Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-][N+:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH2:26].[OH-].[Na+]>C(OC(=O)C)(=O)C>[OH:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:6][C:5]3[CH:4]=[CH:3][NH:2][C:11](=[O:26])[C:10]=3[N:9]=2)=[CH:13][CH:14]=1
Reactant: O
Reactant: [O-][n+]1ccc2cc(-c3ccccc3)c(-c3ccc(CO)cc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]ccc2cc(-c3ccccc3)c(-c3ccc(CO)cc3)nc12
Temperature: 130 °C

Procedure:
A suspension of [4-(7-oxido-3-phenyl-1,7-naphthyridin-2-yl)phenyl]methanol (144 mg, 0.44 mmol) in acetic anhydride (2 mL) was heated at 130° C. for two hours and then cooled to ˜100° C. Water was added and the stirred mixture was allowed to cool to room temperature. This solution was extracted with methylene chloride and the organic layer was washed with NaHCO3/Na2CO3 solutions, dried, filtered and the solvent evaporated. This residue was determined to be mainly the acylated product, 4-(7-oxo-3-phenyl-7,8-dihydro-1,7-naphthyridin-2-yl)benzyl acetate, by NMR. This material was dissolved in tetrahydrofuran (5 mL) and 5 N NaOH (0.5 mL, 2.5 mmol) was added. The mixture was heated at 60° C. for two hours. The cooled solution was extracted with methylene chloride. The organic layer was washed with aqueous NaHCO3 and then dried, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel eluting with 0-5% methanol/ethyl acetate (sat'd with ammonia) to give the title compound. 1H-NMR (500 MHz, CDCl3): δ 10.60 (1H, br s), 7.93 (1H, s), 7.44 (2H, d, J=8 Hz), 7.28-7.34 (4H, m), 7.22-7.27 (4H, m), 6.59 (1H, d, J=7 Hz), 4.65 (2H, s). m/e (m+1): 329.2.
Reaction SMILES: [F:1][C:2]1[C:12]2[N:11]3[C:13]([CH3:16])=[N:14][N:15]=[C:10]3[CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:7]2[CH2:8][CH2:9][C:10]3=[N:15][N:14]=[C:13]([CH3:16])[N:11]3[C:12]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]2=3)=[CH:20][CH:19]=1
Reactant: Clc1ccc(I)cc1
Reactant: Cc1nnc2n1-c1c(F)cccc1NCC2
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Product: Cc1nnc2n1-c1c(F)cccc1N(c1ccc(Cl)cc1)CC2
Temperature: 90 °C
Yield: 35.6 %

Procedure:
A disposable tube was charged with 10-fluoro-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (22 mg, 0.101 mmol), 1-chloro-4-iodobenzene (31.3 mg, 0.131 mmol), RuPhos precat. (3.67 mg, 5.04 μmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (2.352 mg, 5.04 μmol), sodium 2-methylpropan-2-olate (19.38 mg, 0.202 mmol), and a stirbar before being evacuated and purged with nitrogen three times. Toluene (1 mL, 0.4 M) was added, and the mixture was stirred at 90° C. 6 h. The mixture was cooled, diluted with ethyl acetate, filtered, and concentrated before being purified by silica gel chromatography (eluting with methylene chloride/methanol/1% ammonium hydroxide) and reverse phase HPLC to yield the title compound as a white amorphous solid (0.012 g, 0.036 mmol, 36%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](Cl)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1.N1C=CC=CC=1.O>C(Cl)Cl>[Cl:1][C:2]1[C:11]([C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(Cl)c1cc2ccccc2nc1Cl
Reactant: COC(=O)c1ccc(N)cn1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2cc3ccccc3nc2Cl)cn1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A solution of 2-chloroquinoline-3-carbonyl chloride (2.72 g, 12.04 mmol) in methylene chloride (37.7 mL) was added dropwise to a mixture of methyl 5-aminopyridine-2-carboxylate (1.83 g, 12.04 mmol), pyridine (2.9 mL, 36.12 mmol) and methylene chloride (25.1 mL) at 0° C. The mixture was stirred and allowed to warm up to room temperature over 1.5 hours. To the reaction slurry, water (30 mL) was added and a precipitate formed. The solid was filtered, washed with water (2×30 mL), hexanes (2×50 mL), and a small amount of dichloromethane. The solid from the filtrate was isolated and washed with water (1×15 mL) and hexanes (1×20 mL). This solid obtained was dried in the vacuum oven to yield methyl 5-(2-chloroquinoline-3-carboxamido)picolinate (3 g, 73%). ESI-MS m/z calc. 341.06, found 342.2 (M+1)+; Retention time: 1.18 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.85 (s, 1H), 8.42 (dd, J=8.6, 2.5 Hz, 1H), 8.21-8.12 (m, 2H), 8.07 (dd, J=8.6, 1.1 Hz, 1H), 8.02-7.89 (m, 1H), 7.82-7.72 (m, 1H), 3.89 (s, 3H) ppm.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[C:20]([NH2:25])(=[NH:24])[CH2:21][CH2:22][CH3:23]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:24][C:20]([CH2:21][CH2:22][CH3:23])=[N:25][C:11]=3[C:10]=2[CH:13]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=CN(C)C)CC(=O)N2
Reactant: CCCC(=N)N
Agent: Cl
Product: CCCc1ncc2c(n1)-c1cc(C)ccc1NC(=O)C2
Yield: 90 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepine-2,5-dione and butyramidine hydrochloride. Yield: 90%.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:21]([NH:23][CH2:24][CH3:25])=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH2:24]([NH:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:28]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[C:7]5[N:8]([CH:12]=[CH:13][CH:14]=5)[C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:31][CH2:30]2)=[C:18]([F:17])[CH:19]=1)[CH3:25]
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(F)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)c(F)c1
Temperature: 95 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (47.50 mg, 0.221 mmol), 3-fluoro-N-ethyl-4-(piperazin-1-yl)benzamide (69.3 mg, 0.276 mmol) and (cyanomethyl)trimethylphosphonium iodide (86 mg, 0.353 mmol) in Propiononitrile (Volume: 1.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.192 mL, 1.104 mmol) at 23° C. The reaction was stirred at 95° C. for 15 hr. The suspension was cooled to 23° C., concentrated via rotary evaporation, re-constituted in ACN (2.0 mL), stirred for 15 min, filtered, rinsed with ACN (3×1 mL) and dried in vacuo. The crude solid was re-suspended in ACN (2.0 mL), heated to reflux, cooled to 23° C., filtered, rinsed with ACN (3×2.0 mL) to provide N-ethyl-3-fluoro-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.069 g, 0.221 mmol, 70.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3 H) 2.54-2.64 (m, 4 H) 3.07-3.17 (m, 4 H) 3.21-3.28 (m, 2 H) 3.63 (s, 2 H) 6.71-6.76 (m, 1 H) 7.01-7.10 (m, 2 H) 7.55-7.64 (m, 3 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.32 (t, J=5.43 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 11.58 (br. s., 1 H). ESI-MS: m/z 449.4 (M+H)+. mp=262.7-267.4° C.
Reaction SMILES: [CH2:1]=[C:2]([C:10]([O:13]S(F)(=O)=O)([F:12])[F:11])[C:3]([C:6]([F:9])([F:8])[F:7])([F:5])[F:4].[F-:18].[K+].[F:20][C:21]([F:29])([F:28])[C:22]([C:24]([F:27])([F:26])[F:25])=O.COCCOCCOC>O>[CH2:1]=[C:2]([C:10]([O:13][C:22]([C:24]([F:27])([F:26])[F:25])([C:21]([F:29])([F:28])[F:20])[F:18])([F:12])[F:11])[C:3]([C:6]([F:9])([F:8])[F:7])([F:5])[F:4]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C=C(C(F)(F)OS(=O)(=O)F)C(F)(F)C(F)(F)F
Reactant: [F-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: C=C(C(F)(F)OC(F)(C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 20 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
CH2═C(CF2CF3)CF2OSO2F (5 g, 17 mmole) is added at 20° C. to (CF3)2CCFOK, prepared at 10° C. from freshly dried KF (3 g, 17.2 mmole), hexafluoroacetone (HFA) (3 g, 18 mmole) and dry diglyme (15 ml). The reaction mixture is agitated for 1 hour at 20° C. and then poured into water, the organic layer separating. The organic layer is washed with aqueous sodium bicarbonate solution, then water, after which it is dried over (MgSO4). Distillation of the reaction mixture gives CH2═C(CF2CF3)CF2OCF(CF3)2 (4 g, 62% yield, b.pt. 118-120° C.). This example demonstrates that the fluorosulfates of the higher homolog of hexafluoroisobutylene react with nucleophiles under the same mild conditions that characterize the reactions of CH2═C(CF3)CF2OSO2F.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:20]=3[N:19]=[CH:18]2)=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.C(N=C=NC(C)C)(C)C.[NH2:48][CH2:49][CH2:50][OH:51].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[OH:51][CH2:50][CH2:49][NH:48][C:26]([C:24]1[CH:23]=[CH:22][C:21]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:16][CH:15]=3)[CH:18]=[N:19][C:20]=2[CH:25]=1)=[O:27]
Reactant: NCCO
Reactant: O=C(O)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCO)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Reaction time: 0.08 h

Procedure:
To a 20 mL Bohdan MiniBlock 12-position glass reaction tube, 1-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxylic acid (100 mg, 0.27 mmol), PS-HOBt (HL; 269 mg, 0.24 mmol), DMAP (18 mg, 0.15 mmol), CH2Cl2 (1 mL), and DMF (0.25 mL) were added. The reaction mixture was shaken for 5 min. 1,3-Diisopropylcarbodiimide (138 mg, 1.09 mmol) was added to the reaction mixture and shaken for 4 h. The solution was filtered and the resin was washed with CH2Cl2 (3×3 mL), DMF (3×3 mL), and THF (3×3 mL). The resin was resuspended in DMF (1 mL) and 2-aminoethanol (15 mg, 0.24 mmol) and DIEA (31 mg, 0.24 mmol) were added. The reaction mixture was allowed to shake overnight. The reaction mixture was then filtered, and washed with CH2Cl2 (3×3 mL), DMF (3×3 mL), and THF (3×3 mL). The filtrate and the washes were combined and concentrated in vacuo. The crude product was purified by using the Waters mass-directed HPLC purification system to yield N-(2-hydroxyethyl)-1-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxamide as a yellowish white powder. 1H NMR (d6-DMSO, 400 MHz): δ 8.57 (s, 1H), 8.49 (t, J=4.4 Hz, 1H), 8.32 (d, J=1.2 Hz, 1H), 8.19 (ddd, J=5.2, 2.0, 0.8 Hz, 1H), 7.85 (dd, J=8.4, 1.6 Hz, 1H), 7.74 (ddd, J=9.2, 7.2, 2.0 Hz, 1H), 7.61 (ddd, J=5.6, 3.6, 3.6 Hz, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.23 (ddd, J=6.0, 3.6, 3.6 Hz, 2H), 7.01 (ddd, J=7.2, 5.2, 0.8 Hz, 1H), 6.88 (ddd, J=8.4, 0.8, 0.8 Hz, 1H), 4.63 (m, 2H), 4.43 (m, 2H), 2.82 (d, J=4.8 Hz, 3H). MS(ES+): m/z 419 (60) [MH+].
