Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([Si:22]([CH3:32])([CH3:31])S(OC(F)(F)F)(=O)=O)([CH3:21])([CH3:20])[CH3:19]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([O:10][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:32])[CH3:31])=[CH2:9])[N:7]=1
Reactant: CC(C)(C)[Si](C)(C)S(=O)(=O)OC(F)(F)F
Reactant: CC(=O)c1cccc(Br)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 1-(6-bromopyridin-2-yl)ethanone (1000 mg, 5.0 mmol) and triethylamine (2.1 mL, 15.0 mmol) at 0° C. in dichloromethane (14 mL) was added trifluoromethyl tert-butyldimethylsilanesulfonate (1.4 mL, 6.2 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified via flash chromatography (0-30% ethyl acetate in heptanes) to afford 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine as a colorless oil (1450 mg, 92%). 1H NMR (400 MHz, DMSO-d6) δ 0.22 (s, 6H), 0.98 (s, 9H), 4.62-4.63 (m, 1H), 5.52 (s, 1H), 7.56-7.62 (m, 2H), 7.82 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([OH:20])[C:18]=1[OH:19])[C:5]([C:7]1[C:12]([OH:13])=[C:11]([OH:14])[C:10]([OH:15])=[CH:9][CH:8]=1)=[O:6].[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]=1[O:19][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:5]([C:7]1[C:12]([O:13][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:11]([O:14][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:10]([O:15][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:9][CH:8]=1)=[O:6])(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(c1cc(O)c(O)c(O)c1)c1ccc(O)c(O)c1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1cc(C(=O)c2ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c2OC(=O)C(C)(C)C)cc(OC(=O)C(C)(C)C)c1OC(=O)C(C)(C)C

Procedure:
100 mg of 3,4,5,4',5',6'-hexahydroxy benzophenone (0.00036 mole) and 450 MG (0.004 mole) of pivaloyl chloride were warmed to 50° C. in 20 mls of pyridine for 4 hrs. Solvent removed via N2 stream. Water added and extraction of product was done via CH2Cl2. The organic layer was washed with K2CO3 (5%) and dried over MgSo4. Solvent removal left an oil. 250 mg. (88%) yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14]O)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccccc1-c1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(-c2ccccc2CBr)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (4′-fluorobiphenyl-2-yl)-methanol (2.58 g, 12.8 mmol) in CH2Cl2 (100 mL), carbon tetrabromide (7.40 g, 22.3 mmol) is added. The solution is cooled to 0° C. and then triphenylphosphine (7.53 g, 28.7 mmol) is added portionwise. The reaction is stirred at 0° C. for 1.5 h and then at room temperature for 90 h before the solvent is removed. The resulting residue is partitioned between Et2O and water and then filtered. The layers are separated and the aqueous layer is extracted with Et2O. The combined organic layers are washed with water, brine and dried over Na2SO4. After concentration, the residue is purified by flash chromatography (hexane) to give 2-bromomethyl-4′-fluorobiphenyl as an oil. (an alternative preparation appears in J. Med. Chem. 2004, 47(22), 5441) 1H NMR (400 MHz, CDCl3) δ 7.53-7.50 (m, 1H), 7.43-7.31 (m, 4H), 7.24-7.21 (m, 1H), 7.15-6.80 (m, 2H), 4.42 (s, 2H).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.[OH-].[Na+]>C(Cl)Cl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH2:1]([C:4]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:15][CH:14]=2)[C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C=O)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1ccc(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 132.4 %

