Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[K+].[CH:6](=O)[CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH:17]=[O:18].O.[Cl-].[Na+].[C:23](O)(C)([CH3:25])[CH3:24]>>[C:17]1(=[O:18])[CH:16]=[CH:15][CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH2:25][CH:23]=[CH:24]1
Reactant: CC(C)(C)O
Reactant: O=CCCC=CCCC=CCCC=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: O=C1C=CCCC=CCCC=CCCC=C1

Procedure:
A 500 ml round bottom flask equipped with a magnetic stirrer, reflux condenser and gas inlet tube was charged with 4 g of potassium bicarbonate and 125 ml of aqueous 90% t-butanol. The stirred mixture was heated at vigorous reflux under a steady flow of argon, while a solution of 3.10 g (16 mMole) of dodeca-4,8-diene-1,12-dial and 4.40 g (16 mMole) of 1,3-bis(dimethylphosphoro)propan-2-one in 25 ml of 90% aqueous t-butanol was added at a constant rate over a period of 4 h. The reaction mixture was poured into water containing some sodium chloride, to avoid emulsions, extracted with ether, washed with brine, dried over sodium sulphate and evaporated. Distillation of the remaining oil gave 2.15 g (62%) of the desired tetraenone, b.p. 101°-105°/0.05 Torr. A sample was purified by chromatography on silica gel and showed m.p. 30°-37°;
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH:13]([CH2:23][O:24][CH3:25])[C:14]([NH:16][C:17]([CH3:22])([CH3:21])[C:18]#[C:19][CH3:20])=[O:15]>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH:13]([CH2:23][O:24][CH3:25])[C:14]([NH:16][C:17]([CH3:22])([C:18]#[C:19][CH3:20])[CH3:21])=[O:15])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: CC#CC(C)(C)NC(=O)C(Br)COC
Reactant: Oc1ccc2ccncc2c1
Product: CC#CC(C)(C)NC(=O)C(COC)Oc1ccc2ccncc2c1

Procedure:
In a similar procedure to Example 6, 7-hydroxyisoquinoline (commercially available) and 2-bromo-N-(4-methylpent-2-yn-4-yl) 3-methoxypropionamide were reacted to give 2-(7-isoquinolinyloxy)-N-(2-methylpent-3-yn-2-yl)-3-methoxypropionamide (Compound No. 2 of Table 49) as a colourless solid, m.p. 155-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])(O)[CH3:10].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>CCOCC>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[CH2:10]
Reactant: COc1ccccc1C(C)(O)c1ccccc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: C=C(c1ccccc1OC)c1ccccc1OC
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
1,1-Bis(2-methoxyphenyl)ethanol (25.6 g) was combined with 250 ml of acetic anhydride and the mixture was heated at reflux for 4 hours. A drop of concentrated sulfuric acid was added and the heating continued for 10 min. The opaque brown mixture obtained was allowed to cool and was diluted with ether. The resulting solution was extracted twice with water, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a brownish-black solid. This was recrystallized from methanol to obtain 14.0 g of the title compound as tan crystals melting at 88-90° C. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:9][O:10][CH3:11])[C:6]([OH:8])=O)(=[O:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.C(OCC)(=O)C>[C:1]([NH:4][C@H:5]([CH2:9][O:10][CH3:11])[C:6]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: COC[C@@H](NC(C)=O)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
To a suspension of (R)-2-acetylamino-3-methoxypropionic acid (5 g, 31.05 mmol) in tetrahydrofuran (50 mL), under a nitrogen atmosphere at −20° C., was added isobutyl chloroformate (4.04 mL, 31.05 mmol) over a period of 10 minutes. The temperature was maintained at −20° C. for 10 minutes. 4-Methylmorpholine (3.42 mL, 31.05 mmol) was added over a period of 10 minutes, and the temperature was maintained for a further 10 minutes. Benzylamine (3.39 mL, 31.05 mmol) was added directly into the reaction mixture via a syringe at −20° C. over a period of 10 minutes. The temperature of the reaction mixture was maintained at −20° C. for a further 20 minutes. The reaction mixture was quenched with aqueous HCl (1M; 21.88 mL). Solvent was removed by evaporation at 45-50° C., and crude material (16 g) was isolated. Ethyl acetate (50 mL) was added, and the reaction mixture was washed with water (2×2.5 mL). The organic layer was dried over sodium sulphate and the solvent was completely removed by evaporation to give crude material (5.77 g). A portion (5.5 g) of this material was dissolved in ethyl acetate (50 mL) at 50-55° C. The temperature was maintained for 10 minutes, before cooling to 25° C. After stirring at this temperature for 2 hours the reaction mixture was filtered. The wet filter cake was washed with ethyl acetate (2.5 mL). The residue was dried under suction for 20 minutes, then dried under vacuum at 40° C. to constant weight, to give the title compound (1.38 g, 18.5%). Chiral purity: 99.2%. Chemical HPLC: 96.8%.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:40])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][NH:24][C:25](=[O:36])OC2C=CC([N+]([O-])=O)=CC=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:41][NH:42][CH3:43]>ClCCl.O1CCCC1>[Br:1][C:2]1[C:3](=[O:40])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][NH:24][C:25](=[O:36])[N:42]([CH3:43])[CH3:41])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CNC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added 4-nitrophenyl 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzylcarbamate (from step 1) (0.350 g, 0.570 mmol) dissolved in dichloromethane (6.0 mL). The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. A stock solution of N,N-dimethylamine in tetrahydorfuran (0.427 mL, 2.0 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) which afforded an off white solid (0.226 g, 63.3%). 1H NMR (400 MHz, DMF-d6) δ 7.81 (app q, J=7.92 Hz, 1H), 7.40-7.19 (m, 5H), 7.06 (d, J=7.45 Hz, 1H), 6.88 (app t, J=5.84 Hz, 1H), 6.68 (s, 1H), 5.45 (s, 2H), 5.42 (s, 1H), 4.35 (d, J=5.84 Hz, 1H), 2.92 (s, 6H), 2.44 (s, 3H). ES-HRMS m/z 520.1065 (M+H C24H24BrF2N3O3 requires 520.1042).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].FC(F)(F)S([O-])(=O)=O.Br[CH2:27][CH2:28][S+](C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>C(Cl)Cl>[CH2:1]([N:8]1[C@@H:9]2[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[NH:15][CH2:28][CH2:27]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCC[C@@H]1NCc1ccccc1
Reactant: BrCC[S+](c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Product: c1ccc(CN2CCN[C@H]3CCCC[C@@H]32)cc1
Reaction time: 0.08 h
Yield: 69.7 %

