Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25](O)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][CH:29]1[CH:34]([CH3:35])[CH2:33][CH2:32][CH:31]([NH2:36])[CH2:30]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:28][CH:29]1[CH:34]([CH3:35])[CH2:33][CH2:32][CH:31]([NH:36][C:25](=[O:26])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:30]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CC1CCC(N)CC1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC1CCC(NC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)CC1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.7 %

Procedure:
N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine (0.3 g) and 3,4-dimethylcyclohexylamine (0.1 g) were dissolved in dry methylene chloride (30 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.2 g) was added to the solution, followed by stirring at room temperature for 12 hours. According to a conventional post-treatment, N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine 3,4-dimethylcyclohexylamide (I) (0.32 g) was obtained. The above compound (I) (0.3 g) was allowed to react with 4N-hydrogen chloride/dioxane solution to obtain 4-benzyloxy-L-phenylalanine 3,4-dimethylcyclohexylamide hydrochloride (II) (0.26 g). The above compound (II) (0.26 g) and 4-(t-butyloxycarbonyl)aminomethylbenzoic acid (0.16 g) were dissolved in dry methylene chloride (20 ml)-pyridine solution, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g) was added to the solution. The reaction was carried out at room temperature for 12 hours. After a conventional post-treatment, N-[4-(t-butyloxycarbonyl)aminomethylbenzoyl]-4-benzyloxy-L-phenylalanine 3,4-dimethylcyclohexylamide (III) (0.23 g) was obtained. The above compound (III) was allowed to react with 4N-hydrogen chloride/dioxane solution to (2 ml) obtain N-(4-aminomethylbenzoyl)-4-benzyloxy-L-phenylalanine 3,4-dimethylcyclohexylamide hydrochloride (0.18 g).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21](Cl)([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:22]>O1CCCC1>[C:21]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:22]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)Nc1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N(c1ccccc1[N+](=O)[O-])C(C)C
Temperature: 0 °C

Procedure:
To a stirred ice-cooled solution of 2-isopropylamino-nitrobenzene (19.5 g, 0.1 mole) and triethylamine (15 ml 0.11 mole) in tetrahydrofurane (THF, 200 ml) was dropwise added ethoxalyl chloride. The ice bath was removed and the mixture was heated to reflux for 3 hours. The precipitated triethylammonium chloride was filtered off and the filtrate was evaporated in vacuo to give the title compound as an oil.
Reaction SMILES: F[B-](F)(F)F.ClC1C(C)=CC=C[N+]=1CC.O[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C(N(CC)CC)C>C(#N)C>[CH2:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:32])[O:33][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(O)CCCCCCCCCCCCCCO
Agent: CC[n+]1cccc(C)c1Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCCCCCCCCCCCCCO1
Yield: 78 %

Procedure:
To a refluxing solution of 486 mg (2.0 mmol) of 2-chloro-1-ethyl-3-methylpyridinium tetrafluoroborate in 50 ml of acetonitrile, there was added a solution of 129 mg (0.5 mmol) of 15-hydroxypentadecanoic acid and 404 mg (4.0 mmol) of triethylamine in 40 ml of acetonitrile over a period of 8 hours at a continuous and uniform rate, and the reaction mixture was refluxed for an additional 30 minutes after the addition was completed. After evaporation of the solvent, the residue was separated chromatographically on a silica gel column. 1,15-pentadecanolide was obtained in 78% yield.
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:27])([CH3:26])[C@@H:10]([NH:12][CH2:13][CH2:14][C:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:19])[CH2:16][CH:17]=[CH2:18])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:16]([C:15]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:19][C:36](=[O:38])[N:12]([C@H:10]([C:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])([CH3:26])[CH3:27])[CH3:11])[CH2:13][CH2:14]1)[CH:17]=[CH2:18]
Reactant: C=CCC(O)(CCN[C@@H](C)C(C)(C)O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(c2ccccc2)CCN([C@@H](C)C(C)(C)O[Si](C)(C)C(C)(C)C)C(=O)O1
Yield: 52.1 %

Procedure:
To a solution of 1-((S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-ylamino)-3-phenylhex-5-en-3-ol (550 mg, 1.41 mmol) and Et3N (1.4 g, 14.1 mmol) in CH2Cl2 (5 mL) was added triphosgene (138 mg, 0.46 mmol) at 0° C. The formed mixture was heated to reflux overnight. The mixture was washed with water. The organic phase was separated and concentrated to give the crude product which was purified by TLC to afford 6-allyl-3-((2S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-yl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 17%). 1H NMR (CDCl3): 0.00 (s, 6H), 0.73 (s, 9H), 1.08 (s, 3H), 1.12 (d, 3H), 1.21 (s, 3H), 2.83 (q, 1H), 4.08 (brs, 1H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[C:9]2[C@H:16]([CH3:17])[CH2:15][CH2:14][C:10]=2[N:11]=[CH:12][N:13]=1.B1([C:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=2)OC(C)(C)C(C)(C)O1.O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C@H:16]1[C:9]2[C:8]([C:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCc2ncnc(C3=CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 110 °C
Yield: 67 %