Procedure:
To a solution of 5-n-propylpyrrole-2-carboxaldehyde (2.5 g, 18.9 mmol) and t-butyl 4'-bromomethylbiphenyl-2-carboxylate (7.2 g, 20.7 mmol) in methylene chloride (75 ml) was added 2.5N NaOH (15 ml) and Aliquat 336 (1.5 g, 3.7 mmol). The mixture was vigorously stirred at room temperature overnight (~18 hours). The organic phase was washed with water (50 ml) and saturated aqueous sodium chloride (50 ml) before being dried (MgSO4), filtered and concentrated to leave 10.1 g of a dark oily residue. Flash chromatography (silica gel, 300 g; EtOAc/hexanes, 1/9) gave 5.84 g (79%) of a pale yellow viscous oil.
Reaction SMILES: [BH4-].[Na+].CC(=CC)C.B(F)(F)F.CCOCC.C(BCCC(C)C)CC(C)C.C([C:30]1([O:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:35][CH2:36][CH2:37][CH3:38])#C.C[N+]([O-])(C)C>O1CCCC1>[CH3:41][Si:40]([CH3:42])([CH3:43])[O:39][CH:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: C#CC1(O[Si](C)(C)C)CCCC1CCCC
Agent: CC(C)CCBCCC(C)C
Agent: CC=C(C)C
Agent: C[N+](C)(C)[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC1CCCC1O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of 9.2 g of sodium borohydride and 45.8 g of 2-methyl-2-butene in 350 ml of dry tetrahydrofuran at 0° C. with stirring under nitrogen is added, over 20 minutes, 41.1 ml of boron trifluoride etherate. After 3 hours, to this resulting solution of diisoamylborane is added 38.8 g of 1R,2S(and 1S, 2R)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane in 40 ml of tetrahydrofuran in 20 minutes. The mixture is stirred 2 hours and then stored at -20° C. overnight. The mixture is allowed to warm to 0° C. and at 0° C. 85 g of dry trimethylamineoxide is added portionwise over 20 minutes. After stirring at 25° C. for one hour, the mixture is filtered through diatomaceous earth. The filtrate is poured simultaneously with a solution of 230 g of iodine in 250 ml of tetrahydrofuran into a stirred, cold solution of 430 g of sodium hydroxide in 1900 ml of water. After stirring for 30 minutes, the organic layer is separated. The aqueous layer is extracted with ether. The combined organic solutions are washed twice with a saturated solution of sodium thiosulfate and once with brine. The solution is dried over magnesium sulfate, the solvent is removed and the residue is dissolved in hexane. The hexane solution is filtered through diatomaceous earth and silica gel. The hexane is removed and the residue is purified by dry column chromatography on silica gel eluting with hexane: 45.35 g of 1R,2S(and 1S, 2R)-1-trans-2-iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane is obtained.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[N:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][N:34]=[CH:33][N:32]=5)[C:27](=[O:37])[N:26]([CH3:38])[N:25]=4)[C:17]=3[CH:18]=[O:19])[C:14](=[O:15])[C:3]=12.[BH4-].[Na+].CO>O>[F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]([CH2:18][OH:19])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][N:34]=[CH:33][N:32]=5)[C:27](=[O:37])[N:26]([CH3:38])[N:25]=4)[CH:21]=[CH:22][N:23]=3)[C:14](=[O:15])[C:3]=12
Reactant: Cn1nc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2C=O)cc(Nc2ccncn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1nc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2CO)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 263c (100 mg, 0.19 mmol), NaBH4 (30 mg, 0.78 mmol), and methanol (20 mL). The mixture was stirred at room temperature for 0.5 h. It was then diluted with water (30 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×30 mL) and the combined dichloromethane extract was dried and concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 263 as a white solid (67 mg, 68%). MS-ESI: [M+H]+ 517.3. 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.55 (d, J=4.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 7.56 (dd, J=1.0, 6.0 Hz, 1H), 7.43 (d, J=5.0 Hz, 1H), 4.83 (t, J=5.5 Hz, 1H), 4.62-4.58 (m, 1H), 4.39-4.36 (m, 1H), 4.25-4.19 (m, 2H), 4.06-4.04 (m, 1H), 3.92-3.90 (m, 1H), 3.81 (s, 3H), 2.64-2.54 (m, 2H), 2.43-2.41 (m 2H), 1.78-1.76 (m, 2H), 1.69-1.67 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.I[C:11]1[C:12]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:27][N:26]=3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[N:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(Cl)Cl.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:35]1([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([O:17][C:12]4[C:11]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)=[CH:16][N:15]=[CH:14][N:13]=4)=[CH:19][CH:20]=3)=[N:26][N:27]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: OB(O)c1ccncc1
Reactant: Ic1cncnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2nnc(Nc3ccc(Oc4ncncc4-c4ccncc4)cc3)c3ccccc23)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A slurry of 4-pyridylboronic acid (0.0950 g, 0.773 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.0141 g, 0.0193 mmol), and N-(4-(5-iodopyrimidin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine (0.200 g, 0.387 mmol) and sodium carbonate 2.0 M in H2O (0.387 ml, 0.773 mmol) in 1.5 mL dioxane was flushed with nitrogen, sealed, and heated to 80° C. The reaction became dark and solids dissolved after 1 h. After 3 h, the reaction was judged complete. The reaction was cooled and diluted with DCM and water. The resulting aqueous emulsion was extracted 4×DCM. The combined organics were dried over anhyd sodium sulfate, filtered, and concentrated in vacuo. The material was adsorbed onto 1.8 g silica gel from MeOH/DCM, dried, and purified by silica gel chromatography (0-60-100% 90/10 DCM/MeOH in DCM) to give 4-phenyl-N-(4-(5-(pyridin-4-yl)pyrimidin-4-yloxy)phenyl)phthalazin-1-amine as a tan solid. MS m/z=469 [M+H]+. Calc'd for C29H20N6O: 468.5.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:13][CH2:14][C:15]([NH2:17])=[O:16].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:1]1([CH:7]([CH3:11])[CH2:8][CH:9]2[NH:17][C:15](=[O:16])[CH2:14][NH:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CC=O)c1ccccc1
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(CC1NCC(=O)N1)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 3-phenylbutanal (Trifernal®, 0.67 g, 4.5 mmol), glycinamide hydrochloride (0.50 g, 4.5 mmol), triethylamine (0.46 g, 4.5 mmol) and K2CO3 in ethanol (4 ml) was heated to 60° C. for 24 h. Then the solvent was removed under vacuum at 40° C. The residue was taken up in ether and the solvent evaporated to yield 0.52 g (57%) of a highly viscous oil as a mixture of diastereoisomers.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([O:36][CH3:37])[CH2:11][CH2:12][CH:13]([C:24]1[NH:25][C:26](=[O:35])[C:27]([OH:34])=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:29]=1)[N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH3:16])C1C=CC=CC=1.C(O)(=O)C>CCOC(C)=O.CO.[Pd]>[C:20]([O:19][C:17]([N:14]([CH2:15][CH3:16])[CH:13]([C:24]1[NH:25][C:26](=[O:35])[C:27]([OH:34])=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:29]=1)[CH2:12][CH2:11][C@H:10]([O:36][CH3:37])[CH2:9][OH:8])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](COCc1ccccc1)OC)c1nc(C(=O)OC)c(O)c(=O)[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](CO)OC)c1nc(C(=O)OC)c(O)c(=O)[nH]1
Reaction time: 96 h

Procedure:
To a solution of methyl 2-{(4S)-5-(benzyloxy)-1-[(tert-butoxycarbonyl)(ethyl)amino]-4-methoxypentyl}-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (13 g, 25.02 mmol) in EtOAc (30 mL) and MeOH (30 mL) was added acetic acid (20 mL) and palladium on carbon (Degussa, 10% by mass, 13 g, 122 mmol). The reaction mixture was shaken on a Parr apparatus under hydrogen gas (50 psi) for 4 days and then filtrated through a pad of celite. The filter cake was washed with MeOH. The filtrate was concentrated in vacuo. The crude residue was used in the next reaction without further purification. LC-MS: 429.89 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].Cl.Cl[CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O>[NH:2]([CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[NH2:3]
Reactant: ClCCN1CCCC1
Reactant: NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NNCCN1CCCC1

Procedure:
A mixture of 200 g of 85% hydrazine hydrate, 200 ml of water, 170 g of N-chloroethylpyrrolidine hydrochloride, and 70 g of potassium carbonate was boiled under reflux for seven hours. Sodium hydroxide (390 g) was added and the mixture was extracted with ether. The ethereal extract, dried and distilled, yielded the title compound, bp 107°-111° C. (18.5 mm).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH:15]=O)[CH:6]=1)=[O:4].Cl.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[NH2:31][S:28]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][NH:20][CH2:15][C:11]2[C:10]([O:17][CH3:18])=[CH:9][CH:8]=[C:7]3[C:12]=2[CH:13]=[CH:14][C:5]([C:3]([OH:2])=[O:4])=[CH:6]3)=[CH:27][CH:26]=1)(=[O:29])=[O:30]
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: COC(=O)c1ccc2c(C=O)c(OC)ccc2c1
Agent: Cl
Product: COc1ccc2cc(C(=O)O)ccc2c1CNCc1ccc(S(N)(=O)=O)cc1

Procedure:
The title compound was prepared as a white solid (0.245 g, 34% for two steps) from 6-methoxy-5-formyl-2-naphthoic acid methyl ester using p-aminomethyl-benzenesulfonamide hydrochloride and a procedure similar to steps 3-4 of Example 1, mp 283-285° C. (decomp.); 1H NMR (DMSO-d6) δ3.94 (s, 3H), 4.37 (s, 2H), 4.53 (s, 2H), 7.46 (s, 2H), 7.60 (d, J=9.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 8.01 (dd, J=1.4, 9.0 Hz, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.28 (d, J=9.2 Hz, 1H), 8.61 (s, 1H), 9.25-9.46 (bs, 2H), 12.78-13.18 (bs, 1H); IR (neat) 2380-3300, 1670, 1625, 1600, 1485, 1470, 1455, 1430, 1420, 1325, 1310, 1285, 1265, 1220, 1185, 1165, 1105, and 1040 cm−1; mass spectrum [(+) ESI], m/z401 (M+H)+ and [(−) ESI], m/z 399 (M−H)−; Anal. Calcd. for C20H20N2O5S.HCl: C, 54.98; H, 4.84; N, 6.41, Found: C, 54.60; H, 4.93; N, 6.17.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:12])([CH3:11])[CH2:7][NH:8]2)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:11][C:6]1([CH3:12])[C:5]2[C:9](=[CH:10][C:2]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:3][CH:4]=2)[NH:8][CH2:7]1
Reactant: CC1(C)CNc2cc(I)ccc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CNc2cc(N3CCOCC3)ccc21
Temperature: 65 °C

Procedure:
The 6-iodo-3,3-dimethylindoline (250 mg, 0.915 mmol), morpholine (0.399 mL, 4.58 mmol), Pd2(dba)3 (33.5 mg, 0.037 mmol), and 2-(dicyclohexylphosphino)-2,4,6-tri-i-propyl-1,1-biphenyl (34.9 mg, 0.073 mmol) were dissolved in THF (2.0 mL) and 1M lithium bis(trimethylsilyl)amide (5.03 mL, 5.03 mmol) solution in THF was added to a sealed tube and heated to 65° C. for 1 h. The reaction was cooled to rt and then poured into water (30 mL) and extracted with EtOAc (1×150 mL) and DCM (1×150 mL). The combined organic layers were dried over magnesium sulfate and the crude product was purified by medium pressure chromatography (silica, 50 to 100% EtOAc:DCM) to give 4-(3,3-dimethylindolin-6-yl)morpholine. Mass Spectrum (ESI) m/e=233.2 (M+1).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[NH2:14][C:15]1[NH:16][CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:19]=1[C:20]([NH2:22])=[O:21]>O1CCCC1.C(OCC)(=O)C>[C:8]([NH:14][C:15]1[NH:16][CH:17]=[C:18]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C:19]=1[C:20]([NH2:22])=[O:21])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Reactant: CCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Reaction time: 16 h
Yield: 86.3 %

Procedure:
0.227 cm3 (1.62 mmol) of triethylamine and 0.085 cm3 (0.81 mmol) of butyryl chloride are added, at a temperature close to 25° C., to a solution of 0.20 g (0.81 mmol) of 2-amino-4-(4-nitro-phenyl)-1H-pyrrole-3-carboxamide in 25 cm3 of tetrahydrofuran. After stirring for 16 hours at this temperature, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 60 cm3 of ethyl acetate and then washed with three times 20 cm3 of water. The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.221 g of 2-butyrylamino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in the form of a brown powder. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 0.94 (t, J=7.5 Hz, 3H); 1.63 (m, 2H); 2.36 (t, J=7.5 Hz, 2H); from 6.20 to 8.50 (very broad m, 2H); 6.79 (d, J=3.0 Hz, 1H); 7.64 (d, J=9.0 Hz, 2H); 8.18 (d, J=9.0 Hz, 2H); 10.3 (broad s, 1H); 11.6 (broad s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][Br:15])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][Br:15])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OCCBr)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCCBr)c(Br)c1
Yield: 88.7 %