Procedure:
The obtained (1S,2S)-N-benzylcyclohexane-1,2-diamine (2.90 g, 14.2 mmol) was dissolved in methylene chloride (284 nL). To the solution, 60% sodium hydride (1.99 g, 49.7 mmol) was added with ice-cooling and stirring in a nitrogen atmosphere. After 5 minutes, (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (6.92 g, 15.6 mmol) was added to the reaction mixture with ice-cooling and stirring, and the mixture was stirred overnight at room temperature. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added dropwise in small portions, and the product was then extracted twice with methylene chloride (100 mL). The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane) to obtain (4aS,8aS)-1-benzyldecahydroquinoxaline (2.28 g, 70%) in a light brown solid form.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:32][CH2:33][CH2:34][CH3:35])=[C:7](/[C:18](/[CH3:31])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([O:26]CC)=[O:25])[CH:8]=2)[O:3]1.[OH-].[Na+]>>[CH3:1][C:2]1([CH3:36])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:32][CH2:33][CH2:34][CH3:35])=[C:7](/[C:18](/[CH3:31])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([OH:26])=[O:25])[CH:8]=2)[O:3]1
Reactant: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)OCC)C(c1ccccc1)=CC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C(c1ccccc1)=CC(C)(C)O2

Procedure:
Following General Procedure G, ethyl (2E,4E,6E)-7-(2,2-dimethyl-4-phenyl-7-propoxy-2H-chromen-6-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoate (Compound 115, 131 mg, 0.27 mmol) was hydrolyzed with NaOH to yield a yellow oil after purification by column chromatography (silica gel, 100% hexane to 5% to 50% ethyl acetate in hexanes). The resulting oil was recrystallized from acetonitrile to produce the title compound as a yellow solid.
Reaction SMILES: C1(N[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])C=CC=CC=1.C(=O)([O:19][CH2:20][CH3:21])N.N>C(O)C>[CH2:20]([O:19][C:8](=[O:9])[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:21]
Reactant: CCOC(N)=O
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Agent: N
Solvent: CCO
Product: CCOC(=O)Nc1ccccc1