Procedure:
A solution of Na2CO3 (0.36 mL, 2M) was added to a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (101 mg, 0.60 mmol), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid, pinacol ester (204 mg, 0.66 mmol) in 1,4-dioxane (1.8 mL). The mixture was sparged with N2 for 2 minutes. The catalyst Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) was added in one portion. The mixture was heated at 110° C. under N2 for 8 hours. Water (20 mL) was added to the mixture and extracted with DCM (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (first with 0-50% EtOAc/hexane, then with 0-4% MeOH/DCM gradient elution) to give (R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate as an oil (127 mg, 67%). 1H NMR (CDCl3, 500 MHz) δ 8.91 (s, 1H), 6.31 (s, 1H), 3.64-3.55 (m, 1H), 3.10-3.03 (m, 2H), 2.98-2.90 (m, 2H), 2.83-2.78 (m, 1H), 2.42-2.34 (m, 2H), 1.77-1.69 (m, 2H). 1.49 (s, 9H), 1.19 (d, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[C:14]([CH3:26])=[N:13]1.[F-].[Cs+]>COCCOC.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][N:12]1[CH:16]=[C:15]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=2)[C:14]([CH3:26])=[N:13]1
Reactant: Cc1nn(C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1nc(Br)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COc1nc(-c2cn(C)nc2C)ccc1N
Temperature: 150 °C
Yield: 74.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.085 g, 0.074 mmol) was added to a solution of 6-bromo-2-methoxypyridin-3-amine (0.15 g, 0.739 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.180 g, 0.813 mmol) and cesium fluoride (0.337 g, 2.216 mmol) in DME/MeOH 2/1 (4.6 mL). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes. The reaction was concentrated in vacuo. The residue was purified via Biotage silica gel column chromatography eluting with DCM/EtOH (99/1 to 90/10, 12 g column) and then eluted through an SCX-2 column to afford the title product as a yellow solid (120 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:12]([CH3:14])[CH3:13])[N:5]=[C:6]([O:10][CH3:11])[CH:7]([CH3:9])[N:8]=1.C([Li])CCC.IC[C@@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24]>O1CCCC1>[CH:12]([C@@H:4]1[C:3]([O:2][CH3:1])=[N:8][C@@H:7]([CH2:9][C@@H:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH3:24])[C:6]([O:10][CH3:11])=[N:5]1)([CH3:14])[CH3:13]
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1C
Reactant: CC[C@@H](CI)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@@H](C[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC)c1ccccc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine (4.25 g, 23.1 mmol) in tetrahydrofuran (30 ml) was cooled to −78° C., then n-butyllithium (1.6 M in hexane, 15.1 ml, 24.2 mmol) was added and the mixture was stirred for 1 hour. A solution of ((R)-1-iodomethyl-propyl)-benzene (6.30 g, 24.2 mmol) in tetrahydrofuran (30 ml) was added dropwise over 30 min and the mixture was stirred overnight while being allowed to warm slowly from −70° C. to room temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the mixture was extracted with ether. The organic layer was separated, washed with saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc) to yield a light yellow oil (4.69 g, 64%); MS (ISP): 317.0 ([M+H]+).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([NH:29][C:30](=[O:32])[CH3:31])=[CH:27][CH:26]=1>>[C:30]([NH:29][C:28]1[CH:33]=[CH:34][C:25]([NH:24][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:2])=[CH:26][CH:27]=1)(=[O:32])[CH3:31]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CC(=O)Nc1ccc(N)cc1
Product: CC(=O)Nc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 16.9 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4′-aminoacetanilide (51.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-acetamidophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (11.9 mg).
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[CH2:16][CH2:15]2)[N:11]=[CH:10][N:9]=1)(C)(C)C.[CH:23]1(C(Cl)=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(CC)CC.Cl>C(Cl)Cl>[CH2:20]([N:17]1[CH2:16][CH2:15][N:14]([C:12]2[N:11]=[CH:10][N:9]=[C:8]([NH:7][C:6]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:13]=2)[CH2:19][CH2:18]1)[CH3:21]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCN1CCN(c2cc(NC(=O)OC(C)(C)C)ncn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(c2cc(NC(=O)C3CCCC3)ncn2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.9 %

Procedure:
A mixture of 1.6 g (7.75 mmol) 6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-ylamine (intermediate 4), 2.03 g (9.3 mmol) di-tert-butyl dicarbonate and 1.17 g (11.6 mmol) NEt3 in 30 mL DCM was stirred at 50° C. in a sealed tube for 16 h. After evaporation of all volatiles the residue was purified with flash column chromatography on silica. The combined product fractions were evaporated to dryness to yield [6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-carbamic acid tert-butyl ester. MS(m/e): 308.4 (MH+). A mixture of 31 mg (0.1 mmol) [6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-carbamic acid tert-butyl ester, 20 mg (0.15 mmol) cyclopentanecarbonyl chloride and 30 mg (0.3 mmol) NEt3 in 2 mL DCM was shaken at room temperature for 6 h. Subsequently, 3 mL HCl (4N) was added, the mixture was shaken at 50° C. for 4 h and all volatiles removed under reduced pressure. The residue was taken up in methanol/NEt3 and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 20 mg (66%) of the title compound as white solid. MS (m/e): 344.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=1[O:40][CH3:41].CN(C)CCN(C)C.C([Li])CCC.[Br:55]N1C(=O)CCC1=O>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:41][O:40][C:25]1[C:26]([O:36][CH2:37][O:38][CH3:39])=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:30][CH2:31][O:32][CH3:33])[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:4]1[C:5]([O:15][CH2:16][O:17][CH3:18])=[C:6]([O:13][CH3:14])[C:7]([Br:55])=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(Br)c(OC)c2OCOC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
998 Milligrams of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)benzene] was dissolved in a mixed solvent of 30 ml of tetrahydrofuran with 3 ml of hexamethylphosphoric triamide, to this solution was added 1.03 ml of N,N,N',N'-tetramethylethylenediamine, was cooled to -78° C. on a dry ice-acetone mixture bath. 4.56 Milliliters of n-butyllithium (1.6 M, n-hexane solution) was added dropwise to the reaction mixture and stirred for 30 minutes. Next, 15 ml of tetrahydrofuran solution containing 1.22 g of N-bromosuccinimide was added dropwise and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure, and the residue obtained was extracted twice with 50 ml of diethyl ether, and the diethyl ether layer was washed twice with 50 ml of water, and washed twice with 50 ml of a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. The diethyl ether solution was concentrated under reduced pressure, the residue obtained was purified by means of a preparative thin layer chromatography (thickness: 2 mm, adsorbent: Merck 5717 silica gel, developing solvent: 40% ethyl acetate-n-hexane). There were obtained 155 mg of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy- 3,6-bis(methoxymethoxy)-4-bromophenyl]pentane, as well as 22 mg of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)-5-bromobenzene].
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[F:19]C1C=CC([N+]([O-])=O)=CC=1.FC1C=CC(CO)=CC=1>>[F:19][C:18]1[CH:17]=[CH:16][C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: OCc1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1
Yield: 86 %

Procedure:
The title compound is prepared in analogy to 1-(3-fluorobenzyloxy)-4-nitro-benzene, starting from 4-fluoro nitrobenzene and 4-fluoro benzyl alcohol. Yield: 86% of a slightly yellow solid. Mp.=124-126°.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]=O>C([O-])(O)=O.[Na+]>[CH2:1]([N:8]([CH3:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CC(C)(C)OC(=O)NCCNCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(CCNC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a mixture of tert-butyl 2-(benzylamino)ethylcarbamate (2.8 g, 11.2 mmol) and 37% aqueous CH2O (1.0 mL, 11.2 mmol) in 1,2-dicholoroethane (35 mL) at RT was added NaHB(AcO)3 (3.7 g, 11.2 mmol). The mixture was stirred (RT, 16 h), diluted with saturated aqueous NaHCO3 (400 ml) and extracted with EA (3×300 ml). The organic layer was dried over MgSO4 and concentrated under reduced pressure to afford tert-butyl 2-(benzyl(methyl)amino)ethylcarbamate (1.38 g, 46.8%). 1HNMR (CDCl3): δ7.25 (m, 5H, CH), 3.5 (s, 2H, CH2), 3.3 (m, 2H, CH2), 2.48 (m, 2H, CH2), 2.2 (s, 3H, CH3), 1.4 (s, 9H, CH3).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(Br)c1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
500 mg of 3-bromo-2-chlorobenzoic acid are placed in 12.5 ml of tetrahydrofuran in a round-bottomed flask. The reaction mixture is cooled to 0° C. with an ice bath and then 228 mg of N,O-dimethylhydroxylamine hydrochloride, 814 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.21 ml of pyridine are added thereto. The reaction mixture is subsequently stirred at ambient temperature for 16 h and the solvent is evaporated under reduced pressure. The residue is taken up between water and dichloromethane. The separated organic phase is subsequently washed once with a saturated ammonium chloride solution and once with a saturated sodium hydrogencarbonate solution, then dried over magnesium sulphate and concentrated under reduced pressure. 500 mg of compound are obtained.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:27]1[N:32]=[C:31]([NH:33][C:34]([C:36]2([C:39]3[CH:49]=[CH:48][C:42]4[O:43][C:44]([F:47])([F:46])[O:45][C:41]=4[CH:40]=3)[CH2:38][CH2:37]2)=[O:35])[CH:30]=[CH:29][C:28]=1[CH3:50]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:47][C:44]1([F:46])[O:43][C:42]2[CH:48]=[CH:49][C:39]([C:36]3([C:34]([NH:33][C:31]4[CH:30]=[CH:29][C:28]([CH3:50])=[C:27]([C:12]5[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:1])([F:25])[F:24])=[CH:10][CH:11]=5)[N:32]=4)=[O:35])[CH2:38][CH2:37]3)=[CH:40][C:41]=2[O:45]1
Reactant: CC1(C)OB(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)OC1(C)C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 120 °C
Yield: 74.9 %

