Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]#[CH:15]>C(#N)C>[CH2:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:14]#[CH:13]
Reactant: C#CCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN1CCOCC1

Procedure:
To a mixture of morpholine (0.78 mL, 8.98 mmol) and potassium carbonate (3.7 g, 26.9 mmol) in acetonitrile (10 mL) was added propargyl bromide (1.0 mL, 8.98 mmol) and the mixture was heated to about 80 C overnight. The reaction was quenched by addition of water and the mixture was extracted with diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated under vacuum to provide Example 639. 1H NMR (300 MHz, CD3OD) δ 2.57 (m, 4H) 2.68 (t, J=2.4 Hz, 1H) 3.29 (s, 2H) 3.70 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]=[O:13].[CH3:14][Mg]Br.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([OH:13])[CH3:14]
Reactant: C[Mg]Br
Reactant: O=Cc1cc2cccnc2cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cc2cccnc2cc1F
Reaction time: 2 h

Procedure:
To a solution of 7-fluoroquinoline-6-carbaldehyde (4.0 g, 22.84 mmol) in THF (30 ml) at 0° C., was added methylmagnesium bromide (2.85M in THF, 8 mL, 22.84 mmol) dropwise. The solution was stirred for 2 h, and NH4Cl was added to quench the reaction. The resulting mixture was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 and NH4Cl, and dried over Na2SO4, filtered and concentrated to give the crude product, which was purified with Analogix gel silica using hexanes:EtOAc to afford 1-(7-fluoroquinolin-6-yl)ethanol (i). LCMS (method B): [MH]+=192, tR=1.84 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[CH:12]([CH2:13][O:14][CH2:15][CH2:16][OH:17])[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:18]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(N(CC)CC)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([O:17][CH2:16][CH2:15][O:14][CH2:13][CH:12]2[C:6]3[CH:5]=[C:4]([O:19][CH3:20])[C:3]([O:2][CH3:1])=[CH:18][C:7]=3[CH2:8][CH2:9][CH2:10][O:11]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: COc1cc2c(cc1OC)C(COCCO)OCCC2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(COCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1)OCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a mixture of 3.00 g (10.6 mmoles) of 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethanol and 1.63 ml (11.7 mmoles) of triethylamine is added 2.59 g (11.7 mmoles) of p-nitrobenzenesulfonyl chloride. The reaction mixture is stirred at room temperature for 1 hour and then heated at 50° for 30 minutes. To this is added an additional 0.5 g of p-nitrobenzenesulfonyl chloride and 0.5 ml of triethylamine. After stirring at room temperature for 30 minutes, the reaction mixture is extracted with aqueous sodium bicarbonate and brine. The organic layer is filtered through sodium sulfate and taken to dryness. The residue is chromatographed on silica gel using 1% methanol methylene chloride as eluant to give 1.56 g (32%) 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl 4-nitrobenzene sulfonate. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: C[C@H](N)c1nc2cccnc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccnc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 7.9 %

Procedure:
A mixture of (S)-1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine from Example 10 (270 mg, 1.13 mmol), 6-chloro-9H-purine (250 mg, 1.59 mmol) and DIPEA (0.36 mL, 2.04 mmol) in n-butanol (1.5 mL) was stirred in a sealed tube for 48 h at 120° C. After cooling to RT, the crude reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM), then triturated with diethyl ether and then submitted to preparative HPLC (Phenomenex Gemini 5 μm C18 on a 60 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) affording 114 as an off-white solid (32 mg, 8%). LCMS: RT 2.64 min [M+H]+ 357.0. 1H NMR (DMSO, 400 MHz): δ 8.23 (1H, dd, J=4.76, 1.48 Hz), 8.18-7.97 (4H, m), 7.67-7.41 (5H, m), 7.29 (1H, dd, J=7.99, 4.76 Hz), 1.57 (3H, d, J=6.83 Hz)
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:24]([C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2)=O.C(O)(=O)C>C(O)C>[NH:30]1[C:31]2[C:27](=[C:26]([CH:24]=[N:23][NH:22][C:9]3[CH:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]4[N:13]=[C:14]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:15]=[C:11]4[N:10]=3)[CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: O=Cc1cccc2[nH]ccc12
Solvent: CCO
Solvent: CC(=O)O
Product: C(=NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1)c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
To a solution of 7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl-hydrazine (15 mg, 0.048 mM) in absolute ethanol (2.0 mL), there were added 4-formyl-indole (11 mg, 0.076 mM) and acetic acid (2.0 μL) and the mixture was stirred at room temperature for 3 hours. The precipitated solid was filtered off and then washed with ethanol to thus give the title compound (12 mg, yield: 58%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH2:15]([O:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25](OC)=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>O1CCOCC1>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:1]([CH2:2][C:25](=[O:26])[C:24]1[CH:29]=[CH:30][CH:31]=[CH:32][C:23]=1[O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:3]
Reactant: COC(=O)c1ccccc1OCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(O)c(C(=O)CC(=O)c2ccccc2OCc2ccccc2)c1
Reaction time: 5 h
Yield: 65.8 %