Procedure:
637 g of N,N'-diphenyl urea, 267 g of ethyl carbamate and 1880 g of ethanol (approximately 96%) were reacted for 8.5 hours at 200° C. in the pressure apparatus described in Example 1, with the ammonia gas given off being removed. After cooling and venting of the apparatus, the reaction mixture was removed, filtered and subjected to fractional distillation. Excess alcohol was initially distilled off at atmospheric pressure, after which the mixture was distilled off at 0.2 mbar. 766 g (77.3% of the theoretical yield) of N-phenyl carbamic acid ethyl ester which solidified into crystals melting at from 48° to 51° C. were produced.
Reaction SMILES: [CH3:1]I.C[Mg]I.[Br:6][C:7]1[CH:18]=[CH:17][C:10]([C:11](N(OC)C)=[O:12])=[C:9]([F:19])[CH:8]=1>C(OCC)C.O1CCCC1>[Br:6][C:7]1[CH:18]=[CH:17][C:10]([C:11](=[O:12])[CH3:1])=[C:9]([F:19])[CH:8]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1F
Reactant: CI
Agent: C[Mg]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
Into a 500-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of Mg (6 g, 250.00 mmol, 2.60 equiv) in diethyl ether (50 mL). To the resulting mixture was then added a solution of CH3I (118.4 g, 833.80 mmol, 7.80 equiv) in diethyl ether (75 mL) dropwise with stirring at room temperature. The resulting solution was allowed to react for 1 hr at room temperature. The above methylmagnesium iodide solution (2M) was then added to a solution of 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide (25 g, 95.42 mmol, 1.00 equiv) in tetrahydrofuran (150 mL) dropwise with stirring at −20° C. The resulting solution was stirred for an additional 2 h at room temperature. The resulting mixture was cooled to 0° C. with a water/ice bath. The reaction was then quenched by the addition of NH4Cl/H2O (300 mL). The resulting solution was extracted with ethyl acetate (2×200 ml) and the organic layers combined. The resulting mixture was washed with water (1×200 mL) and brine (1×200 mL). The resulting mixture was dried over NaSO4 and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:PE (1:20) to yield 1-(4-bromo-2-fluorophenyl)ethanone as colorless oil.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[CH2:23]([NH3+:27])[CH2:24][CH2:25][CH3:26]>>[CH2:23]([NH:27]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[NH3+]
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Agent: CC(=O)[O-]
Product: CCCCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 64 %

Procedure:
Prepared as in Example 35 from 2-benzoyl-benzo[b]thiophen-3-ol and n-butylammonium acetate with a yield of 64% of theory; m.p. 106°-107° C. (petroleum ether/ethyl acetate 1:1).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[NH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[NH:13][C:12]2=[O:22])[CH2:7][CH2:6]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[O:22]=[C:12]1[N:11]([CH:8]2[CH2:9][CH2:10][N:5]([C:1]([Cl:4])=[O:2])[CH2:6][CH2:7]2)[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[NH:13]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cl)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6 g (12.1 mmol) phosgene (20 percent by weight in toluene) were added to a solution of 2.5 g (10.2 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 2.6 mL (14.9 mmol) ethyldiisopropylamine in 75 mL DCM cooled to 0° C. and the reaction mixture was stirred for 30 min at this temperature. The mixture was allowed to warm up to RT, evaporated down i.vac. to approx. 50 mL and filtered through silica gel, this was washed with 200 mL DCM/EtOAc (1:1) and the combined organic filtrates were again evaporated down i.vac. The residue was stirred with DIPE, suction filtered and dried i.vac.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][C:32](O)=[O:33])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:35])[CH3:16])=[CH:11][CH:10]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][C:32]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:33])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:35])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCC(=O)NS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
A mixture of 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid (60 mg, 0.13 mmol), methanesulfonamide (24 mg, 0.26 mmol), HOBt (53 mg, 0.39 mmol), EDCl (75 mg, 0.39 mmol) and DIEA (1 mL) in CH2Cl2 was stirred at rt overnight. The solvent was removed to give the crude product. It was purified by preparative HPLC to give 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-N-(methylsulfonyl)propanamide (7 mg, 10%). 1H NMR (CDCl3): 1.50 (m, 3H), 2.21 (m, 6H), 2.54 (m, 1H), 2.93 (m, 1H), 3.15 (s, 3H), 5.59 (m, 1H), 6.83 (m, 2H), 6.98 (m, 4H), 7.18 (m, 2H), 7.24 (m, 3H), 9.58 (s, 1H). LC-MS Method 3, tR=1.26 min, m/z=561.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]1[C:26]2([CH2:29][NH:28][CH2:27]2)[CH2:25][O:24]1.C(=O)([O-])[O-].[K+].[K+].N1CCCC1C(O)=O>[Cu](I)I>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]([C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:28]4[CH2:29][C:26]5([CH2:23][O:24][CH2:25]5)[CH2:27]4)[CH:3]=3)[N:9]=2)[NH:14][CH:15]=1)=[O:22]
Reactant: C1NCC12COC2
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(I)c3)nc12
Agent: I[Cu]I
Agent: O=C(O)C1CCCN1
Agent: O=C([O-])[O-]
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CC5(COC5)C4)c3)nc12
Temperature: 100 °C
Yield: 25.1 %