Procedure:
To a mixture of 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (110 mg, 0.30 mmol) and N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) in DME (2 mL) and 2 M Na2CO3 (0.2 mL) was added Pd(PPh3)4 (12 mg, 0.010 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (10-20% ethyl acetate-hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-5-methylpyridin-2-yl)cyclo-propanecarboxamide (86 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.3 Hz, 2H), 7.65 (s, 1H), 7.54-7.48 (m, 1H), 7.45 (d, J=8.6 Hz, 2H), 7.13 (td, J=10.0, 1.7 Hz, 2H), 6.99 (d, J=8.2 Hz, 1H), 2.21 (s, 3H), 1.68 (q, J=3.6 Hz, 2H), 1.09 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 575.3.
Reaction SMILES: CO.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([C:24]([NH:26][CH3:27])=[O:25])=[CH:14][C:13]2=[O:28])[CH2:6][CH2:5]1.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH:39]=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([C:15]([C:24]([NH:26][CH3:27])=[O:25])=[CH:14][C:13](=[O:28])[N:12]2[CH2:11][CH2:10][N:7]2[CH2:8][CH2:9][CH:4]([NH:3][CH2:39][C:30]3[CH:31]=[CH:32][C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:29]=3)[CH2:5][CH2:6]2)=[CH:17][CH:18]=1
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N)CC2)c2cc(OC)ccc12
Reactant: O=Cc1ccc2ccccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc4ccccc4c3)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 119.6 %

Procedure:
To 4 mL of a methanol solution containing 0.14 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide, 55 mg of 2-naphthoaldehyde and 40 μL of acetic acid were added, and stirred at room temperature for 80 min. To the reaction mixture, 52 mg of sodium cyanoborohydride was added, and stirred at the same temperature for 75 min. After the solvent was removed under reduced pressure, chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=30:1], to give 0.21 g of 7-methoxy-N-methyl-1-(2-(4-((naphthalen-2-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide as a yellow foam.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:4]=1.[CH3:15][C@@H:16]1[CH2:21][NH:20][CH2:19][C@H:18]([CH3:22])[NH:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][C@H:16]1[NH:17][C@@H:18]([CH3:22])[CH2:19][N:20]([CH2:2][C:3]2[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:4]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)n1ccc(CBr)n1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccn(C(=O)OC(C)(C)C)n2)C[C@H](C)N1
Yield: 99.6 %

Procedure:
D6 (1.67 g, 6.41 mmol), (2R,6S)-2,6-dimethylpiperazine (0.73 g, 6.41 mmol) and potassium carbonate (1.95 g, 14.1 mmol) in DMF (20 ml) were heated at 50° C. for 2 h. The mixture was concentrated and the residue partitioned between DCM and water (50 ml each). The aqueous layer was re-extracted with DCM (50 ml) and the combined organics washed with brine (100 ml), dried (Na2SO4) and concentrated to yield the title compound as an orange oil (1.88 g). δH (CDCl3) 1.25 (6H, d), 1.15 (1H, br s), 1.64-1.71 (11H, m), 2.77 (2H, m), 2.93 (2H, m), 3.59 (2H, s), 6.40 (1H, d), 8.00 (1H, d). MS (ES): MH+ 295