Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[C:20](Cl)[N:19]=[C:18]([NH2:23])[N:17]=3)=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2].N1C=CC=CC=1>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:23])[N:17]=3)=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc2cc(Oc3cc(Cl)nc(N)n3)ccc12
Agent: [Pd]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1csc2cc(Oc3ccnc(N)n3)ccc12

Procedure:
A solution of 3.70 g (10.6 mMol) 6-(2-amino-6-chloro-pyrimidin-4-yloxy)-benzo[b]thiophene-3-carboxylic acid ethyl ester in 300 ml THF and 8.68 ml (108 mMol) pyridine is hydrogenated in presence of 3.0 g Pd/C (10%; added in 3 portions during 23 h). The mixture is filtered and the solid washed extensively with MeOH. The filter cake still contains product and is therefore stirred in EtOAc and water. The separated EtOAc layer is washed twice with water, added to the filtrate and concentrated. The residue is re-dissolved in 300 ml EtOAc and 50 ml MeOH. Then water is added, the aq. layer separated off and extracted 4× with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated together with 21 g SiO2. The resulting powder is put on top of a SiO2-column and the title compound eluated with EtOAc/hexane 9:1: m.p.: 144-145° C.; TLC(EtOAc/hexane 9:1): Rf=0.27.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=1)=[N+]=[N-].C(N(CC)CC)C.[H][H]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]=1
Reactant: [N-]=[N+]=Nc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
To a stirred solution of 2-Azido-5,6-diphenylpyrazine (45 mg, 0.17 mmol) in 50 mL EtOAc at room temperature was added triethylamine (100 μL) followed by Pearlman's Catalyst (50 mg). The suspension was put through a vacuum/purge cycle three times with hydrogen gas and then held under I atmosphere of hydrogen for 2 hours. The suspension was then filtered through GF/F filter paper with EtOAc and concentrated. The crude product was eluted through a Biotage 12S column with 1/1 EtOAc/hexane to give pure product, as a clear oil (25 mg, 59%)., 1H-NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.42-7.20 (m, 10H), 4.62 (br s, 2H).
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20](=[O:37])[C:19]=1[CH3:38]>O1CCOCC1.[Pd]>[CH3:36][C:26]([S:32]([CH3:35])(=[O:34])=[O:33])([CH2:25][CH2:24][N:21]1[CH:22]=[CH:23][C:18]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:19]([CH3:38])[C:20]1=[O:37])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C(C)(CCn1ccc(I)c(C)c1=O)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(C)(CCn1ccc(-c2ccccc2)c(C)c1=O)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Water (1 mL) was added to a suspension of potassium carbonate (392 mg, 2.84 mg), phenylboronic acid (76.1 mg, 0.624 mmol), and ethyl 4-(4-iodo-3-methyl-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (250 mg, 0.567 mmol) in 1,4-dioxane (5 mL) at ambient temperature. To this mixture was added Pd EnCat™ (154 mg, 0.06 mmol) and the mixture was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, filtered, diluted with ethyl acetate and washed with water. To the organic extract was added silica gel and the mixture was concentrated to dryness. The material was purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford ethyl 2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)butanoate as an oil. 118.3 mg
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:16]=2)[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:10]1[C:32]([O:34]CC)=O)[CH3:2].C(O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][CH2:7][CH2:8][N:9]2[C:17]3[C:12]([C:11]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[C:10]2[C:32]1=[O:34])=[CH:13][C:14]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:15][CH:16]=3)=[O:37])[CH3:2]
Reactant: CCOC(=O)CCCCn1c(C(=O)OCC)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc21
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCn2c(c(-c3ccccc3)c3cc(OCc4ccccc4)ccc32)C1=O

Procedure:
Twenty-three grams (46 m mole) of 5-(2-ethoxycarbonyl-5-benzyloxy-3-phenyl-1H-indole-1-yl)-valeric acid ethylester were dissolved in 150 ml of toluene and added dropwise within four hours to a boiling suspension of 5.2 g (46 m mole) of potassium-tert.-butylate in 150 ml of toluene. Then the ethanol formed was distilled off with toluene. After cooling, ice-cold dilute hydrochloric acid was added and the mixture was extracted with toluene. The toluene extracts were evaporated, and the residue was purified by chromatography on silicagel (solvent: toluene).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[O:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1.C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:15]2[CH:16]=[CH:17][O:13][CH:14]=2)=[CH:6][N:7]=1
Reactant: OB(O)c1ccoc1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: CC(=O)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ccoc2)cnc1N

Procedure:
(Step 8-iv) Methyl 3-amino-6-bromopyrazine-2-carboxylate (700 mg, 3 mmol) was dissolved in dioxane (4 mL) with 3-furan boronic acid (0.36 g, 3.2 mmol), potassium acetate (980 mg 10 mmol) and tetrakispalladium triphenylphosphine (200 mg, 0.17 mmol) in a microwave vessel. Nitrogen was bubbled through for 5 minutes, followed by sealing the vessel and microirradiating the mixture for 20 minutes at 170° C. The reaction mixture was diluted with ethyl acetate/saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to give a solid, which was purified by silica gel column chromatography (0 to 70% EtOAc/hexanes) to give methyl 3-amino-6-(furan-3-yl)pyrazine-2-carboxylate as a solid. This methyl ester was dissolved in THF/MeOH and an aqueous solution of LiOH hydrate (150 mg, 3.6 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature, concentrated to half the volume, and diluted with ethyl acetate/10% aqueous citric acid solution. The organic layer was washed with brine, dried, and concentrated in vacuo to yield 3-amino-6-(furan-3-yl)pyrazine-2-carboxylic acid as a solid (0.46 g, 2.3 mmol, 77% overall yield).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([O-:4])=O.[CH3:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14].[O-]CC.[Na+].OS(O)(=O)=O>C(O)C.O>[O:4]=[C:2]([CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: CCCCC(C)=O
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCC(=O)CC(=O)C(=O)OCC
Temperature: 0 °C
Yield: 80.4 %

Procedure:
A mixture of ethyl oxalate (97.21 g) and hexan-2-one (66.58 g) was added dropwise to a solution of sodium ethoxide (50.1 g) in ethanol (160 ml) at reflux. The resultant mixture was heated at reflux for 2 h. The cooled reaction mixture was poured into a stirring mixture of ice (500 g) and water (100 ml) and the resultant slurry adjusted to pH 1.5(conc.H2SO4). The two layers were separated and the bottom layer extracted with toluene (2×200 ml). The combined organics were washed with brine (200 ml), dried and concentrated in vacuo to give a residue (107 g) which was purified by distillation to afford the title compound as a colourless liquid (67.2 g).
Reaction SMILES: CCOCCO[CH2:7][CH2:8][O:9][C:10]([CH:12]=[CH2:13])=[O:11].[CH3:14][C:15](N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH3:14][CH2:15][CH2:7][CH2:8][O:9][C:10]([CH:12]=[CH2:13])=[O:11]
Reactant: C=CC(=O)OCCOCCOCC
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCCC
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A solution of 39.2 g (0.208 mol) of di(ethylene glycol) ethyl ether acrylate and 916 mg (0.0056 mol) of AIBN in 100 ml of dry toluene is degassed by purging with argon for 3 hours. This solution was added to the above solution [Example 3a] by syringe. The mixture is stirred at 60° C. under argon for 48 hours. The solvent is removed by evaporation under vacuum. (viscous yellow oil; 1H NMR: total conversion ˜100%; GPC: not available due to incomplete solubility in THF).
Reaction SMILES: [Mg].I[CH3:3].II.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:12]>CCOCC>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([C:11]([C:10]2[CH:21]=[CH:22][CH:23]=[C:8]([O:7][CH3:6])[CH:9]=2)([OH:12])[CH3:3])[CH:18]=[CH:17][CH:16]=1
Reactant: CI
Reactant: COc1cccc(C(=O)c2cccc(OC)c2)c1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: COc1cccc(C(C)(O)c2cccc(OC)c2)c1
Temperature: 25 °C

Procedure:
A dry 100 mL three-necked, round-bottomed flask equipped with magnetic stirring, reflux condenser, nitrogen bubbler and thermometer is charged with 0.73 g (30 mgat) of magnesium shavings and ca. 1 mL of dry ether. 4.5 g (30 mmoles) of iodomethane as a solution in ca 5 mL of ether are placed in a pressure equilibrated dropping funnel. The funnel is mounted in the central neck of the flask. A small crystal of iodine is dropped in the flask followed by about 1 mL of the iodomethane solution. When the reaction starts, the rest of the iodomethane is added dropwise, so as to maintain a gentle reflux. When the addition is complete, the solution is refluxed for 15 minutes, then cooled in an ice bath. The dropping funnel is now charged with a solution of 4.85 g (20 mmoles) of 3,3′-dimethoxybenzophenone in 10 mL of ether. The ketone is added to the Grignard reagent solution dropwise or in small portions so that the reaction is not too violent. After addition of the ketone the resulting solution is refluxed briefly (15 minutes), then cooled to room temperature. The reaction is quenched by addition of 15 g of ice. The precipitated magnesium hydroxide is dissolved by addition of 2 g of citric acid. The different layers are separated, the lower aqueous layer is extracted with 5 mL of ether. Both ethereal extracts combined are washed consecutively with water and 10% sodium carbonate, dried over anh. K2CO3 and evaporated to yield 5.28 g (quant. based on benzophenone) of 1,1-bis-(3-methoxyphenyl)ethanol. 1H NMR (CDCl3): 6.7-7.3 (m, ArH, 8H), 3.75 (s, OMe, 6H), ˜2.2 (bs, OH, 1H), 1.9 (s, C—Me, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21]>C1(C)C=CC=CC=1>[Br:21][C:16]1[CH:17]=[CH:18][C:19]([N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:20][CH:15]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1ccccc1Br
Solvent: Cc1ccccc1
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 37.5 %

Procedure:
In a two-neck round bottom flask, diphenylamine (50 g, 0.30 mol), dibromobenzene (104 g, 0.44 mol), BINAP[2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl] (7.4 g, 4% mol), Pd(OAc)2[Palladium(II)acetate] (2.0 g, 3% mol), and NaOtBu[Sodium tert-butoxide] (42.6 g, 0.44 mol) are dissolved in toluene (400 mL), and then are maintained for 24 hours by reflux. On completion of the reaction, the flask having the resultant solution is cooled, and then toluene, a solvent of the reaction, is removed from the resultant solution. After that, the resultant solution having no toluene reacts on methylene-chloride and water, and then methylene-chloride is removed therefrom, and is performed by silica gel column chromatography with a solvent of methylene-chloride and hexane at a ratio of 3 to 1. After that, the solvent is removed from the resultant solution of completing silica gel column chromatography, and is recrystallized and filtered with methylene-chloride and petroleum ether, thereby obtaining a white solid, (4-bromo-phenyl)-diphenyl-amine (36.5 g, 40%).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Br:24])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:9][CH2:8]1)(=O)=O.Cl.[CH3:31][O:32][CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+].C(N(CC)C(C)C)(C)C>C(#N)C>[Br:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:25]([CH:27]1[CH2:28][CH2:29]1)=[O:26])=[C:14]2[NH:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][N:35]2[CH2:36][CH2:37][CH:33]([O:32][CH3:31])[CH2:34]2)[CH2:12][CH2:11]1
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COC1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC1CCN(C[C@H]2CC[C@H](Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Temperature: 80 °C