Procedure:
1-[2-(3-Iodo-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2,-dimethyl-propan-1-one (150 mg, 0.37 mmol), the oxalate salt of 2-oxa-6-aza-spiro[3.3]heptane (267 mg, 0.93 mmol), potassium carbonate (255 mg, 1.85 mmol), copper iodide (14 mg, 0.074 mmol), and d,l-proline (17 mg, 0.148 mmol) were added to a microwave vial. The vial was capped and purged with nitrogen. DMSO (3.7 ml) was added and the vial was purged with nitrogen again. The reaction was heated in a sand bath at 100° C. for 72 hours. The reaction was poured into ice water, extracted into ethyl acetate, washed with water and brine, dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography using a gradient of 30% to 50% ethyl acetate in hexanes to yield 35 mg (25%) of 2,2-dimethyl-1-{2-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-propan-1-one as a yellow solid. (M+H)+=377; MP=260.0-262.0° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)Cl>[Br:16][C:5]1[C:6]([CH3:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(N)n1
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)ncc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-4-methylpyrimidine (10 g, 91.6 mmol), n-bromosuccinimide (17.9 g, 100.8 mmol) and CHCl3 are mixed together and stirred at room temperature for 1 hour. The solvent is removed in vacuo, water is added and the mixture is stirred at room temperature for 30 minutes. The resulting precipitate is collected by filtration and dried under vacuum oven to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.[H-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1F)[C:20]#[N:21].O>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]2[C:10]([CH:11]([CH3:13])[CH3:12])=[N:9]1)[C:20]#[N:21]
Reactant: CC(C)c1n[nH]c2nccc(Cl)c12
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nn(-c2ccc(C#N)cc2Cl)c2nccc(Cl)c12
Reaction time: 0.5 h

Procedure:
Compound (6b) (0.5 g) was dissolved in DMF (13 mL), and sodium hydride (0.145 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring for 30 min. Then, 3-chloro-4-fluorobenzonitrile was added to the reaction solution, followed by stirring at 60° C. for 1 hr. Water was added to the reaction solution. The precipitate was collected by filtration and washed by sprinkling water to obtain compound (99a) (0.72 g, 85′. %) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=O)[C:5]#[N:6].[CH3:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16].C(O)(=O)C.N1CCCCC1>ClCCl.C1CCCCC1.C(OCC)(=O)C>[C:15]([C:14]([C:13](=[O:18])[CH3:12])=[CH:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Cl:1])(=[O:17])[CH3:16]
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)C(=Cc1ccc(C#N)cc1Cl)C(C)=O
Yield: 89.8 %

Procedure:
300 mg (1.812 mmol) of 3-chloro-4-formylbenzonitrile, 181.4 mg (1.812 mmol) of 2,4-pentanedione, 163.2 mg (2.72 mmol) of acetic acid and 30.9 mg (0.36 mmol) of piperidine are dissolved in 15 ml of dichloromethane and heated under reflux with an inverse water trap overnight. The mixture shows complete conversion (TLC check, mobile phase: cyclohexane/ethyl acetate 5:1). The mixture is diluted with dichloromethane, washed with water and saturated sodium chloride solution and dried with sodium sulfate. The solvent is removed in a rotary evaporator. 403 mg (89.8% of theory) of 4-(2-acetyl-3-oxobut-1-en-1-yl)-3-chlorobenzonitrile are obtained and are reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[C:13]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-chloro-3-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 486.2 (M+H)+.
Reaction SMILES: C([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][C:15](=[O:21])[NH:16]2)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][C:15](=[O:21])[NH:16]2
Reactant: O=C1Cc2c(cccc2OCCNCc2ccccc2)N1
Agent: [Pd]
Solvent: CCO
Product: NCCOc1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 96 h
Yield: 87.5 %

Procedure:
A mixture of 4-(2-benzylaminoethoxy)-1,3-dihydro-indol-2-one (1.93 g, 6.84 mmol) in absolute ethanol (50 mL) containing 10% palladium on carbon (400 mg) was shaken in a Parr hydrogenator for 4 days at room temperature. The catalyst was filtered and washed with methanol. The solvent was removed under vacuum to afford a light tan solid (1.15 g, 87.5%): mp 146°-148° C.; MS EI m/e 192 (M+): HRMS for C10 H12N2O2 calc 192.089878, found 192.0845365.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[NH:14]C(=O)CCC.CC([O-])(C)C.[K+]>CN1C(=O)CCC1.CCOC(C)=O>[CH:2]([C:3]1[NH:14][C:6]2[C:5]([CH:4]=1)=[CH:10][CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=2)([CH3:20])[CH3:1]
Reactant: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1C#CC(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of N-(2-(3-methylbut-1-ynyl)-5-nitrophenyl)butyramide (Compound 119, 900 mg, 3.29 mmol) in NMP (10 ml) was added KOt-Bu (552 mg, 4.94 mmol) and the mixture was stirred at 70° C. for 16 h, cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound.