Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[Cu][C:31]#[N:32]>CN(C)C=O>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:31]#[N:32])[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: N#C[Cu]
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C#N)cnc43)cc2OC)cn1
Temperature: 150 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
To a stirred solution of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (1.00 g, 1.99 mmol) in N,N-dimethylformamide (15 mL) was added copper(I) cyanide (0.53 g, 6.00 mmol). The mixture was heated to 150° C. After 5 h, the mixture was allowed to cool to room temperature and was concentrated. The residue was purified by silica gel chromatography (2% methanol/dichloromethane elute) to give 0.53 g (66%) of 3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile as a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:12])=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:13]([O:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:14]>>[CH2:13]([O:15][C@@H:16]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:11][CH2:10]/[CH:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)\[CH3:12])=[CH:27][CH:28]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:14]
Reactant: C/C(=C\CO)c1ccc(I)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(I)cc2)cc1)OCC
Yield: 80.5 %

Procedure:
The title compound (398 mg, 80%) was prepared as a colourless gum, from (E)-3-(4-iodophenyl)-but-2-en-1-ol (example 107a) (275 mg, 1.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (256 mg, 1.07 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[O:21])[C:16]3([CH2:19][CH2:18][CH2:17]3)[N:15]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=O)=[CH:24][CH:23]=3)[C:14]2=[S:32])=[CH:9][C:8]=1[C:33]([F:36])([F:35])[F:34])#[N:6].[CH3:37][NH2:38]>C1COCC1>[CH3:37][NH:38][C:29](=[O:31])[CH2:28][C:25]1[CH:24]=[CH:23][C:22]([N:15]2[C:14](=[S:32])[N:13]([C:10]3[CH:11]=[CH:12][C:7]([C:5]#[N:6])=[C:8]([C:33]([F:35])([F:36])[F:34])[CH:9]=3)[C:20](=[O:21])[C:16]32[CH2:19][CH2:18][CH2:17]3)=[CH:27][CH:26]=1
Reactant: CN
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CC(=O)O)cc3)C2=S)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CNC(=O)Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Thionyl chloride (0.238 g, 2 mmol) was added dropwise to a mixture of {4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}acetic acid (46c) (0.357 g, 0.777 mmol) in THF (5 ml) cooled to 0° C. The mixture was stirred for 1 hour at room temperature and then methylamine (0.5 ml) was added into the mixture. The mixture was stirred for an additional 2 hours. The medium was filtered and the filtrate was concentrated and chromatographed (dichloromethane:acetone, 80:20) to yield N-methyl-2-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}acetamide (46e) [RD149] (0.348 g, 0.738 mmol, 95%), the structure of which is illustrated in Formula 18, as an off-white powder.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[CH2:7][CH2:6][NH:5][C@@H:4]1[C:8]([OH:10])=[O:9].[CH3:11]O>>[ClH:1].[OH:2][C@H:3]1[CH2:7][CH2:6][NH:5][C@@H:4]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CO
Reactant: O=C(O)[C@H]1NCC[C@@H]1O
Agent: Cl
Product: COC(=O)[C@H]1NCC[C@@H]1O
Reaction time: 8 h
Yield: 94 %

Procedure:
Hydrogen chloride gas was bubbled through a suspension of trans-3-hydroxy-L-proline (1.5 g, 11.4 mmol) in 20 ml of freshly distilled MeOH at 0° C. for 30 min. The resulting clear solution was stirred overnight, then concentrated under reduced pressure to afford the title compound as a white solid (1.96 g). Yield 94%.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.[CH:42]([NH2:45])([CH3:44])[CH3:43]>C(Cl)Cl>[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30](=[O:32])[NH:45][CH:42]([CH3:44])[CH3:43])=[CH:28][N:27]=3)=[O:25])[CH2:22][CH2:23]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:9])[CH3:10]
Reactant: CC(C)N
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Reaction time: 1 h
Yield: 81 %

Procedure:
Triethylamine (1.6 ml) was added to 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid (4 g) in methylene chloride (50 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (1.4 ml) at 0° C.˜5° C., the mixture was stirred at 5 C for 1 hour. With the addition of triethylamine (1.7 ml) and isopropylamine (1.2 ml), the mixture was stirred at 10° C. for 2 hours. The solution was washed with aqueous sodium bicarbonate and water twice. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Isopropanol (40 ml) was added to the concentrated residue, stirred and filtered. The solid was recrystallized with ethyl acetate and ether to give a desired compound of 3.6 g (yield: 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([S:18][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)S[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
In dichloromethane (5 ml) was dissolved (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (143 mg), followed by addition of triethylamine (0.076 ml) and isobutyryl chloride (58.6 mg) under ice-cooling. The mixture was stirred at room temperature for 15 minutes, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane-ethyl acetate=1:2). The desired fraction was concentrated to give (2R,3R)-2-(2,4-difluorophenyl)-3-isobutyrylthio-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 62, 140 mg) as a colorless syrup. This product was treated with 4N hydrochloric acid (in ethyl acetate) to give the hydrochloride, which was then crystallized from ether to give compound 62 hydrochloride (156 mg) as a colorless powder. m.p. 129°-138° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[F:15].Cl>[OH-].[Na+]>[CH2:5]([O:4][C:2](=[O:3])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[F:15])[CH3:6]
Reactant: Nc1ccc(O)cc1F
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Nc1ccc(O)cc1F
Temperature: 80 °C

Procedure:
Ethyl chloroformate (0.37 ml, 3.9 mmol) was added to a stirring solution of 4-amino-3-fluorophenol (0.5 g, 3.9 mmol) in 2 ml of 10% NaOH. The reaction mixture was heated at 80° C. for 30 min. After cooling, the solution was acidified with hydrochloric acid to give the product. 1H NMR (400 MHz, DMSO-d6): 1.20 (3H, t, J=7.0 Hz), 4.06 (2H, q, J=7.0 Hz), 6.53-6.59 (2H, m), 7.16-7.21 (1H, m), 8.79 (1H, s), 9.72 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]([CH2:28][C:29]#[C:30][CH3:31])[C:17](=[O:27])[N:18]3CCC#N)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].O.Cl>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]([CH2:28][C:29]#[C:30][CH3:31])[C:17](=[O:27])[NH:18]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCn1c(=O)n(CCC#N)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC#CCn1c(=O)[nH]c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 117.1 %

Procedure:
4-[7-(2-Butynyl)-9-(2-cyano-ethyl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazine-1-carboxylic acid t-butyl ester (1.22 g) was dissolved in ethanol (20 mL). Sodium hydride (60%, in oil) (344 mg) was then added slowly to this solution. After stirring the reaction solution at room temperature for 72 hours, water (50 mL) and 1 N hydrochloric acid (10 mL) were added to the reaction solution, and this was extracted using ethyl acetate. The obtained organic layer was washed with water and saturated brine. The obtained organic layer was then dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.25 g).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].Cl.[NH2:8][C:9]1[C:10]([CH3:15])=[CH:11][CH:12]=[CH:13][CH:14]=1>O1CCCC1>[Cl:6][C:1](=[O:5])[C:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:3]
Reactant: Cc1ccccc1N
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)C(=O)Cl

Procedure:
Oxalyl chloride (5.8 g, 46 mmol) in tetrahydrofuran (2 mL) was heated to reflux and o-toluidine hydrochloride was added portionwise over ten minutes. After addition, the reaction mixture was refluxed for four hours and concentrated in vacuo to yield 1-Chloro-2-[(2-methylphenyl)amino]ethandione. This intermediate was dissolved in chloroform (4 mL) and aluminum chloride (2.6 g) was added portionwise. The reaction mixture was heated at reflux overnight, and chromatographed through Merck silica gel (100 g) using (9:1:0.1) toluene:acetone:acetic acid solvent system. The appropriate fractions were combined and concentrated to yield the title compound (90 mg, 5.6%).
Reaction SMILES: [CH2:1]([C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[CH2:5]1)[CH:2]=[CH2:3].CN(C)C=[O:20]>O.C(OCC)(=O)C.[Pd](Cl)Cl>[O:20]=[C:2]([CH3:3])[CH2:1][C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[CH2:5]1
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1CC(C)=O
Reaction time: 3.5 h

Procedure:
A mixture of methyl 2-[(4R)-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (100 mg), palladium chloride (16 mg) and cuprous chloride (44 mg) in a mixture of dimethylformamide (1 ml) and water (0.12 ml) was stirred under an oxygen atmosphere for 3.5 hours. The reaction mixture was diluted with ethyl acetate (20 ml), and filtered. The filtrate was washed with water and brine. The combined aqueous layer was extracted with ethyl acetate (10 ml×2) and the extract was washed with brine. The organic layers were combined, and dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed on silica gel (1 g) eluting with methylene chloride and acetone (100:2-100:5) to give methyl 2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (89 mg as an oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[C:25][C:26]([O:28]CC)=O.[Cl-].[Al+3].[Cl-].[Cl-].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:10])[C:26](=[O:28])[CH:25]=1
Reactant: CCOC(=O)C#Cc1ccccc1C
Reactant: CCC(=Nc1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(=O)c(C)c(-c2ccccc2)n1-c1ccccc1
Temperature: 60 °C
Yield: 3.7 %

Procedure:
To 300 ml of toluene were added 7.5 g (0.036 mole) of N-phenyl-1-phenylpropaneimine, 5.8 g (0.031 mole) of ethyl 2-methylphenylpropiolate and 6.0 g (0.045 mole) of aluminum chloride. The reaction mixture was stirred with heating at 60° C. for 3 days in a nitrogen atmosphere. After cooling, the reaction mixture was poured into 500 ml of 2N sulfuric acid, followed by extraction with chloroform. After washing the organic layer with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate). The resultant crystals were washed with a 2:1 mixed solvent of acetone and hexane to obtain 0.4 g of 6-(2-methyl-phenyl)-3-methyl-1,2-diphenyl-4(1H)-pyridinone having a melting point of 188°-191° C.
Reaction SMILES: C(O[CH:4]([O:8][CH2:9][CH3:10])OCC)C.[CH2:11]([C:14]#[N:15])[C:12]#[N:13]>C(OC(=O)C)(=O)C>[CH3:10][CH2:9][O:8][CH:4]=[C:11]([C:14]#[N:15])[C:12]#[N:13]
Reactant: CCOC(OCC)OCC
Reactant: N#CCC#N
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)C#N
Reaction time: 2.5 h
Yield: 98.5 %

Procedure:
A two-liter, four necked flask is charged with 1332 g (9 moles) of orthoformic acid triethyl ester, 198 g (3 moles) of malonic acid dinitrile and 4 g of acetic acid anhydride. With vigorous stirring, the solution is heated to ebullition. At about 110° C. sump temperature, alcohol begins to distil out through the top of the column. During the course of the reaction, approximately 8 g of acetic acid anhydride is fed in continuously, and the heating of the reaction mixture and the reflux flow are so regulated that the temperature at the top of the condenser is between 75° and 79° C. The condensed distillate is collected and consists substantially of ethanol, acetic acid ethyl ester, formic acid ethyl ester and a small amount of orthoformic acid triethyl ester. During the reaction the sump temperature rises slowly to 130 to 140 degrees C. After 2 to 3 hours the reaction has ended. The unreacted orthoformic acid triethyl ester is distilled out through the column and is fed back to the next batch. Then ethoxymethylene malonic acid dinitrile is separated from the remainder through a simple distillation bridge at 0.1 to 0.02 Torr. In this manner, 361 g of ethoxymethylene malonic acid dinitrile is obtained, with a melting point of 64° C. and a purity of better than 99%. This corresponds to a yield of 98.7% with respect to the malonic acid dinitrile charged.
Reaction SMILES: B.C1(C)C=CC=CC=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1)=[O:14]>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([C@H:13]([OH:14])[C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16]2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc(F)cc(Cl)c2)C1
Agent: B
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cc(F)cc(Cl)c2)C1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A mixture of 10 M H3B.S2Me in THF (47.7 mL, 0.477 mol) and 1M R-CBS-oxazaborolidine in toluene (72 mL, 0.072 mol) were dissolved in 100 mL anhydrous THF and cooled to −15° C. (R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylate in 400 mL anhydrous THF was added dropwise to the above solution and stirred at −15° C. for 2 hr. The reaction was quenched with methanol (500 mL). The solvent was removed under reduced pressure and the residue was purified by column chromatography. The product was re-crystallized three times with EtOAc/Hexanes to give (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (55 g, 0.156 mol). 1H NMR (CDCl3, 400 MHz) δ 7.10 (s, 1H), 7.04-6.90 (dd, 2H), 4.46-4.30 (d, 1H), 4.05-2.40 (m, 5H), 1.74 (s, 1H), 1.60 (s, 1H), 1.53-1.31 (m, 1H), 1.30-1.14 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:53][CH2:54][F:55]>O1CCCC1.O>[F:55][CH2:54][CH2:53][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: FCCI
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(OCCF)cc2)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 66.1 %

