Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[N:21]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22]([Br:26])=[C:23]([Br:25])[N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[CH:36]=[CH2:37].C(Cl)Cl>CN(C=O)C>[CH2:37]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[N:21]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:22]([Br:26])=[C:23]([Br:25])[N:24]=1)[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3nc(Br)c(Br)n3COCC[Si](C)(C)C)[nH]c2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCn1c(-c2nc(Br)c(Br)n2COCC[Si](C)(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 3-cyclohexyl-2-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1H-indole-6-carboxylate (428 mg, 0.7 mmol) in dry DMF (5 mL) was added KH (30% in oil, 0.8 mmol, 109 mg) proportion-wise at RT. The mixture was stirred at RT for 10 min until no further effervescence was observed. Allyl bromide (420 mg, 3.5 mmol) was added and the resulting mixture was stirred at RT for 15 min. Methylene chloride (10 mL) was added and the solution was washed with 1N HCl (3×10 mL), dried (Na2SO4), filtered and evaporated to give the title compound in a form pure enough for use in the following step (100%). 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 0.80 (m, 2H), 1.00-2.00(m, 10H), 2.45 (m, 1H), 3.43 (dd, 2H, J=7.5, 9.6 Hz), 3.91 (s, 3H), 4.50 (dd, 1H, J=4.8, 15.0), 4.60 (dd, 1H, J=6.0, 15.0), 4.88 (dd, 1H, J=1.2, 17.1 Hz), 5.03 (s, 2H), 5.04 (dd, 1H, J=0.9, 9.0 Hz), 5.78 (m, 1H), 7.75 (dd, 1H, J=1.5, 8.5 Hz), 7.82 (d, 1H, J=8.5 Hz), 8.02 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[C@H:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][O:14][C:13]2=O)=[O:11])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C1C[O:47]CC1>>[O:47]=[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]1[CH2:17][C@@H:16]1[CH2:15][O:14][CH2:13][N:12]1[C:10](=[O:11])[C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]
Reactant: C1CCOC1
Reactant: O=C(CCc1ccc(Cl)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)N1COC[C@H]1CC1C=CC=CC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4R)-3-[3-(4-chlorophenyl)propanoyl]-4-benzyl-1,3-oxazolidin-2-one (Step 2) (3.0 g, 8.72 mmol) in anhydrous THF (100 mL, Aldrich) at −78° C. was added a THF solution of NaHMDS (13.1 mL, 1M, Aldrich). The solution was stirred at −78° C. for 30 min then at −20° C. for 30 min. The solution was cooled to −78° C. again and t-butyl bromoacetate (1.93 mL, 13.1 mol) was added to the reaction mixture via a syringe. The reaction was stirred at −78° C. for 2 h. After warming to RT, the reaction mixture was poured onto 1M NaH2PO4 (50 mL). The desired compound was extracted with 100 mL of EtOAc and the organic phase was washed with 50 mL of brine, dried over Na2SO4 and concentrated in vacuo. The compound was further purified with silica gel column chromatography (20% to 50% EtOAc in hexane) to provide tert-butyl 4-[(4R)-2-oxo-4-benzyl(1,3-oxazolidin-3-yl)](3S)-3-[(4-chlorophenyl)methyl]-4-oxobutanoate as a light yellow solid (3.5 g). MS (ESI, pos. ion) m/z: 458.0 (M+1). Calc'd for C25H28ClNO5: 457.17.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1.[CH3:13][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[F:12][C:2]([F:11])([F:1])[C:3]1[N:8]=[CH:7][C:6]([CH:9]([OH:10])[CH3:13])=[CH:5][CH:4]=1
Reactant: C[Mg]Cl
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C

Procedure:
To a solution of 2.0 g 6-trifluoromethyl-pyridine-3-carboxaldehyde in 20 mL of dry THF under inert atmosphere at −78° C. was added dropwise 6 ml of MeMgCl (3 M in THF). This mixture was allowed to warm up to room temperature slowly. Aqueous ammonium chloride was added to reaction mixture. The whole was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate. Purification by flash chromatography (silica, haptane/ethyl acetate) provided 0.85 g of 1-(6-trifluoromethyl-pyridin-3-yl)-ethanol.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].N1[CH:11]=[CH:10]N=C1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:30]=[C:29]([O:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:28]=[CH:27][N:26]=1)[CH2:20][CH2:19]2)(=[O:15])=[O:14].[Cl-].[NH4+]>O1CCOCC1>[CH3:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:26]=[CH:27][N:28]=[C:29]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:1]([O:2][C:10]4([CH3:11])[CH2:23][CH2:24][CH2:16][CH2:17]4)=[O:4])[CH2:34][CH2:33]3)[CH:30]=1)[CH2:20][CH2:19]2)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Reactant: O=C([O-])[O-]
Reactant: c1c[nH]cn1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CC1(OC(=O)N2CCC(Oc3cc(N4CCc5cc(S(C)(=O)=O)ccc54)ncn3)CC2)CCCC1
Yield: 84.2 %

Procedure:
Potassium carbonate (153 mg, 1.11 mmol) and the imidazole compound (129 mg, 0.665 mmol) were added to a dioxane (10 mL) solution of the 5-(methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]indoline (82.9 mg, 0.222 mmol) produced in Reference Example 28, and the mixture was heated to reflux for 8 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride was added, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-3:2, V/V) to obtain the title compound as white powder (46.8 mg, yield: 42%).