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)(O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]=[C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:11]([F:12])([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)nc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
After adding 2.42 g of toluene to 0.81 g (1.82 mmol) of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 0.44 g (3.64 mmol) of thionyl chloride and 0.29 g (3.64 mmol) of pyridine were added at 80° C., and stirred for 3 hours. The reaction solution was cooled to room temperature, and separated by adding 15 ml of ethyl acetate and 10 ml of water. After washing the ethyl acetate phase with an aqueous solution of 0.15 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 0.63 g of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (yield 81.4%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([C:16]2[O:20][N:19]=[C:18]([CH3:21])[C:17]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:13]([OH:30])=[CH:12][C:11]=1[OH:31].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.CCCCCC>[CH2:1]([O:30][C:13]1[CH:12]=[C:11]([O:31][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([Br:9])=[CH:15][C:14]=1[C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(-c2c(C)noc2-c2cc(Br)c(O)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C)noc2-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzyl bromide (0.36 ml, 3 mmol) was added suspension of 4-bromo-6-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzene-1,3-diol (Example 2) (0.55 g, 1.5 mmol) and cesium carbonate (0.85 g, 2.6 mmol) in DMF (5 ml) and the mixture stirred for ˜18 hrs, at room temperature. Water (100 ml) was added and the mixture extracted with diethyl ether (2×30 ml). The combined extracts were washed with water (4×75 ml) and saturated aqueous sodium chloride solution (50 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a pale brown gum. Trituration with hexane gave 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole as an off-white solid, dried in vacuo, (0.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])=[O:28])=[C:22]([CH3:38])[C:21]=3[CH3:39])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:40][CH3:41])[C:2]1C=CC=CC=1.[H][H].CN(C)[CH:46]=[O:47]>C(N(CC)CC)C.[OH-].[Pd+2].[OH-]>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[NH:29][C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([O:8][CH2:1][CH2:2][O:47][CH3:46])=[C:10]([O:40][CH3:41])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)=[C:21]([CH3:39])[C:22]=1[CH3:38])=[O:28]
Reactant: [H][H]
Reactant: CN(C)C=O
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(C)c3C)ccnc2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(C)c3C)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h

Procedure:
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,3-dimethylphenyl)-N′-(2,4-difluorophenyl)urea (213 mg) was dissolved in N,N-dimethylformamide (5 ml) and triethylamine (1 ml), and palladium hydroxide (40 mg) was added to the solution. The mixture was stirred in a hydrogen atmosphere at room temperature overnight. The reaction solution was filtered through Celite and was then washed with chloroform/methanol. The solvent was removed by distillation under the reduced pressure. A 90 mg portion of the residue (184 mg) was dissolved in N,N-dimethylformamide (1.5 ml), and potassium carbonate (32 mg), tetra-n-butylammonium iodide (7 mg), and 2-bromoethyl methyl ether (32 mg) were added to the solution. The mixture was stirred at 70° C. overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with chloroform/acetone (2/1) to give 110 mg of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[N:18]([CH2:19][CH2:20][NH2:21])[CH:13]([CH2:14][CH2:15]2)[CH:12]=1.Br[C:23]1[CH:24]=[C:25]([O:33][CH3:34])[CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:34][O:33][C:25]1[CH:26]=[C:27]2[C:32](=[C:23]([NH:21][CH2:20][CH2:19][N:18]3[CH:16]4[CH2:15][CH2:14][CH:13]3[CH:12]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=3)[CH2:17]4)[CH:24]=1)[N:31]=[CH:30][CH:29]=[CH:28]2