Procedure:
120 mg (0.19 mmol) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 2.11 ml tetrahydrofurane. 126 mg (0.39 mmol) cesium carbonate and 64 mg (0.37 mmol) 1-iodo-2-fluoroethane were added. The mixture was stirred at room temperature for 70 hours. 64 mg (0.37 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 48 hours. 64 mg (0.37 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 70 hours. 64 mg (0.37 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours. 64 mg (0.37 mmol) 1-iodo-2-fluoroethane, 2 ml tetrahydrofurane and 126 mg (0.39 mmol) cesium carbonate were added and the mixture stirred at room temperature for 24 hours. 64 mg (0.37 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 84 mg (62%) tert-butyl 4-(3-{(3R)-3-[(1-{5-[4-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1ccc(F)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(4-fluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=O.[CH2:20]([NH2:23])[CH2:21][NH2:22]>[Cl-].[Na+].O>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:6]([C:4]2[C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[NH:23][CH2:20][CH2:21][N:22]=2)[CH:7]=1
Reactant: NCCN
Reactant: O=C(c1cnc2ccccc2c1)c1ccccc1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: c1ccc2c(c1)NCCN=C2c1cnc2ccccc2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 13 %

Procedure:
3-(2-Bromobenzoyl)quinoline (10.30 g, 33.0 mmol) was added to 100 mL of ethylene diamine, followed by stirring at 100° C. for 18 hours. Then the resulting reaction solution was cooled to room temperature, and poured into brine, followed by extracting with ethyl acetate. The organic layer was washed with brine twice, followed by drying with magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=9:1) to obtain the target compound (1.19 g, yield: 13%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)(C(F)(F)F)=O>>[CH3:27][C:25]1[CH:24]=[CH:23][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:26]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[CH3:21])=[CH:16][CH:15]=1)=[CH:7]3
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: CN1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)N4CCN(C)CC4)cc3)cc12

Procedure:
8-Methyl-2-(4-(1-(4-methylpiperazin-1-yl)ethyl)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and 1-methylpiperazine (commercially available) following the procedures described for Example 182. 1H NMR (Acetone-d6) TFA Salt: δ 8.84 (s, 1H), 8.80 (s, 1H), 8.41 (d, 1H), 7.52 (s, 1H), 7.42-7.46 (m, 3H), 7.36-7.38 (m, 2H), 3.53 (m, 1H), 3.18 (m, 2H), 3.12 (m, 2H), 2.92 (s, 2H), 2.66 (s, 2H), 2.56 (s, 2H), 2.16 (s, 3H), 1.99 (m, 2H), 1.69 (d, 3H), 1.30 (s, 3H). LRMS [M+H]=440.2
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[C:11]([C:16]4[CH:17]=[C:18]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[N:19]5[C:24]=4[C:23]([NH2:25])=[N:22][CH:21]=[N:20]5)[CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:32][S:33]([N:29]1[CH2:30][CH2:31][CH:26]([C:18]2[N:19]3[C:24]([C:23]([NH2:25])=[N:22][CH:21]=[N:20]3)=[C:16]([C:11]3[CH:12]=[CH:13][C:14]4[C:9]([CH:10]=3)=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]=4)[CH:17]=2)[CH2:27][CH2:28]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(-c5ccccc5)nc4c3)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(c2cc(-c3ccc4cn(-c5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 28.7 %

Procedure:
To a suspension of 5-(2-phenyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.20 mmol) in DMF (1 mL) was added methanesulfonyl chloride (17 μL, 0.22 mmol) and N,N-diisopropylethylamine (68 μL, 0.39 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 28 mg (29%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1 H), 8.10 (d, 2 H), 7.93 (s, 1 H), 7.85 (d, 1 H), 7.69 (s, 1 H), 7.55-7.63 (m, 2 H), 7.41-7.48 (m, 1 H), 7.22 (dd, 1 H), 6.68 (s, 1 H), 3.63-3.73 (m, 2 H), 3.21-3.32 (m, 1 H), 2.86-2.98 (m, 5 H), 2.10-2.21 (m, 2 H), 1.69-1.86 (m, 2 H); ES-MS m/z 488.23 [M+H]+, HPLC RT (min) 2.72.