Procedure:
A solution of methyl 3-acetyl-4-hydroxy-benzoate (54 g) and methyl 2-benzyloxy-benzoate (135 g) in dioxane (400 ml) was slowly added under stirring at room temperature to a suspension of sodium hydride 50% (40 g) in dioxane (150 ml). The mixture was kept for 5 hours at 70° C., then cooled and diluted with petroleum ether, and subsequently filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethylacetate. The organic phase was washed with potassium carbonate 5% and water, then evaporated to dryness. After crystallisation from methanol, (2-hydroxy-5-carbomethoxy-benzoyl)--(2-benzyloxy-benzoyl)-methane (74 g; m.p. 95°-97° C.) was obtained, which was then refluxed for 24 hours with formic acid 99% (500 ml). After cooling and dilution with ethanol (500 ml), the precipitate obtained was filtered and washed with ethanol to give 6-carbomethoxy-2'-hydroxy-flavone (31 g; m.p. 290°-291° C.) which was then reacted in dimethylformamide (150 ml) with 1-chloro-2-benzoyloxy-propane (26 g) and potassium carbonate (18 g) at 70° C. for 16 hours. The mixture was cooled, diluted in water (600 ml), filtered, then washed with water to obtain 6-carbomethoxy-2'-(2-benzoyloxy-propoxy)-flavone (45 g), which was hydrolysed with a solution of potassium hydroxide 1% (1. 1,250) in ethanol (95%) at reflux temperature for an hour. After cooling, acidification with acetic acid, concentration to small volume under vacuum and dilution in water, the precipitate obtained was filtered, then washed with water to give, after crystallisation with methylene chloride/ethylacetate, 6-carboxy-2'-(2-hydroxy-propoxy)-flavone (18.5; m.p. 211°-213° C.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[C:8]1([CH2:14][SH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:16][C:17]1[N:25]=[C:24](Cl)[N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[Cl-].[Na+].O>[NH2:16][C:17]1[N:25]=[C:24]([S:15][CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: SCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(SCc2ccccc2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 71.6 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (410 mg, 10 mmol, 60% in mineral oil) were added α-toluenethiol (1.7 ml, 14 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred under heating at 100° C. for 4.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtrated and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (97 mg, yield 73%).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:3]#[CH:4].C[O:18][C:19]([CH3:21])=[CH2:20].CS(O)(=O)=O.CC([O-])=O.[Na+]>CCCCCCC>[CH3:15][C@H:8]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][C@H:2]([CH2:3][CH2:4][CH2:20][C:19]([CH3:21])=[O:18])[CH3:1]
Reactant: C=C(C)OC
Reactant: C#CC(C)(O)CCC=C(C)CCC=C(C)C
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CCCCCCC
Product: CC(=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 25 °C
Yield: 76 %

