Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH3:17])=[CH:13][C:14]=1[B:23]([OH:28])[OH:24])(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(B(O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.85 g (11.2 mmol) of N-t-butyl-4-n-propylbenzenesulfonamide (from Step A) in anhydrous THF (20 mL) cooled to -40° C. under N2 was added 2.5M n-BuLi solution (11.2 mL, 2.5 equiv). The mixture was warmed to room temperature and stirred for 2 hours. To the mixture, containing the bright red dianion at 0° C., was added triisopropyl borate (3.9 mL, 1.5 equiv). The next day, 2N HCl (3 mL) was added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate. The organic solution was washed with 2N HCl, H2O and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled compound; Rf =0.5 (1:1 EtOAc-hexane). The material was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[CH3:22])=[O:4].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=1)[N:7]=[C:6]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(Cl)cc2c1-c1ccccc1
Reactant: CCNCC
Product: CCN(CC)c1nc2c(C)cc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 40 step D from 2,6-dichloro-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 40 step C) and diethylamine. Brown solid. MS (ESI): 369.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:28][C:20]3[C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:36]([C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40]Br)#[N:37]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:28]([CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=3[C:36]#[N:37])[C:20]3[C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1ccc2nc(C3CCCC(NC(=O)OCc4ccccc4)C3)[nH]c2c1=O
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ccc2nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n(Cc3ccccc3C#N)c2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 54.9 %

Procedure:
To a solution of [3-(5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.1 g, 0.25 mmol) in DMF (3 mL) were added Cs2CO3 (0.17 g, 0.51 mmol) and 60 mg (0.30 mmol) of 2-cyanobenzyl bromide as a solution in 3 mL of DMF. After stirring at room temperature for 17 h, the reaction mixture was diluted with water (10 mL) then extracted with CH2Cl2. The combined extracts were dried with MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 1% MeOH in CH2Cl2 to give {3-[3-(2-cyano-benzyl)-5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]-cyclohexyl}-carbamic acid benzyl ester (70 mg, 54% yield). 1H-NMR (CDCl3): δ 7.73 (m, 1H), 7.49 (m, 1H), 7.34 (m, 6H), 7.13 (m, 1H), 6.89 (d, 1H, J=8.4 Hz), 6.69 (m, 1H), 6.19 (m, 1H), 5.94 (m, 1H), 5.06 (s, 2H), 4.73 (m, 1H), 4.07 (m, 2H), 3.58 (m, 1H), 2.79 (m, 1H), 2.02 (m, 2H), 1.87 (m, 1H), 1.68 (m, 2H), 1.51 (m, 2H), 1.38 (t, 3H, J=7.2 Hz), 1.16 (m, 1H). MS: calculated for C30H31N5O3+H 510.3; found: 510.5.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16][CH2:17][CH2:18]O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C([Br:35])C=C.C(OCC)C>C(#N)C>[Br:35][CH2:18][CH2:17][CH2:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2
Reactant: C=CCBr
Reactant: COc1nc2cc(Cl)cc(CCCO)c2nc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCOCC
Product: COc1nc2cc(Cl)cc(CCCBr)c2nc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
0.5 g (1.77 mmol) of 3-(7-chloro-2,3-dimethoxy-quinoxalin-5-yl)-propan-1-ol and 0.287 g (1.77 mmol) of 1,1'-carbonyidiimidazole are placed in 5 ml of acetonitrile under N2. 0.75 ml of allyl bromide is added, and the mixture is then stirred at room temperature for 30 minutes and at reflux for 2 hours. The reaction mixture is cooled to room temperature, diethyl ether is added and extraction is carried out with water, 0.1N hydrochloric acid, saturated sodium hydrogen carbonate solution and brine. The aqueous phases are then washed with diethyl ether. The organic phases are combined, dried over sodium sulfate, filtered over a layer of silica gel and concentrated. 0.438 g (79.9%) of 5-(3-bromopropyl)-7-chloro-2,3-dimethoxy-quinoxaline is obtained in the form of a yellow oil which is used further without further purification.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5](C#N)[CH:6]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])C.O.OS(O)(=O)=O>C(O)(=O)C>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[CH2:5][C:4]([OH:24])=[O:3])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(C#N)C(c1ccc(Br)cc1)c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CC(c1ccc(Br)cc1)c1ccc(F)cc1F
Temperature: 120 °C

Procedure:
To a solution of 3-(4-bromo-phenyl)-2-cyano-3-(2,4-difluoro-phenyl)-propionic acid ethyl ester (2.4 g) in acetic acid (11 mL) was added water (6 mL) and concentrated H2SO4 (6.83 mL) at 0° C. The reaction mixture was heated to 120° C. overnight, then cooled and poured on ice and extracted with ethyl acetate (3×100 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude reaction product was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane/ethyl acetate (1:0 to 1:1) to provide the title compound as an off-white solid. MS (ESI−): m/z=339.0 ([M−H]−).
Reaction SMILES: C([O:4][C:5](=[O:28])[CH2:6][C:7]1([CH2:13][NH:14][C:15]([O:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[O:19]2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C=C.C(O)=O>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:27]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]([O:17][C:15]([NH:14][CH2:13][C:7]2([CH2:6][C:5]([OH:28])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:16])[O:19]1
Reactant: C=CCOC(=O)CC1(CNC(=O)OC2OC(=O)c3ccccc32)CCCCC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=C(O)CC1(CNC(=O)OC2OC(=O)c3ccccc32)CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.3 %

Procedure:
To a stirred solution of (55) (0.12 g, 0.31 mmol) in dry tetrahydrofuran was added tetrakis(triphenylphosphine)-palladium(0) (5.5 mg, 4.8×10−3 mmol) and formic acid (57 mg, 1.24 mmol). The resulting reaction was stirred at room temperature for 12 h (monitored by LC/MS), then filtered through a Celite® and activated charcoal pad. The pad was washed with ethyl acetate (2×15 mL) and the combined filtrates were washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. The resulting residue was purified using preparative-LC/MS to provide 80 mg of compound (53) as a white solid (74% yield). 1H NMR (400 MHz, CDCl3) δ 1.35-1.58 (10H, m); 2.34 (2H, s); 3.23-3.40 (2H, m); 5.56 (1H, t, J=7.2 Hz); 7.42 (1H, s); 7.60-7.66 (2H, dd, J=7.6 Hz); 7.74 (1H, t, J=7.6 Hz); 7.91 (1H, d, J=7.6 Hz). MS (ESI): m/z=346.40 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH:14]=[C:10]([Cl:9])[N:11]=[CH:12]2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Clc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(-n2cnc(Cl)c2)ncn1
Yield: 54.6 %

Procedure:
A mixture of 4,6-dichloropyrimidine (1.8 g, 12 mmol), 4-chloro-1H-imidazole (1.23 g, 12.00 mmol), and cesium carbonate (3.91 g, 12.00 mmol) was stirred in DMF (8 mL) at room temperature for 18 h. The reaction was diluted into water and extracted with EtOAc. The combined organic layers were concentrated and purified by flash chromatography on a 120 g silica gel cartridge with 0 to 40% ethyl acetate in hexane to yield 4-chloro-6-(4-chloro-1H-imidazol-1-yl)pyrimidine (1.41 g, 54.6% yield). The positive identification of the 4-chloroimidazole regioisomer was accomplished by its NMR NOE properties. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.86 (1H, d, J=0.76 Hz), 8.33 (1H, d, J=1.51 Hz), 7.54 (1H, d, J=1.76 Hz), 7.30 (1H, d, J=0.76 Hz). LCMS: RT=0.81 min, MH+=215.1
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:11])[CH2:4][S:3]1(=[O:13])=[O:12].[I:14]I>C(Cl)(Cl)Cl>[I:14][C:9]1[S:8][C:7]2[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[CH2:4][C:5](=[O:11])[C:6]=2[CH:10]=1
Reactant: CN1c2sccc2C(=O)CS1(=O)=O
Reactant: II
Solvent: ClC(Cl)Cl
Product: CN1c2sc(I)cc2C(=O)CS1(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a stirring solution of 1-methyl-1H-thieno[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide (Preparation 33, 1.0 g) in CHCl3 (100 ml) at ambient temperature is added HgO (1.19 g) and iodine (1.17 g). The resulting mixture is stirred overnight at ambient temperature and the solids removed by filtration through diatomaceous earth. The solvent is removed in vacuo and the residue purified via flash column chromatography (4/1, hexanes/EtOAc) to afford 0.68 g (43%) of the title compound as a tan solid. Physical characteristics: 1H NMR (CDCl3) δ3.40, 4.20, 7.53; IR (diffuse reflectance) 2986, 1675, 1664, 1505, 1478, 1405, 1338, 1327, 1275, 1245, 1177, 1158, 1129, 818, 781 cm1; MS (EI) m/z 343 (M+). Anal. Found: C, 24.65; H, 1.82; N, 4.08.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[N+:8]([O-:31])[CH:9]=[C:10]([Cl:30])[C:11]=1[CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:16]=1)[OH:14].[CH:32]1([CH2:35][O:36][C:37]2[CH:49]=[CH:48][C:40]([C:41]([O:43][CH2:44][C:45](O)=[O:46])=[O:42])=[CH:39][C:38]=2[CH2:50][N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)[CH2:34][CH2:33]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[N+:8]([O-:31])[CH:9]=[C:10]([Cl:30])[C:11]=1[CH2:12][C@H:13]([O:14][C:45](=[O:46])[CH2:44][O:43][C:41](=[O:42])[C:40]1[CH:48]=[CH:49][C:37]([O:36][CH2:35][CH:32]2[CH2:34][CH2:33]2)=[C:38]([CH2:50][N:51]2[CH2:52][CH2:53][O:54][CH2:55][CH2:56]2)[CH:39]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:16]=1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)COC(=O)c1ccc(OCC2CC2)c(CN2CCOCC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(COC(=O)c1ccc(OCC2CC2)c(CN2CCOCC2)c1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
EDC (82 mg, 0.429 mmol) was added to a solution of compound (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (120 mg, 0.286 mmol), 2-(4-(cyclopropylmethoxy)-3-(morpholinomethyl)-benzoyloxy)acetic acid (300 mg, 0.859 mmol) and DMAP (18 mg, 0.143 mmol) in DCM (1 ml) at RT under nitrogen atmosphere. The mixture was stirred at RT overnight. The mixture was then diluted with DCM and washed with NaHCO3 sat. sol., HCl 0.1N and brine. The organic phase was dried over Na2SO4, and the solvent was evaporated. The crude was purified through Preparative HPLC to give (S)-3,5-dichloro-4-(2-(2-(4-(cyclopropylmethoxy)-3-(morpholinomethyl)-benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-ethyl)pyridine 1-oxide (150 mg, 70% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15]Br>C(COC)OC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:15][C:14]2[C:13]([F:12])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: COCCOC
Product: O=S(=O)(Cc1c(F)cccc1F)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To dimethoxyethane (10 ml) were added sodium 4-chlorobenzenesulfinate (205 mg, 1.03 mmol) and 2,6-difluorobenzyl bromide (214 mg, 1.03 mmol). The resulting mixture was stirred at 70° C. for 18 hours. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. Ethyl acetate was added to the residue and from the resulting mixture, the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column and the fraction obtained from the ether eluate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column. The fraction obtained from the hexane:ethyl acetate (=10:1) eluate was concentrated under reduced pressure, whereby the title compound (289 mg, 93%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[NH2:5][C:6]1[C:7]2[C:32]([CH3:38])([C:33](OCC)=[O:34])[C:31](=[O:39])[NH:30][C:8]=2[N:9]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[N:13]=2)[N:11]=1>>[NH2:5][C:6]1[C:7]2[C:32]([CH3:38])([C:33]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:34])[C:31](=[O:39])[NH:30][C:8]=2[N:9]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:25])([F:27])[F:26])[N:13]=2)[N:11]=1
Reactant: NC1CC1
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Product: CC1(C(=O)NC2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21

Procedure:
Cyclopropylamine (10.71 mL, 155 mmol) was added to ethyl 4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate, as prepared by the procedure described in Example 158, (594 mg, 1.189 mmol) and the resultant mixture heated at 50° C. for 16 hours. The mixture was concentrated in vacuo and the residue purified by silica gel column chromatography using a hexanes/EtOAc gradient. Chiral separation using SFC on a Chiralpak AD-H column provided both enantiomers of the title compound, 1H NMR (500 MHz, DMSO-d6): δ 9.02 (1H, d, J=8.09 Hz), 8.63 (1H, d, J=4.45 Hz), 7.63 (1H, d, J=4.01 Hz), 7.38 (1H, dd, J=8.08, 4.48 Hz), 6.75 (2H, s), 4.87 (2H, t, J=6.77 Hz), 3.03-2.90 (2H, m), 2.68-2.62 (1H, m), 1.56 (3H, s), 0.63-0.54 (2H, m), 0.51-0.44 (2H, m). m/z=511.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCNCC2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCNCC2)cc1
Temperature: 120 °C

Procedure:
This compound could be made in the following manner: 1-(4-Bromo-benzyl)-piperazine would be combined with 1 equ of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 2M sodium carbonate solution, toluene and ethanol. The reaction mixture would be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture would then be filtered through Celite and concentrated in vacuo. The residue would then be purified by flash chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:27][CH3:28].O>CN(C=O)C>[CH2:27]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
Next, to a mixture of tert-butyl (7-hydroxy-1-naphthyl)carbamate (64.0 g, 247 mmol) and cesium carbonate (161 g, 493 mmol) in 300 mL anhydrous DMF was added iodoethane (42.3 g, 272 mmol) at room temperature. The mixture was stirred at 60° C. for 2 hours. Water was added to the mixture, and the product was extracted with ethylacetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. To the obtained residue was added diisopropyl ether and the precipitate was collected and dried to afford tert-butyl (7-ethoxy-1-naphthyl)carbamate (47.9 g, 67.5% yield).
Reaction SMILES: [N+:1]1([O-])[C:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C[Si]([C:19]#[N:20])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:19]([C:6]1[N:1]=[C:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:3]=[CH:4][CH:5]=1)#[N:20]
Reactant: CC(C)(C)OC(=O)c1cccc[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CC(C)(C)OC(=O)c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.3 %

Procedure:
A mixture of tert-butyl 2-pyridinecarboxylate N-oxide (12.4 g, 63 mmol), trimethylsilyl cyanide (9.6 g, 96 mmol), N,N-dimethylcarbamoyl chloride (10.3 g, 95 mmol) and nitroethane (80 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (3;1, v/v) and recrystallized from tetrahydrofuran-hexane to give the titled compound (11.1 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=O.[NH2:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[NH2:32])[C:16]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)=[O:17]>CS(C)=O>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[NH:18][C:16]([C:15]1[CH:29]=[CH:30][C:31]2[N:32]=[C:4]([C:3]3[C:2]([Cl:1])=[CH:9][C:8]([Cl:10])=[CH:7][C:6]=3[Cl:11])[NH:12][C:13]=2[CH:14]=1)=[O:17]
Reactant: O=Cc1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Solvent: CS(C)=O
Product: O=C(Nc1ccc2ccccc2n1)c1ccc2nc(-c3c(Cl)cc(Cl)cc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2,4,6-trichlorobenzaldehyde (150 mg, 0.72 mmol) and 3,4-diamino-N-quinolin-2-yl-benzamide (200 mg, 0.72 mmol) in DMSO (10 mL) was added FeCl3 (23 mg, 0.14 mmol). The solution was stirred at ambient temperature for 2 days. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (1/3) as eluent to give the title compound as a white solid. 1H NMR (Methanol-d4, 400 MHz): δ 8.45 (m, 3H), 8.08 (d, 1H), 7.93 (m, 2H), 7.85 (s, 1H), 7.76 (s, 2H), 7.75 (m, 1H), 7.55 (m, 1H). MS (m/z) 467.0 (M+1); Retention time: 1.48 min (Method 10).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:17])[CH2:4][CH2:3]1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)(O)[O-].[Na+]>C(O)C>[ClH:1].[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][N:2]2[CH2:3][CH2:4][CH:5]([CH:8]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]3=[O:17])[CH2:6][CH2:7]2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=C1c2ccccc2CC1C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2CC1C1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A mixture of 0.46 g (0.00183 mol) of 2-(4-piperidyl)-1-indanone hydrochloride, 0.578 g (0.00251 mol) of p-nitrophenethyl bromide, 0.422 g (0.00502 mol) sodium bicarbonate and 20 mL of ethanol was stirred and refluxed for 72 hours. The ethanol was removed by evaporation, and the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was washed with water, dried over magnesium sulfate, filtered, and the ethyl acetate removed. The residue was purified by chromatography on silica gel using 2.5% methanol in chloroform as an eluant. Evaporation of the solvent gave a crystalline product that was converted to a hydrochloride salt. Recrystallization from ethanol gave 2-[1-(4-nitrophenethyl)-4-piperidyl]-1-indanone hydrochloride, mp 259°-261° C.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:3].[I-].[CH3:13][C:14]1[CH:19]=[CH:18][N+:17]([CH3:20])=[CH:16][CH:15]=1.[C:21]1([B-:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na+]>>[C:40]1([B-:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1.[CH3:1][N:2]([C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:13]/[C:14]2[CH:19]=[CH:18][N+:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1cc[n+](C)cc1
Agent: [I-]
Agent: [Na+]
Agent: c1ccc([B-](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CN(C)c1ccc(/C=C/c2cc[n+](C)cc2)cc1

Procedure:
14.9 g (0.1 mol) of 4-(N,N-dimethylamino)benzaldehyde were reacted with 23.6 g (0.1 mol) of 4-methyl-N-methylpyridinium iodide, prepared according to Example 3, and the resulting solution was treated with 34.6 g (0.1 mol) of sodium tetraphenyborate, under the conditions described in Example 6, to form dye2 as a red solid in a yield of 70%. 1H-NMR (DMSO-d6) δ3.00 (s, 6H), 4.1 (s, 3H), 6.70 (t, 4H), 6.8 (t, d, 2H), 6.9 (t, 8H), 7.02 (d, 1H), 7.10 (d, 8H) 7.50 d, 2H), 7.9 (d, 1H), 8.0 (d, 2H), 8.62 (d, 2H) ppm. Td 266° C.