Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:24]=[C:25]([Br:33])[CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:24]=[C:25]([Br:33])[CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1cc(Br)cc2cccnc12
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cc(Br)cc3cccnc23)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
To a stirred solution of 80 mg (0.279 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 8-amino-6-bromoquinoline (93 mg, 0.417 mmol) was added. The resulting mixture was stirred at room temperature or one day. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 3:1) to yield the title compound (110 mg, 85.3% yield).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.[NH2:31][OH:32]>CS(C)=O.O>[OH:32][N:31]=[C:27]([C:26]1[CH:29]=[CH:30][C:23]([CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([CH2:14][O:13][C:12]4[CH:15]=[C:16]5[C:20](=[CH:21][C:11]3=4)[CH2:19][CH2:18][O:17]5)[C:2]2=[O:1])=[CH:24][CH:25]=1)[NH2:28]
Reactant: NO
Reactant: N#Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Solvent: O
Solvent: CS(C)=O
Product: NC(=NO)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a stirred solution of 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile (1.30 g, 32.9 mmol) in dimethyl sulfoxide (10 mL) was added 50% wt solution hydroxylamine in water (2 mL). The reaction was heated with stirring at 80° C. for 1 h, then cooled to ambient temperature and the product was precipitated by adding distilled water (25 mL). The solid was filtered and air dried to afford N′-hydroxy-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide (1.32 g, 93%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 7.40-7.03 (m, 13H), 6.99-6.92 (m, 2H), 6.79-6.74 (m, 2H), 6.58-6.50 (m, 1H), 5.10 (s, 1H); MS (ES−) m/z 468.2, 470.2 (M−1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][Si](CC)(CC)CC)[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)#[CH:18]
Reactant: CC[Si](C#Cc1ccc2c(c1)c(CCN1CCCC1)cn2S(=O)(=O)c1ccc(C)cc1)(CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc2[nH]cc(CCN3CCCC3)c2c1
Yield: 66.2 %

Procedure:
3-(2-Pyrrolidinylethyl)-1-(p-toluenesulfonyl)-5-(triethylsilylethynyl)-indole (Example 6a, 130 mg, 0.26 mmol) was mixed with 5% potassium hydroxide in methanol (20 mL) and stirred at reflux for up to 48 h. The solvent was evaporated to about 4 mL, poured into dichloromethane (40 mL), washed with brine (40 mL), dried over sodium sulfate and evaporated. Chromatography on silica gel (dichloromethane/methanol/ammonium hydroxide 50:7:1) gave the title compound as a yellow oil (41 mg, 66%). HRMS-FAB+ for C16H19N2 : calculated MH+ : 239.15483, found MH+ : 239.15766.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][OH:19].C(N(CC)C(C)C)(C)C.[CH2:29](Cl)[O:30][CH3:31]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][O:19][CH2:29][O:30][CH3:31]
Reactant: COCCl
Reactant: CCc1ccc(Cc2cc(Br)c(CO)cc2Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(Cc2cc(Br)c(COCOC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a cooled (0° C.) solution of (2-bromo-5-chloro-4-(4-ethylbenzyl)phenyl)methanol (4.0 g, 11.8 mmol) in CH2Cl2 (60 mL), was added N,N-Diisopropylethylamine (DIPEA) (10.5 mL, 59.0 mmol) and MOMCl (4.5 μL, 59.0 mmol) successively. The reaction mixture was kept at 0° C. for 1 h, and then warmed to room temperature and kept at that temperature for 4 h. The reaction was quenched with H2O, the organic layer was separated and the aqueous layer was extracted 2× with CH2Cl2. The combined organic layers were washed 1× with brine prior to drying over Na2SO4. The volatiles were removed using a rotary evaporator and the resulting residue was purified by a silica gel column (50:1 petroleum ether:ethyl acetate as eluent) to give 4.05 g of pure product as colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.52 (s, 1H), 7.33 (s, 1H), 7.12 (q, 4H), 4.77 (s, 2H), 4.60 (s, 2H), 4.03 (s, 2H), 3.44 (s, 3H), 2.64 (q, J=7.5 Hz, 2H), 1.24 (t, J=7.5 Hz, 3H).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[C:8](/[CH:11]=[C:12]2\[NH:13][C:14](=[O:22])[N:15]([CH2:18][CH2:19][CH2:20][CH3:21])[C:16]\2=[O:17])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:41][C:42]1[S:43][CH:44]=[C:45]([CH2:47][Cl:48])[N:46]=1.Cl>CN(C=O)C.CCOCC>[ClH:48].[ClH:1].[CH2:2]([C:6]1[N:7]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[C:8](/[CH:11]=[C:12]2\[N:13]([CH2:47][C:45]3[N:46]=[C:42]([CH3:41])[S:43][CH:44]=3)[C:14](=[O:22])[N:15]([CH2:18][CH2:19][CH2:20][CH3:21])[C:16]\2=[O:17])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(CCCC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2csc(C)n2)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 0.5 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate hydrochloride (0.474 g, 1.0 mmol) in DMF (5 mL) is added K2CO3 (2.0 g, 15 mmol). After stirring for 5 minutes 2-methyl-4-(chloromethyl)thiazole hydrochloride (0.184 g, 1.0 mmol) is added. An additional amount of DMF (10 mL) is added after stirring for 30 minutes. The mixture is stirred for 5 days and then filtered. The filtrate is concentrated in vacuo and dissolved in ether (50 mL). This solution is washed with water and dried over K2CO3 and charcoal. A viscous oil is obtained by evaporation of the solvents in vacuo which is dissolved in ether and treated with ethereal HCl and then evaporated in vacuo to afford a solid foam. Recrystallized from 2-propanol/ether. Anal. Calcd. for C29H35N5O4S. 2HCl.0.5 H2O: C, 55.14; H, 6.07; N, 11.08
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([C:3]3([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]3)=[O:7])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)C3(C(F)(F)F)CC3)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 1-trifluoromethylcyclopropanecarboxylic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (72% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.83, 6.98, 3.90-3.80, 3.48, 1.66, 1.48, 1.39-1.35, 1.18-1.14, 0.92. MS (ES+) m/z 414.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15](C(OCC)=O)=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1ncc2n1C(c1ccc(C#N)cc1)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 1.65 g of 5-(p-cyanophenyl)-3-ethoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 10 ml of methanol containing 0.2 g of sodium hydroxide is stirred for 3 h at room temperature. The solution is warmed to reflux and 5 ml of 1N hydrochloric acid is added. After 1 h the reaction mixture is cooled and evaporated. The residue is partitioned between water and ethyl acetate. The organic layer is separated, dried over sodium sulfate and evaporated to yield 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, m.p. 128°-131°.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6](=[O:17])[N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=1.CO.[NH2:21][O:22][K].C(O)(=O)C>CO.C(Cl)(Cl)Cl>[CH2:10]([N:7]1[CH2:8][CH:9]=[C:5]([CH2:4][C:3]([NH:21][OH:22])=[O:2])[C:6]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CC1=CCN(Cc2ccccc2)C1=O
Reactant: NO[K]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CC1=CCN(Cc2ccccc2)C1=O)NO
Temperature: 0 °C
Reaction time: 4 h
Yield: 49.8 %