Procedure:
To a stirred solution of methyl 3-bromo-4-(2-bromoethoxy)benzoate (4.0 g, 1.0 eq) in MeOH/H2O (v/v 2:1, 60 mL) was added NaOH (0.715 g, 1.5 eq). The mixture was then refluxed for 25 min, and concentrated under reduced pressure. The residue was poured into water and washed with EtOAc. To the aqueous layer was added 3 N HCl to give the desired product as a white solid (3.4 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 4.50 (t, J=5.6 Hz, 2H), 3.85 (t, J=5.6 Hz, 2H)
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][CH3:15])[C:11](=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:22]Br.O>C(O)(=O)C>[Br:22][CH:1]([C:3]1[N:12]([CH2:13][CH2:14][CH3:15])[C:11](=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCCn1c(CC)nc2ccccc2c1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCn1c(C(C)Br)nc2ccccc2c1=O
Yield: 92.3 %

Procedure:
To a solution of 2-ethyl-3-propyl-3H-quinazolin-4-one (125 mg, 0.58 mmol) and sodium acetate (48 mg, 0.58 mmol) in glacial acetic acid (1 mL) cooled in an ice bath was added dropwise a solution of bromine (29.8 μL, 0.58 mmol) in glacial acetic acid (0.5 mL). After addition was complete the reaction was heated to reflux for 2 hours. Water was then added to the solution and the mixture extracted with dichloromethane. The organic layer was then washed with 10% sodium bisulfite solution, water and then dried over magnesium sulfate, filtered and concentrated to yield the product as a brown oil (158 mg, 92%). 1H NMR (CDCl3) δ 1.05 (t, 3H, J=7.3 Hz), 1.66 (m, 1H), 1.91 (m, 1H), 2.19 (d, 3H, J=6.3 Hz), 3.89 (m, 1H,), 4.53 (m, 1H,), 5.04 (q, 1H, J=6.6 Hz), 7.49 (t, 1H, J=7.3 Hz), 7.73 (m, 2H), 8.27 (d, 1H, J=8.4 Hz).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH2:16]([CH:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([CH3:25])[C:19]1=[O:26])[CH3:17].Cl[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]>CCCCCC.O1CCCC1.O>[CH2:16]([C:18]1([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([O:34][CH3:35])[CH:28]=2)[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([CH3:25])[C:19]1=[O:26])[CH3:17]
Reactant: COc1ccccc1Cl
Reactant: CCC1CCCCN(C)C1=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCC1(c2cccc(OC)c2)CCCCN(C)C1=O
Temperature: 25 °C

Procedure:
2,2,6,6-tetramethylpiperidine (8.48 g) was added dropwise with cooling and stirring under nitrogen to a solution of butyl lithium (0.05 mole) in hexane (31.25 ml) and tetrahydrofuran (15 ml). 3-Ethylhexahydro-1-methyl-2H-azepin-2-one (7.75 g) in dry tetrahydrofuran (20 ml) was added. On completion of this addition a further portion of butyl lithium (0.06 mole) in hexane (37.5 ml) was added with cooling. After ten minutes o-chloroanisole (8.54 g) was added dropwise in tetrahydrofuran (20 ml). The reaction was then stirred at ambient temperature for c.a. 20 hours. The reaction mixture was poured into water, and the tetrahydrofuran removed under reduced pressure. After acidifying with 5 M hydrochloric acid the mixture was extracted with toluene. Toluene extracts were washed with water, dried (MgSO4) and after removal of the solvent the product distilled affording 2.37 g, b.p. 150°-170° C. at 0.6 mm. Corrected by purity by g.l.c. assay, the yield of the title compound was 15.8%.