Reaction SMILES: O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([N:19]([C:21]([C@@H:23]1[CH2:29][CH2:28][C@@H:27]2[CH2:30][N:24]1[C:25](=[O:39])[N:26]2[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:22])[NH2:20])(=O)C.N1C=CC=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:32]([O:31][N:26]1[C:25](=[O:39])[N:24]2[CH2:30][C@H:27]1[CH2:28][CH2:29][C@H:23]2[C:21]1[O:22][C:41]([CH3:42])=[N:20][N:19]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: c1ccncc1
Reactant: CC(=O)N(N)C(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
(CF3SO2)2O (0.50 mL) was slowly added to a solution of (2S,5R)—N-acetyl-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (0.5 g) and pyridine (0.5 mL) in dry DCM (10 mL) at −10° C. The reaction mixture was stirred at 0° C. for 1 h and then quenched carefully with sat. NaHCO3. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (gradient elution 10:1 to 1:1 petroleum ether/EtOAc) to afford (2S,5R)-6-(benzyloxy)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (0.3 g, 63%) as a slight yellow solid. ESI-MS (EI+, m/z): 315.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19]C)=[O:18])[C:3]=1/[CH:21]=[CH:22]/[Si:23]([CH3:26])([CH3:25])[CH3:24].C1COCC1.O.O.[OH-].[Li+]>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([OH:19])=[O:18])[C:3]=1/[CH:21]=[CH:22]/[Si:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1/C=C/[Si](C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)/C=C/c1c(C(=O)O)nc(-c2ccc(Cl)c(F)c2)c(F)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
(E)-methyl 4-amino-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(2-(trimethylsilyl)vinyl)picolinate (169 mg, 0.426 mmol) was dissolved in methanol (2 mL), THF (2 mL) and Water (1 mL). Lithium hydroxide hydrate (93 mg, 2.216 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under vaccum. The resulting residue was partitioned between 1 N HCl and ethyl acetate. The aqueous phase was extracted three more times with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound as an off-white solid (146 mg, 0.381 mmol, 90% yield): 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 9H), 6.26 (d, J=19.4 Hz, 1H), 6.49 (s, 2H), 6.93 (d, J=19.5 Hz, 1H), 7.68-7.83 (m, 2H), 7.88 (dd, J=10.9, 1.8 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ −145.32 , −116.04 . ESIMS m/z 384 ([M+H]+).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20](=[O:31])[CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.Cl.Cl[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)(O)[O-].[Na+]>>[N:3]1([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([C:38]5[CH:37]=[CH:36][N:35]=[CH:34][CH:39]=5)[CH2:27][CH2:26]4)[C:20](=[O:31])[CH2:19]3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Clc1ccccn1
Reactant: O=C1CN(S(=O)(=O)c2ccc(Cn3ccnc3)cc2)CCN1CC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CN(S(=O)(=O)c2ccc(Cn3ccnc3)cc2)CCN1CC1CCN(c2ccncc2)CC1
Temperature: 130 °C
Reaction time: 15 h
Yield: 48.4 %

Procedure:
A mixture of 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone dihydrochloride (209 mg) and chloropyridine hydrochloride (93 mg) was added to sodium bicarbonate solution, and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (10 ml), and the mixture was stirred at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=7:1) to give colorless solid of 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone (102 mg). The obtained 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone was dissolved in ethyl acetate (5 ml), and to the solution was added a solution of 4N hydrochloric acid in ethyl acetate. Precipitates were filtered, washed with ethyl acetate and dried to give colorless solid of the title compound (103 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:16]2[CH2:21][C:20](=[O:22])[C:19]([C:23](=O)[CH2:24][CH3:25])=[CH:18][CH2:17]2)=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]2[C:10]=1[CH2:9][C:8]([CH2:12][CH3:13])([CH3:11])[CH2:7]2.C([O-])(=[O:29])C.[Na+].Cl.[O:33]([NH2:36])[CH2:34][CH3:35]>C(O)C>[Cl:1][C:2]1[C:3]([CH:16]2[CH2:21][C:20](=[O:22])[C:19]([C:23](=[N:36][O:33][CH2:34][CH3:35])[CH2:24][CH3:25])=[C:18]([OH:29])[CH2:17]2)=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]2[C:10]=1[CH2:9][C:8]([CH2:12][CH3:13])([CH3:11])[CH2:7]2
Reactant: CC(=O)[O-]
Reactant: CCON
Reactant: CCC(=O)C1=CCC(c2c(C)c(C)c3c(c2Cl)CC(C)(CC)C3)CC1=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)c(C)c3c(c2Cl)CC(C)(CC)C3)CC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 78.9 %

Procedure:
To a solution 0.37 g of the 5-(7-chloro-2-ethyl-2,4,5-trimethylindan-6-yl)-2-propionyl-cyclohex-2-en-1-one in 10 ml of ethanol was added 0.16 g of sodium acetate (NaOAc.3H2O) and 0.13 g of ethoxylamine hydrochloride. After stirring at room temperature for 10 hours, the reaction mixture extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 0.338 g of the title compound as yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5](F)=[CH:4][CH:3]=1>N1CCCCC1.CS(C)=O.CO>[CH3:8][N:10]([CH3:11])[C:5]1[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])=[N:7][C:2]([N:7]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:3][CH:4]=1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Solvent: C1CCNCC1
Solvent: CS(C)=O
Solvent: CO
Product: CN(C)c1ccc(N2CCCCC2)nc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 160 °C
Yield: 24.3 %

Procedure:
6-Chloro-3-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.12 mmol) was placed in a microwave vial and dissolved in piperidine (0.5 ml). The mixture was heated at 160° C. for 1 h under microwave irradiation. The solvent was removed under a stream of nitrogen to give a crude residue that was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with MeOH and the solvent removed under a stream of nitrogen to give the title compound (7 mg) as a yellow solid.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26]([CH2:30][C:31](O)=[O:32])[N:25]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(OC(=O)C)C>CN(C)C=O>[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[N:25]=1
Reactant: Cc1cc(C)n(CC(=O)O)n1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)n(CC(=O)N2CCc3cc(-c4cn(C)c5ncnc(N)c45)ccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a mixture of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride (175 mg, 0.517 mmol) and (3,5-dimethyl-1H-pyrazol-1-yl)acetic acid (80 mg, 0.517 mmol) in N,N-Dimethylformamide (DMF) (3 mL) was added DIPEA (0.271 mL, 1.552 mmol) dropwise. The mixture was cooled in an ice bath, and T3P (1-propanephosphonic acid cyclic anhydride), 50% in ethylacetate (˜1.68M) (0.370 mL, 0.621 mmol) was then added dropwise. After stirring 30 minutes, the ice bath was removed and the mixture was allowed to warm to room temperature and stir 2 hours. The mixture was diluted with water (˜5 mL) and basified to pH 7-8 with 0.5M NaOH. Methanol was added to give a clear solution. This solution was loaded onto a reversed phase C18 SF25-55g Analogix cartridge and the product purified by eluting with a gradient of 30-95% methanol-water. The combined pure fractions containing the product was evaporated and azeotroped with acetonitrile and then benzene to give a solid that was triturated with acetonitrile (˜4 mL), filtered and washed with acetonitrile to afford 5-{1-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (90 mg, 41.2% yield) as a white solid after drying under vacuum. LCMS (ES) m/z=402.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (s, 1H) 8.07 (d, J=8.1 Hz, 1H) 7.34 (s, 1H) 7.20-7.29 (m, 2H) 6.08 (br. s, 2H) 5.86 (s, 1H) 5.09 (s, 2H) 4.26 (t, J=8.3 Hz, 2H) 3.74 (s, 3H) 3.27 (t, J=8.3 Hz, 2H) 2.17 (s, 3H) 2.10 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[NH:18][CH2:17][CH:16]([O:19][C:20](=[O:30])[C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[CH2:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[C:31]([O-:34])(O)=O.[Na+].C(Cl)(Cl)=O.[CH2:40]([NH:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[N:18]([C:31](=[O:34])[N:47]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46])[CH2:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)[CH2:17][CH:16]([O:19][C:20](=[O:30])[C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[CH2:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1)C(=O)OCC
Reactant: C=CCCCCCNCc1ccc(OC)cc1
Reactant: O=C([O-])O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Reaction time: 1 h
Yield: 91 %

Procedure:
Compound 131 (4.68 g, 11.2 mmol) was dissolved in THF (100 ml), NaHCO3 (s) (appr. 5 ml) was added followed by phosgene-solution (20% in toluene, 11.6 ml, 22.5 mmol). The reaction mixture was stirred vigorously for 1 h and then filtrated, evaporated and redissolved in DCM (100 ml). NaHCO3 (s) (appr. 5 ml) was added followed by hept-6-enyl-(4-methoxy-benzyl)-amin (3.92 g, 16.8 mmol). The reaction mixture was stirred at room temperature overnight, filtrated and evaporated on silica. The crude product was purified by column chromatography on silica (EtOAc/n-Heptane 25/75) to give the title compound (6.9 g, 91%).
Reaction SMILES: [H-].[Na+].CO.[CH3:5][CH:6]([CH3:19])[CH2:7][C:8]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[OH:18])=[O:9].Cl[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]>CCCCCC.CCOCC>[CH3:5][CH:6]([CH3:19])[CH2:7][C:8]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH:12][C:11]=1[OH:18])=[O:9]
Reactant: Cc1cc(O)cc(O)c1C(=O)CC(C)C
Reactant: CC(C)=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)=CCOc1cc(C)c(C(=O)CC(C)C)c(O)c1
Yield: 7.8 %

Procedure:
Under an atmosphere of nitrogen, 300 mg (7.50 mmol, 1.50 equivalents) of an oil dispersion of 60% sodium hydride was washed with petroleum ether to remove paraffin and then combined with 7.5 ml of dry methanol. Then, a methanol (5.0 ml) solution of 1.04 g (5.00 mmol) of (2,4-dihydroxy-6-methylphenyl) (2-methylpropyl) ketone (47) was added cooling with ice and stirred. Further, a methanol (5.0 ml) solution of 784 mg (7.50 mmol, 1.50 equivalents) of 1-chloro-3-methyl-2-butene was slowly added dropwise. The resultant mixture was stirred at room temperature for two hours. The mixture was combined with ether. The ether layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, and distilled to remove the solvent and obtain 1.296 g of a dark red oily substance. This oily substance was combined with a small amount of hexane and left standing in a refrigerator to recover 277 mg of the starting substance in the form of colorless needle crystals. The filtrate, 965 mg in weight, was subjected to silica gel column chromatography (49 g of Wako Gel C-300, eluted with hexane:ethyl acetate at varying ratios=29 1-7:3) to produce sequentially by fractionation in the order of elution 108 mg of {2-hydroxy-6-methyl-4-(3-methyl-2-butenyloxy)phenyl} (2-methylpropyl) ketone (48) in the form of a yellow oily substance, 78 mg of {2,4-dihydroxy-6-methyl-3-(3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (49) in the form of colorless fine crystals, and 260 mg of a yellowish brown oily substance which was again purified by column chromatography (6.0 g of Wako Gel C-300, eluted with hexane:ethyl acetate=19:1) to obtain 162 mg of {4,6-dihydroxy-2-methyl-3-(3-methyl-2-butenyl)phenyl} (3-methylpropyl) ketone (50) in the form of a yellow viscous oily substance.
Reaction SMILES: COP([C:7](=[N+:11]=[N-])[C:8](=O)[CH3:9])(=O)OC.[C:13]([NH:17][C:18]1C(C=O)=N[C:21]2[C:26]([N:27]=1)=[C:25]([C:28]1[NH:36][C:35]3[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=3[CH:29]=1)[CH:24]=[CH:23][CH:22]=2)([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+].CO.C(Cl)Cl>CO.CCOCC>[C:13]([NH:17][C:18]1[C:7]([C:8]#[CH:9])=[N:11][C:21]2[C:26]([N:27]=1)=[C:25]([C:28]1[NH:36][C:35]3[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=3[CH:29]=1)[CH:24]=[CH:23][CH:22]=2)([CH3:16])([CH3:14])[CH3:15]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: C#Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 23 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
Dimethyl(1-diazo-2-oxopropyl)phosphonate (Anichem, Inc., North Brunswick, N.J.; 8.63 μl, 0.06 mmol) was added to a suspension of 3-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbaldehyde (307b) (19.0 mg, 0.05 mmol) and K2CO3 (28.9 mg, 0.21 mmol) in MeOH (1.0 mL) and the resulting mixture was stirred at 23° C. for 16 h. Additional dimethyl(1-diazo-2-oxopropyl)phosphonate (20 μl, 0.13 mmol) was added, and the resulting mixture was stirred at 23° C. for 17 h. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-(3-(tert-butylamino)-2-ethynylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (2.8 mg, 7.79 μmol, 15% yield) as a yellow solid (following trituration with Et2O (0.5 mL)): 1H NMR (400 MHz, CDCl3) δ ppm 12.39 (1H, br. s.), 8.14 (1H, d, J=7.4 Hz), 8.10 (1H, d, J=8.0 Hz), 8.04 (1H, d, J=3.9 Hz), 7.72 (1H, t, J=7.8 Hz), 6.82 (1H, d, J=3.7 Hz), 5.49 (1H, br. s.), 3.81-3.86 (1H, m), 3.68-3.75 (2H, m), 3.06 (2H, t, J=6.9 Hz), 1.96 (9H, s). m/z (ESI, +ve) 360.2 (M+H)+.
Reaction SMILES: [B-](F)(F)(F)F.CN(C(O[N:14]1[C:19](=O)[CH2:18][CH2:17]C1=O)=[N+](C)C)C.[F:21][C:22]1[CH:23]=[C:24]([NH:29][CH:30]([C:32]2[CH:33]=[C:34]([C:49]([OH:51])=O)[CH:35]=[C:36]3[C:41]=2[O:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][C:37]3=[O:48])[CH3:31])[CH:25]=[C:26]([F:28])[CH:27]=1.C(N(C(C)C)C(C)C)C.N1CCC1>C(Cl)Cl.CN(C=O)C>[N:14]1([C:49]([C:34]2[CH:35]=[C:36]3[C:41](=[C:32]([CH:30]([NH:29][C:24]4[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=4)[CH3:31])[CH:33]=2)[O:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][C:37]3=[O:48])=[O:51])[CH2:17][CH2:18][CH2:19]1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Agent: C1CNC1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N2CCC2)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (409 mg, 1.36 mmol) was added portionwise to a suspension of the enantiomer 2 of 8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid ([α]D20°: −102°, enantiomer 2, see Example 7.0a) (450 mg, 1.05 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.310 mL, 1.78 mmol) in DCM (5 mL) at RT under nitrogen. The resulting mixture was stirred at RT for 4 hrs. Azetidine (0.211 mL, 3.14 mmol) was then added to the mixture and stirring was maintained overnight. The mixture was diluted with DMF and concentrated to remove DCM. The reaction mixture was purified by preparative HPLC on a Waters X-Bridge system. The fractions were evaporated to dryness to afford a white solid 6-(azetidine-1-carbonyl)-8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4H-chromen-4-one (300 mg, 61%). Mass Spectrum: M+H+ 470. [α]D20°: −113° in MeCN. NMR Spectrum (DMSOd6): 1.50 (d, 3H), 2.18-2.28 (m, 2H), 3.50-3.63 (m, 4H), 3.69-3.78 (m, 4H), 3.98-4.07 (m, 2H), 4.09-4.19 (m, 2H), 4.97-5.05 (m, 1H), 5.61 (s, 1H), 6.15 (d, 2H), 6.21 (t, 1H), 7.03 (d, 1H), 7.79 (d, 1H), 8.02 (d, 1H).