Procedure:
24 mg of (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-acetic acid methyl ester (p) prepared by the above Step 2 was dissolved in methanol solution (0.1 mmol) and then 1.7 M methanolic suspension solution containing NH2OK (0.4 ml, 0.68 mmol) was added thereto at 0° C. and the resulting mixture was stirred for 4 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10% methanol/chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 12 mg of 2-(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-hydroxy-acetamide (q) (yield: 48%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1.[CH3:22][O-:23].[Na+]>CO.C1COCC1>[CH3:22][O:23][C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(Cl)nn1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Yield: 28.5 %

Procedure:
To a solution of 3-chloro-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine (200 mg, 0.66 mmol) in a mixture of methanol (3 mL) and THF (1 mL) was added dropwise sodium methoxide (5.4 M in MeOH, 0.16 mL, 0.86 mmol) and the reaction mixture was heated under reflux for 24 h. After dilution with tert-butylmethylether (4 mL) and water (2 mL) it was extracted with tert-butylmethylether (15 mL) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (56 mg, 27%) as a colorless oil. MS: m/e=298.3 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[S:24](N)([NH2:27])(=[O:26])=[O:25].O>O1CCOCC1>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NS(=O)(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Yield: 100.4 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.25 gms, 0.7 mmole), sulfamide (70 mg) and water (10 mL) were added to 30 mL dioxane. The reaction mixture was refluxed for 24 hours, then cooled and concentrated under reduced pressure. The residue was recrystallized from EtOAc to give 280 mg of (R)—N-[6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-aminosulfonamide, MS M+H=399.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=2[O:30][CH3:31])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1[O:30][CH3:31])[C:17](=[O:19])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1ccc(Br)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)ccc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A suspension of (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino) phenyl)acrylate (86.95 g, 174 mmol) in 350 mL MeOH was heated to 70° C., was treated with sodium methoxide 25% wt in MeOH (19.06 ml, 69.8 mmol) and was allowed to stir overnight. The reaction mixture was then concentrated. The crude solid was triturated with IPA yielding 47.13 g clean product. The IPA washings were concentrated. Purification of the crude residue by silica gel column chromatography (0-100% EtOAc/heptane) gave an additional 10.76 g of slightly impure product. 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinolin-2(1H)-one (57.89 g, 128 mmol, 73.4% yield). (ESI) 451.8 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]#[N:12])=[N:8][CH:9]=1.[CH3:13]I>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[N:8][CH:9]=1
Reactant: N#CCc1ccc(Br)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C#N)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydride (7 mg, 0.17 mmol) is added to 2-(5-bromopyridin-2-yl)acetonitrile (300 mg, 0.15 mmol) in THF at −5° C. After 30 minutes methyl iodide is added (56 μL, 1.5 mmol) and the mixture warmed to r.t. After stirring for 4 hours, the mixture is partitioned between brine and methylene chloride. The organics were separated, dried over magnesium sulfate and the solvent removed under reduced pressure. The crude material is purified by silica gel chromatography to give the title compound (128 mg): LCMS [M+H] 196.0.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][C:21]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:22][C:21]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a mixture of 1.0000 M of potassium tert-butoxide in tetrahydrofuran (17 mL) and THF (10 mL) was added dropwise, at 0° C., diethyl cyanomethylphosphonate (2.7 mL, 0.017 mol). The reaction was warmed to rt and 30 min later cooled to 0° C. again. To the reaction mixture was added a solution of diisopropyl 3-oxocyclobutane-1,1-dicarboxylate (2.7 g, 0.011 mol) in THF (10 mL). The reaction was allowed to warm up to rt gradually and stirred at rt for 2 h. The reaction was quenched with saturated aq. NH4Cl and the organic solvent was reduced. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-35% EtOAc/Hex) to give the desired product (2.65 g) as light yellow oil.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:9]([NH2:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>>[CH2:9]([NH:20][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCCC(=O)O
Reactant: C=CCCCCCCCCCN
Product: C=CCCCCCCCCCNC(=O)CCCC=C