Procedure:
44.1 g 3,7,11-trimethyl-6,10-dodecadien-1-in-3-ol, 50.5 g isopropenyl methyl ether and 80 mL n-heptane were initially introduced into a 500 ml flask. 29 mg methanesulfonic acid were added, while stirring. The reaction mixture was stirred under reflux for 6 hours. After the end of the reaction, the mixture was cooled to room temperature, neutralized with 2.5 ml methanolic NaOAc solution (10 g/1) and evaporated. The residue was hydrogenated in 2-propanol with 10% Pd/A-charcoal. Phytone was obtained in a yield of 76%.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:14][C:15]([F:21])([F:20])[S:16]([OH:19])(=[O:18])=[O:17].N([O-])=O.[Na+]>O>[F:14][C:15]([F:21])([F:20])[S:16]([O:19][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:18])=[O:17]
Reactant: COc1nc(N)cc2cccnc12
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(OS(=O)(=O)C(F)(F)F)cc2cccnc12
Temperature: 25 °C

Procedure:
To a solution of 6-amino-8-methoxy-1,7-naphthyridine (19 g, 0.108 mol) in a 1:1 mixture of water and trifluoromethane sulfonic acid (380 ml) is carefully added a solution of sodium nitrite (11.2 g, 0.162 mol) in water (40 ml) at 0° C. After 1 h the cooling bath is removed and the reaction mixture stirred for an other hour at ambient temperature. Then, ethyl acetate (500 ml) is added and the solution is neutralized by adding sodium bicarbonate (4N, 1 l). The water phase is extracted again with ethyl acetate (3×500 ml). The organic solvent is evaporated and the crude product is purified by flash column chromatography on silica gel (20:3 toluene/acetone) affording the title compound. M+308; Melting point 99-101° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:26]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:33])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2cccnc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-4-oxo-1-phenyl-3-{[(pyridine-3-carbonyl)-amino]-methyl}-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate I and nicotinoyl chloride. MS calcd. for C24H19ClN3O4 [(M+H)+] 448.1, obsd. 447.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:23])[C:5]([NH:10][CH2:11][C:12]2[CH:22]=[CH:21][C:15]3[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=3[CH:13]=2)=[CH:6][C:7]=1[O:8][CH3:9].[CH2:24](OC(OCC)OCC)C>C(O)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]2[N:10]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=4[CH:13]=3)[CH:24]=[N:23][C:4]=2[CH:3]=1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: COc1cc2c(cc1Br)ncn2Cc1ccc2nc(SC)sc2c1
Yield: 40 %