Reactant: COc1cc(Br)c2ncccc2c1
Reactant: NCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(NCCN2C3C=C(c4ccc5ccccc5c4)CC2CC3)c2ncccc2c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A mixture of 0.17 g, (0.61 mmol) 2-[3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]ethylamine, 0.13 g (0.55 mmol) 8-bromo-6-methoxyquinoline, 30 mg (0.03 mmol) Pd2(dba)3, 20 mg (0.08 mmol) 2-(di-t-butylphosphino)biphenyl and 10 mL PhMe is stirred at 23° C. for 16 h. The reaction mixture is poured into 100 mL of H2O and extracted 3×50 mL EtOAc. The combined organics are washed with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered, and the volatiles are evaporated. The crude product is subjected to flash chromatography on SiO2, eluting with EtOAc to EtOAc/2M NH3 in MeOH (40/1), to give the title compound as an off-white solid. This solid is dissolved in 4 mL of absolute EtOH and treated with 0.01 g (0.14 mmol) (CO2H)2 to give 0.07 g (0.13 mmol, a 23% yield) of the oxalate salt of the title compound as a dark green solid: mp: 179-182 C; MS (ES) m/z 436 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=O)[C:5]([N:8]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.C[O-].[Na+].O>C(=O)(OC)OC.CO>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:20][C:4]=2[CH:3]=1
Reactant: COC(=O)CCCN(CC(C)C)c1ncc(Br)cc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: COC(=O)OC
Product: COC(=O)C1=Cc2cc(Br)cnc2N(CC(C)C)CC1
Temperature: 50 °C
Yield: 91.8 %

Procedure:
To a solution of methyl 4-[(5-bromo-3-formylpyridin-2-yl)(isobutyl)amino]butanoate (750 mg) in dimethyl carbonate (20 ml) was added a 28% sodium methoxide solution in methanol (810 mg), and the mixture was heated at 50° C. for 2 hours under a nitrogen atmosphere. The mixture was returned to room temperature, water was added thereto and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→hexane:ethyl acetate=6:1) to give methyl 3-bromo-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylate (654 mg) as a yellow oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([CH3:12])[C:2]([Cl:1])=[CH:7][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(Cl)ccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(Cl)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Yield: 99.9 %

Procedure:
A mixture of 1.50 g (8.00 mmols) of 4-chloro-3-methyl-2-nitrophenol, 1.50 g (8.80 mmols) of benzyl bromide, 2.43 g (17.6 mmols) of potassium carbonate and 70 ml of acetone was refluxed for 2 hours. Thereafter insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography to give 2.22 g (>99%) of 3-benzyloxy-6-chloro-2-nitrotoluene.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:25][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([C:22](O)=[O:23])[CH:17]=[CH:16]3.[NH:26]1[C:36]2[C:37]3[CH:28]([CH2:29][C:30](=[O:38])[NH:31][C:32]=3[CH:33]=[CH:34][CH:35]=2)[CH2:27]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:38]=[C:30]1[CH2:29][CH:28]2[CH2:27][N:26]([C:22]([C:18]3[CH:17]=[CH:16][C:15]4[C:20](=[CH:21][C:12]5[CH2:11][C@:3]6([C:4]7[C:5](=[N:6][CH:7]=[CH:8][CH:9]=7)[NH:10][C:2]6=[O:1])[CH2:25][C:13]=5[CH:14]=4)[N:19]=3)=[O:23])[C:36]3[C:37]2=[C:32]([CH:33]=[CH:34][CH:35]=3)[NH:31]1
Reactant: O=C(O)c1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Reactant: O=C1CC2CNc3cccc(c32)N1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C1CC2CN(C(=O)c3ccc4cc5c(cc4n3)C[C@]3(C5)C(=O)Nc4ncccc43)c3cccc(c32)N1

Procedure:
A mixture of (S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylic acid (15 mg, 0.045 mmol, described in Intermediate 14), 1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one, enantiomer B (8 mg, 0.045 mmol, described in Intermediate 19), EDC (13 mg, 0.068 mmol), HOBT (9 mg, 0.068 mmol), and N,N-diisopropylethylamine (0.039 mL, 0.226 mmol) was stirred in DMF (0.7 mL) at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=488 (M+1). HRMS: m/z=488.1703; calculated m/z=488.1717 for C29H22N5O3.