Procedure:
Following the aforementioned procedure, diene was prepared from hex-5-enoic acid and undec-10-en-1-amine. The resulting yellow solid was purified by silica gel chromatography (5:1 hexanes:ethyl acetate) to afford the desired product as a white solid. IR (neat): 3291 (br, s), 3078 (m), 2924 (s), 2853 (s), 1640 (s), 1550 (s), 1438 (s), 1369 (m), 1257 (m), 991 (s), 908 (s), 722 (m), 634 (m); 1H NMR (400 MHz, CDCl3): δ 5.86-5.73 (2H, m), 5.39 (1H, s, br), 5.05-4.91 (4H, m), 3.23 (21-1, dt, J=13.2, 7.2, 6.6 Hz), 2.16 (2H, t, J=7.4 Hz), 2.12-2.00 (4H, m), 1.78-1.70 (2H, m), 1.50-1.46 (2H, m), 1.38-1.27 (12H, m); 13C NMR (100 MHz, CDCl3): δ 172.8, 139.3, 138.1, 115.4, 114.3, 39.6, 36.2, 33.9, 33.3, 29.8, 29.6, 29.5, 29.4, 29.2, 29.1, 27.1, 24.9; HRMS (ESI+) [M+H]+ calcd for C17H32N1O1: 266.2484. found: 266.2491.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:22])[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:28]=1)[CH3:19]
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)c1
Yield: 50.9 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (2.25 g, 10.0 mmol) was converted, using 3-ethoxycarbonylphenylboronic acid (2.89 g, 15 mmol), instead of 4-fluorophenylboronic acid, which after purification by chromatography (SiO2, heptane:ethyl acetate=50:50) afforded the title compound (1.9 g, 52%) which was obtained as a light yellow solid. MS: m/e=374.1[M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1B(O)O>COCCOC.O.[Cl-].[Na+].O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Reactant: Cc1ccc(B(O)O)c(Cl)c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1Cl
Temperature: 100 °C
Yield: 66.4 %

Procedure:
A suspension of methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 2-chloro-4-methylphenylboronic acid (0.064 g; 0.375 mmol) in a mixture of DME-water (3:1, 1 mL) was heated at 100° C. in a sealed tube for 2.5 h. The mixture was diluted with brine and extracted with ethyl acetate. The combined organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane furnished 0.069 g (64%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([CH:28]=[CH:27][C:26]([O:30][CH3:31])=[O:29])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(c2ncc(Br)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C=Cc1cnc(N2CCN(C(=O)OC(C)(C)C)[C@H](C)C2)c(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A mixture of (2R)-4-(5-bromo-3-trifluoromethyl-pyridin-2-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester from step (c) above (8.48 g, 20 mmol), methyl acrylate (1.9 g, 22 mmol, Aldrich), palladium acetate (49 mg, 2.0 mmol, Aldrich) and benzyltriethyl ammonium chloride (456 mg, 2.0 mmol, Aldrich) in DMF (20 mL) was stirred at 40° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (2×80 mL). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 20% EtOAc/hexane to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 430 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[NH:10]2)=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>O>[CH:35]1([CH2:34][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:12]=3)[CH:8]=[C:9]2[C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)[CH2:37][CH2:36]1
Reactant: CCOc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)[nH]c2c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Yield: 87.9 %

Procedure:
6-Ethoxy-2-(4-nitro-phenyl)-1H-indole (4.5 g, 16 mmol), Cs2CO3 (7.8 g, 24 mmol), DMF (23 mL), and bromomethylcyclopropane (1.8 mL, 18 mmol) were stirred at 80° C. in a sealed tube for 16 hours. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried and concentrated. Purification by silica gel chromatography (1:1 CH2Cl2/hexane) provided 1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (4.73 g, 88%) as an orange solid.