Procedure:
To a stirred mixture of 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (120 mg, 0.3 mmol) from Step 2 of this Example and triethylorthoformate (20 mL) was added formic acid (1 mL). The mixture was heated under reflux for 2 h, then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% EtOAc to afford 6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (50 mg, 40%) as an oil. 1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1H), 7.78-7.91 (m, 2H), 7.46 (s, 1H), 7.25 (m, 1H), 6.69 (s, 1H), 5.42 (s, 2H), 3.81 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 420 and 422 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:35])[C:26]([NH:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)=[N:27][C:28]([Cl:29])=[C:23]3[C@H:22]([CH2:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])(C)(C)C.Cl.O1CCOCC1>CO>[ClH:29].[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:35])[C:26]([NH:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)=[N:27][C:28]([Cl:29])=[C:23]3[C@H:22]([CH2:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:21]2)=[O:19])=[CH:14][CH:15]=1)(=[NH:7])[NH2:9]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2C[C@@H](CCCc3ccccc3)c3c(Cl)nc(NC4CCC4)c(=O)n32)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N=C(N)c1ccc(CNC(=O)[C@@H]2C[C@@H](CCCc3ccccc3)c3c(Cl)nc(NC4CCC4)c(=O)n32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution the compound (54 mg, 0.085 mmol) obtained from Step G was added HCl in dioxane (4.0 M, 0.38 mL, 1.5 mmol) and 2 drops of methanol. The mixture was stirred at rt overnight. Solvent was removed to give a white solid as product in quantitative yield. 1HNMR (300 MHz, CDOD3) δ 9.35 (s, 2H), 9.07 (s, 2H), 7.80 (d, 2H, J=8.5 Hz), 7.47 (d, 2H, J=6.6 Hz), 7.30–7.16 (m, 5H), 4.96 (t, 1H, J=7.3 Hz), 4.42–4.23 (m, 3H), 3.24 (m, 1H), 2.60 (m, 2H), 2.2–1.6 (m, 12H). MS m/e 533.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19]OC(C)(C)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]=[CH2:19])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(C)(C)C
Reactant: O=CCCCc1ccc(-c2ccc(Br)cc2)nc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=CCCCc1ccc(-c2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 6.64 g of methyltriphenylphosphonium bromide in 80 ml of t-butyl methyl ether in a sulphonation flask fitted with a mechanical stirrer is treated while gassing with argon at -10° C. within 3 minutes with 2.12 g of solid potassium t-butylate. The mixture is stirred at room temperature for a further 1 hour, then treated at 0° C. within 5 minutes with a solution of 3.61 g of 4-[2-(p-bromophenyl)- -5-pyridyl]butyraldehyde in 20 ml of t-butyl methyl ether and stirred at room temperature for a further 15 hours. The reaction mixture is subsequently partitioned three times in diethyl ether/water. The organic extracts are washed twice with water, dried over magnesium sulphate, filtered and evaporated. The residue is taken up in ethyl acetate and then the mixture is diluted with petroleum ether and filtered. Evaporation of the filtrate and purification of the residue by chromatography on silica gel gives 2-(p-bromophenyl)-5-(4-pentenyl)pyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[S:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]=1[C:24]#[N:25])([O-])=O.[Sn](Cl)[Cl:27]>C(O)C.Cl>[ClH:27].[F:11][C:10]([F:13])([F:12])[C:8]1[CH:7]=[CH:6][C:5]2[NH:14][C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:24]([NH2:25])=[N:1][C:4]=2[CH:9]=1
Reactant: N#Cc1c(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])sc2ccccc12
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: NC1=Nc2cc(C(F)(F)F)ccc2Nc2sc3ccccc3c21
Yield: 97.5 %

Procedure:
Combine 2-(2-nitro-4-trifluoromethyl-phenylamino)-benzo[b]thiophene-3-carbonitrile (5.14 g, 14.1 mmol) and tin(II) chloride (8.05 g, 42.4 mmol) in absolute ethanol and 5N HCl (60 mL each) and reflux the suspension for 1.5 hours. Cool the reaction to ambient temperature. Collect the reaction solid by suction filtration, wash it with cold ethanol, and dry it at 40° C. under reduced pressure to give the title compound (5.083 g). Isolate a second crop of material from the initial filtrate and dry at 40° C. under reduced pressure to give the title compound (0.482 g). Total solid: 5.20 g (94.6%). Mass spectrum (APCI+, m/e): 334 (M+1-HCl); NMR (1H, 300 MHz, DMSO-d6), δ (ppm): 11.71 (s, 1H), 10.32 (s, 1H), 9.32-9.10 (m, 2H), 7.94-7.85 (m, 1H), 7.74-7.65 (m, 1H), 7.60-7.51 (m, 1H), 7.49-7.40 (m, 1H), 7.39-7.27 (m, 2H), 7.23-7.14 (m, 1H).
Reaction SMILES: CN(CCN(C)C)C.C([Li])(CC)C.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]1[N:25]([CH3:28])[CH2:26][CH2:27][C:18]21[CH3:29].[CH:30]([N:33]([C:37](=[O:43])[C:38](OCC)=[O:39])[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31]>CCOCC>[CH:34]([N:33]([CH:30]([CH3:32])[CH3:31])[C:37](=[O:43])[C:38](=[O:39])[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]1[N:25]([CH3:28])[CH2:26][CH2:27][C:18]21[CH3:29])([CH3:36])[CH3:35]
Reactant: CN1CCC2(C)c3cc(Br)ccc3N(C)C12
Reactant: CCOC(=O)C(=O)N(C(C)C)C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)N(C(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C)C(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of TMEDA (2.85 ml) in anhydrous ether (5.0 ml) was added at -78° C. under N2 atmosphere, sec-butyllithium (14.5 ml). The resulting solution was subsequently treated with a solution of 5-bromo-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (3.80 g) in anhydrous ether (10 ml). The mixture was held at this temperature for 3 hours and then added to a solution of diisopropylamino-oxo-acetic acid, ethyl ester (7.5 g) in anhydrous ether (15 ml). After stirring at -78° C. for 4 hours, the reaction mixture was quenched with 50 ml of aqueous NH4Cl solution. The organic and aqueous phases were separated and the organic phase washed successively with saturated aqueous NaHCO3 and brine. The organic phase was dried (Na2SO4), filtered and concentrated to an oil which was purified by HPLC (silica gel, 10% MeOH in ethyl acetate as eluent). 2.8 g of 1,2,3,3a,8,8a-Hexahydro-α-oxo- 1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, diisopropyl amide was obtained as a foam. Trituration with hexane and drying under reduced pressure yielded an analytically pure sample.
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.[CH3:23][C:24](C)([CH3:28])[CH2:25]CN.C1COCC1>C(Cl)Cl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:24]([CH3:28])([CH3:25])[CH3:23])=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Reactant: CC(C)(C)CCN
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(COC(=O)NCCC(C)(C)C)ccc1OC(C)=O
Reaction time: 2 h