Procedure:
To a solution of (trans-4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)cyclohexyl)methyl methanesulfonate (362 mg, 0.75 mmol) and 3-methoxypyrrolidine hydrochloride (410 mg, 2.98 mmol) in acetonitrile (15 mL) was added K2CO3 (1.24 g, 9 mmol) and KI (300 mg, 1.81 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.9 mmol) and the reaction mixture was heated at 50° C. for 16 h and 80° C. for 24 h. The solution was cooled to room temperature, diluted with satd. aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purification by column chromatography (silica, 0-20% methanol/dichloromethane) to afford the desired product (155 mg, 42%) as an off-white solid. ESI MS m/z 486 [C25H32BrN3O2+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[CH2:11]([O:13][C:14](=[O:34])[CH:15]=[C:16](C1C=CC(OC)=C2C=1C=CN2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:34])[CH:15]=[C:16]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Reactant: Brc1cccc2cn[nH]c12
Product: CCOC(=O)C=C(c1ccccc1)c1cccc2cn[nH]c12

Procedure:
3-(1H-Indazol-7-yl)-3-phenyl-acrylic acid ethyl ester CCXLVII was prepared from 7-bromo-1H-indazole using the procedure described for preparation of 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([NH:16][C:17]([NH2:19])=[N:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:5][CH:4]=[C:3]([C:20]([NH:22][C@@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:2]=1.[Na+:32].[Na+].[OH2:34]>CCO>[CH:5]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([N:16]=[C:17]([NH2:19])[NH:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:1][CH:2]=[C:3]([C:20]([NH:22][C@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:4]=1.[OH2:34].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[Na+:32].[Na+:32]
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)[O-])C(=O)[O-])cc3)c2c(=O)[nH]1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1

Procedure:
To a suspension of Pemetrexed Disodium Form A in EtOH was added water until a mixture of EtOH containing 25% water (v/v) was obtained. The resulting suspension was stirred at 20° C. to 30° C. until conversion was complete according to PXRD. Pemetrexed Disodium Heptahydrate was isolated by filtration, washed with EtOH and dried in vacuo at 200 mbar at 20° C. to 30° C. until water content of the dried product was 20.1% to 22.1%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl[C:6]1[N:7]=[N+:8]([O-:19])[C:9]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][CH2:16]3)=[CH:12][C:10]=2[N:11]=1>COCCOC>[O-:19][N+:8]1[C:9]2[CH:18]=[C:17]3[C:13](=[CH:12][C:10]=2[N:11]=[C:6]([NH:1][CH2:2][CH2:3][OH:4])[N:7]=1)[CH2:14][CH2:15][CH2:16]3
Reactant: NCCO
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Product: [O-][n+]1nc(NCCO)nc2cc3c(cc21)CCC3
Yield: 99.1 %

