry THF (10 mL), N-methylpiperazine (0.16 L, 1.40 mmol) was added. The reaction was stirred at room temperature for four hours, the solvent removed under reduced pressure and the crude product purified by flash chromatography (CH2Cl2/MeOH 90/10) to afford 0.20 g (yield 70%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.O1CCCC1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CSc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To an ice-cooled mixture of 4-methoxythiophenol (15 g, 0.11 mol), triethylamine (28 mL, 0.20 mol) and tetrahydrofuran (150 mL) was added ethyl bromoacetate (21 g, 0.13 mol), and the mixture was stirred overnight at room temperature. Ethanol (10 mL) was added, the solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10:1) to give title compound (22 g, yield 92%). oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][NH:29][CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:15])[F:14])[C:5]=12.C(N(CC)CC)C.[CH3:40][C@H:41]1[CH2:43][O:42]1>C(O)(C)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][N:29]([CH2:40][C@@H:41]([OH:42])[CH3:43])[CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:14])[F:15])[C:5]=12
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a mixture of 5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitrile dihydrochloride (20 mg, 0.04 mmol, racemic intermediate from Example 129, Step 2) and triethylamine (18 μL, 0.13 mmol) in isopropyl alcohol (0.1 mL) was added (S)-(−)-methyloxirane (9.1 μL, 0.13 mmol). The resulting mixture was stirred at 90° C. for 5 h. The crude mixture was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to 2.5 mg (10%) of give the desired product. The product was isolated as a mixture of diastereomers. LCMS calculated for C23H28F2N7O2 (M+H)+: m/z=472.2; Found: 472.2.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][CH:4]([OH:11])[C:5]([CH3:10])([CH3:9])[C:6](=[O:8])[CH3:7].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Cl:1][C:2]([C:12]([F:13])([F:14])[F:15])=[CH:3][CH:4]([O:11][S:24]([CH3:23])(=[O:26])=[O:25])[C:5]([CH3:9])([CH3:10])[C:6](=[O:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)C(C)(C)C(O)C=C(Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)C(C)(C)C(C=C(Cl)C(F)(F)F)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
733 g (3 mol) of 6-chloro-3,3-dimethyl-4-hydroxy-7,7,7-trifluoro-hept-5-en-2-one, 360 g (3.6 mol) of triethylamine and 1.5 g of 4-(N,N-dimethylamino)pyridine in 1 l of toluene were admixed at 5° C. with 378 g (3.6 mol) of methanesulfonyl chloride. The mixture was subsequently stirred at 25° C. for 3 hours, the precipitate was filtered off, and the filtrate was extracted with dilute hydrochloric acid and with saturated sodium bicarbonate solution. Drying and concentrating the organic phase gave 948 g of product. Melting point: 50°-52° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]1N2CN3CN(C2)CN1C3.[OH2:20].S(=O)(=O)(O)O>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3]([OH:9])=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH:10]=[O:20]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: Oc1ccc(F)cc1Br
Reactant: O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cc(F)cc(Br)c1O
Reaction time: 0.33 h

Procedure:
1.0 g (5.24 mmol) of 2-bromo-4-fluorophenol is initially charged in 4 ml of TFA. Over a period of 20 min, 1.47 g (10.47 mmol) of hexamethylenetetramine are added a little at a time. The mixture is then heated under reflux for 28 h. At RT, 6 ml of water and 3 ml of 50% strength sulfuric acid are added. After 2 h at RT, the reaction mixture is extracted twice with in each case 30 ml of ethyl acetate. The combined organic phases are washed four times with 1N hydrochloric acid and once with water and then dried over magnesium sulfate. The crude product is reacted further without further purification.
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:19](O)=[O:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:57][C@H:58]([C:63]([O:65][CH3:66])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61].CCN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:19]([NH:57][C@H:58]([C:63]([O:65][CH3:66])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:20])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
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: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 101.6 %

Procedure:
Cbz-Phe(4-CH2NHBoc)-OH (214 mg, 0.5 mmol, 1 equiv.) was dissolved in DCM. HBTU (228 mg, 0.6 mmol, 1.2 equiv.), HCl.H-Leu-OMe (100 mg, 0.55 mmol, 1.1 equiv.) and DiPEA (0.29 ml, 1.75 mmol, 3.5 equiv.) were added and the mixture was stirred for 2 hours before being concentrated. The residue was dissolved in ethyl acetate (EA) and washed with 1M HCl (2×), sat. aq. NaHCO3 (4×), brine and dried over MgSO4. Column chromatography (tol->30% EA:tol) yielded the title compound (282 mg, 508 μmol, quant.). 1H NMR (400 MHz, CDCl3): δ ppm 7.35-7.22 (m, 5H), 7.19-7.04 (m, 4H), 6.81 (d, J=6.7 Hz, 1H), 5.76 (d, J=8.4 Hz, 1H), 5.16-4.94 (m, 2H), 4.69-4.45 (m, 2H), 4.26-4.11 (m, 2H), 3.67 (s, 3H), 3.13-2.88 (m, 2H), 1.64-1.47 (m, 3H), 1.44 (s, 9H), 0.94-0.81 (m, 6H). 13C NMR (101 MHz, CDCl3): δ ppm 172.83, 170.76, 155.81, 137.23, 136.04, 135.30, 129.37, 128.28, 127.92, 127.70, 127.57, 79.13, 66.70, 55.73, 52.06, 50.51, 44.19, 41.08, 37.94, 28.23, 24.51, 22.52, 21.69.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]1[CH2:36][C@H:35]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:34]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[C:40]([O:39][C:38](=[O:44])[NH:37][C@H:35]1[CH2:36][C@@H:33]([NH:32][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:19]=2)=[O:23])[CH2:34]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N)C1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (110 mg, 0.25 mmol) and cis-tert-butyl 3-aminocyclobutylcarbamate (65 mg, 0.35 mmol). Then DMF (1.2 ml) was added followed by N,N-diisopropylethylamine (0.12 ml, 0.69 mmol) and HATU (104 mg, 0.27 mmol). The yellow reaction mixture was stirred at room temperature overnight then water and petroleum ether were added. The suspension was filtered and the solids were washed with water and a little petroleum ether. The product collected was dried under high vacuum to afford 145 mg (95%) of (cis-3-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-cyclobutyl)-carbamic acid tert-butyl ester as an off-white powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12]Br)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C([O-])=[O:16].[K+].C(=O)(O)[O-].[Na+]>CCO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][OH:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C[O-]
Reactant: CC(=O)Nc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)CO)cc1
Temperature: 38 °C
Reaction time: 22 h
Yield: 95.2 %

Procedure:
To a suspension of 4′-acetamido-2-bromoacetophenone 3 (10.0 g, 39 mmol) in EtOH (800 mL), aqueous potassium formate (35.4 g in 200 mL) was added then followed by sodium bicarbonate (3.68 g). The mixture was stirred at 38° C. (inner temp.) for 22 h. The mixture was evaporated in vacuo until the total volume reached to ca. 300 mL The mixture was diluted with ethyl acetate (1200 mL), washed with water (200 mL), then brine (2×400 mL). Aqueous layers were extracted with ethyl acetate (800 mL then 400 mL). Combined organic layer was dried over anhydrous sodium sulfate and then evaporated in vacuo to give crude 4 as a solid (7.17 g, 95%) which was used to the next step without any purification. MS(ES) m/e 194 [M+H].