Procedure:
This compound was prepared from VII (288.5 mg, 0.845 mmol), 3,3-dimethylbutylamine (85.5 mg, 114 μL, 0.845 mmol) and anhydrous THF (4.2 mL) as described for 13. The reaction was complete within 2 hours. The reaction solution was diluted with CH2Cl2 and extracted with in 1N HCl and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The crude material was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (7:3, v/v) to render 95.8 mg (35%) of 16 as an oil; 1HNMR (CDCl3) δ 6.99 (d, 3J=7.95 Hz, 1H), 6.95 (s, 1H), 6.92 (d, 3J=7.95 Hz, 1H), 5.04 (s, 2H), 4.60 (bs, 1H), 3.82 (s, 3H), 3.21-3.17 (m, 2H), 2.29 (s, 3H), 1.42-1.38 (m, 2H) and 0.91-0.90 (m, 9H). Exact mass (ESI) calculated for C17H26NO5 [M+H]=324.1805. found 324.1814.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[C:5]#[N:6].O.[NH2:19][NH2:20].O>O1CCOCC1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:7]1[C:4]([C:5]#[N:6])=[CH:3][C:2]([NH:19][NH2:20])=[N:9][CH:8]=1
Reactant: NN
Reactant: N#Cc1cc(Cl)ncc1-c1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(NN)ncc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 116.4 %

Procedure:
A solution of 2-chloro-5-(2,4-dichloro-phenyl)-isonicotinonitrile (453 mg, 1.6 mmol) and hydrazine monohydrate (7.76 mL, 160 mmol) in dioxane (9 mL) was heated at 90° C. and stirred for 14 h. The reaction mixture was cooled to RT, poured into water (50 mL) and extracted with AcOEt (3×25 mL). The combined organic fractions were dried over Na2SO4, filtered, and evaporated to provide the crude title compound (520 mg, quant.) as a yellow solid, which was used without further purification. MS: 279 [M+1]+; HPLC: AtRet=1.44.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([O:16]CC)=[O:15])[N:10]([CH3:19])[N:9]=[CH:8]2.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])[N:10]([CH3:19])[N:9]=[CH:8]2
Reactant: CCOC(=O)c1cc2c(cnn2C)cc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cc3F)c(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of ethyl 5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole-6-carboxylate (1.19 g, 3.5 mmol) in THF/H2O (15 mL/5 mL) is added LiOH (0.2 g, 8.3 mmol). After the reaction is stirred at RT for 2 hours, the solvents are removed. The residue is acidified with 2N HCl to pH 5, and extracted with EtOAc (50 mL). The organic phase is washed with saturated aqueous sodium chloride, dried and concentrated to give the product (1.1 g, 100% yield). MS (m/z): 332.0 (M+H).