Procedure:
2-Aminoethanol (1.80 mL, 30.0 mmol) was added to a stirred solution of chloride 21 (2.21 g, 10.0 mmol) in DME (100 mL) and the solution stirred at reflux temperature for 90 min. The solvent was evaporated and the residue stirred with water (150 mL) at 20° C. for 30 min. The solid was filtered, washed with water several times and dried to give alcohol 24 (2.44 g, 99%) as an orange solid: mp (DME/water) 222-224° C.; 1H NMR [(CD3)2SO] δ 7.92 (s, 1H, H-9), 7.54 (br t, J=6.0 Hz, 1H, NH), 7.36 (s, 1H, H-5), 4.68 (t, J=6.0 Hz, 1H, OH)), 3.56 (q, J=6.0 Hz, 2H, CH2O), 3.40 (q, J=6.0 Hz, 2H, CH2N), 2.89-3.00 (m, 4H, H-6, H-8), 2.00-2.08 (m, 2H, H-7); 13C NMR [(CD3)2SO] δ 158.7, 154.0 148.0, 142.3, 128.8, 120.0, 113.9, 59.3, 43.2, 32.4, 31.6, 25.2. Anal. calcd for C12H14N4O2: C, 58.5; H, 5.7; N, 22.8. Found: C, 58.8; H, 5.9; N, 22.9%.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:26][CH:22]4[CH2:23][NH:24][CH2:25][CH:21]4[CH2:20]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[C:34](#N)C.O.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O>[F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:26][CH:22]4[CH2:23][N:24]([CH3:34])[CH2:25][CH:21]4[CH2:20]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CNCC2C1
Reactant: CC#N
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CN(C)CC2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline (2.1 g, 3.9 mmol, 1.0 eq.) and acetonitrile/water 1:1 (5 ml, 5 ml). The reaction mixture was then cooled to 0° C. and 37% solution of formaldehyde in water was added (0.2 g, 7.8 mmol, 2.0 eq). While keeping the temperature at 0° C. Na(OAc)3BH was added (4.4 g, 20.7 mmol, 3.0 eq). After 1 hour the pH was adjusted to 10 and the aqueous was extracted 2×DCM (100 ml). Removal of the DCM resulted in a white solid. The compound was further purified with a biotage system using an eluent EtOAc and 5% MeOH, affording 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methyl-octahydrocyclopenta-[c]pyrrol-5-ylmethoxy)-quinoline (0.9 g, 50% yield).). 1H NMR (400 MHz, CDCl3): 8.57 (d, 1H), 8.14 (dd, 1H), 8.12 (dd, 1H), 7.41 (s, 2H), 7.34 (t, 1H), 6.54 (d, 1H), 4.19 (d, 2H), 4.01 (s, 3H), 2.61 (m, 4H), 2.43 (m, 1H), 2.33 (s, 3H), 2.11 (m, 4H), 1.32 (m, 2H); MS (EI) for C25H26FN3O5: 468 (M+H+).
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]=[CH:34][N:35]=1)(=[O:3])[CH3:2].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]=[CH:34][N:35]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1nccn1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)SC1CCNC/C1=C\c1nccn1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-1H-imidazol-2-yl]methylidene}-1-(triphenylmethyl)piperidine (0.72 g) in dichloromethane (20 ml) was added trifluoroacetic acid (0.29 ml) under ice-cooling, and the resulting mixture was stirred at the same temperature for 15 minutes. The reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of methanol and dichloromethane (1:20 to 1:10) as the eluent to afford the title compound (0.58 g, yield: quantitative) as a colourless amorphous solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[NH2:17][C:18]1([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25].C(N(CC)CC)C>CN(C=O)C>[N+:13]([C:12]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:2][N:17]([C:18]1([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[C:5]2=[O:7])([O-:15])=[O:14]
Reactant: NC1(CCCCNC(=O)OCc2ccccc2)CCC(=O)NC1=O
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)N1
Reaction time: 18 h
Yield: 59.9 %

Procedure:
To a stirred mixture of 18 (0.25 g, 0.912 mmol) and 4 (0.337 g, 0.912 mmol) in DMF (3.0 mL) was added triethylamine (0.320 mL, 2.28 mmol) and resulting mixture was stirred at 114° C. to 130° C. After 18 h, the mixture was cooled and concentrated. Purification by flash chromatography (95:5 DCM:MeOH) afforded 19 (0.27 g, 60%) as a light brown fluffy solid. 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.45 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.80 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.44-7.19 (m, 5H), 5.17-4.84 (m, 4H), 3.05-2.96 (m, 2H), 2.69-2.52 (m, 3H), 2.20-1.94 (m, 3H), 1.35 (m, 4H). MS (ESI) m/z calcd for C25H27N4O7 [M+H]+ 495.5, found 495.9.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[O:39])=[CH:34][N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[O:39])=[CH:34][N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 75.1 %

Procedure:
69 mg of 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde was weighed into a 20 mL reaction vial fitted with a stir bar and cap. Added 2 mL of CH2Cl2 and 2 mL MeOH and stirred to obtain a clear amber solution. Added 14 mg of sodium borohydride. Stirred at room temperature for 3 hr. Quenched with 5 mL of saturated aqueous NH4Cl. Separated phases and extracted the aqueous phase with 2×2 mL CH2Cl2. Washed the combined organic phases with 5 mL of saturated aqueous NaHCO3. Dried over Na2SO4 and removed the solvent on rotavap. Crystallized the residue from isopropyl acetate to obtain 52 mg of the title compound as a white solid. MS (ESI) 639 (M+H)+.