Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][CH2:12][O:13]C(C)=O.[CH:17]([C:19]1[C:20]([NH:27][C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:31]=[CH:32][CH:33]=2)=[N:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=1)=O>CC1OCCC1>[CH3:26][S:25][C:22]1[N:23]=[CH:24][C:19]2[CH:17]=[CH:11][C:12](=[O:13])[N:27]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:31]=[CH:32][CH:33]=3)[C:20]=2[N:21]=1
Reactant: CSc1ncc(C=O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC1CCCO1
Product: CSc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
LiHMDS (41.6 mL of 1.0 M in THF solution, 41.6 mmol) was added to 2-MeTHF (70 mL) at −78° C. and treated with EtOAc (4.34 mL, 44.4 mmol). The solution was stirred at −78° C. for 10 min, then solid tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (50) (5.00 g, 13.87 mmol) was added in one portion and the solution was stirred at −78° C. for 10 min then removed from the cooling bath warmed to RT for 3 h. The reaction was cooled in an ice bath and quenched with a saturated solution of NH4Cl and extracted with EtOAc (2×100 mL), dried over MgSO4, filtered and concentrated. The crude solid was suspended in Et2O (50 mL) and collected by filtration, washed with Et2O (2×15 mL) and dried under vacuum affording tert-butyl (3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (51) (4.24 g, 11.03 mmol, 80% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.60-8.65 (1H, m), 7.64-7.71 (1H, m), 7.52 (1H, s), 7.39-7.47 (1H, m), 7.29 (2H, dd, J=8.3, 1.3 Hz), 6.89-6.95 (1H, m), 6.71 (1H, d, J=9.6 Hz), 6.56 (1H, s), 2.19 (3H, s), 1.50 (9H, s). m/z (ESI, +ve ion) 385.0 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1[N:13](CC2C=CC3/C(=C(\C)/C#N)/C4C=CC=CC=4OCC=3C=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].OCC1C=CC2/C(=C(\C)/C#N)/C3C=CC=CC=3OCC=2C=1>>[CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C(/C)C#N
Agent: C/C(C#N)=C1\c2ccc(CO)cc2COc2ccccc21
Product: CCc1nc2c(C)cc(C)nc2[nH]1
Yield: 264 %

Procedure:
[step 1] (Z)-2-[8-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (158 mg, 57%) was obtained in the same manner as in step 1 of Example 104, using (Z)-2-(8-hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiononitrile (178 mg, 0.64 mmol) obtained in Reference Example 31 and 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (169 mg, 0.96 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]=[C:13]1[NH:17][CH2:16][CH2:15][NH:14]1.CO.[H][H]>[Ni].O1CCCC1>[NH2:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]=[C:13]2[NH:17][CH2:16][CH2:15][NH:14]2)[CH:4]=1
Reactant: Cc1cc(Cl)c(N=C2NCCN2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(N=C2NCCN2)cc1N
Yield: 30.5 %

Procedure:
25.4 gm (0.10 mol) of 2-(2-chloro-4-methyl-5-nitro-phenylimino)-imidazolidine were hydrogenated in a shaker autoclave at 25° to 30° C. and atmospheric pressure in the presence of Raney nickel and in a 1:1 mixture of methanol and tetrahydrofuran until the theoretical amount of hydrogen had been absorbed. Thereafter, the catalyst was separated by suction filtration, and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 2 N hydrochloric acid, and the solution was extracted with ether; the ether extracts were discarded. The aqueous phase was fractionally extracted with ether at stepwisely increasing pH-values (alkalization with 2 N NaOH), and the uniform fractions were combined, dried over magnesium sulfate and filtered. The ether was removed from the filtrate in vacuo until the weight of the residue remained constant, leaving 6.85 gm (30.5% of theory) of 2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine, m.p. 155°-157° C., Rf -value 0.70 in the mobile phase 70 parts ethyl acetate, 50 parts isopropanol, 20 parts concentrated ammonium hydroxide; carrier: silicagel G; detector: ultraviolet light and potassium iodoplatinate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](Cl)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].N12CCCN=C1CCCCC2.[CH3:24][O:25][C:26](=[O:30])[CH2:27][N+:28]#[C-:29]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][C:10]1[O:11][CH:29]=[N:28][C:27]=1[C:26]([O:25][CH3:24])=[O:30]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(Cl)Cc1ccc(F)c(F)c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ncoc1Cc1ccc(F)c(F)c1
Reaction time: 0.08 h
Yield: 3.4 %

Procedure:
3,4-Difluorophenylacetic acid (3.61 g, 20.9 mmol) in oxalyl chloride (7.31 ml, 83.8 mmol) was refluxed for 4 hours. The solution was cooled to room temperature, concentrated under reduced pressure to give 3,4-difluorophenylacetyl chloride which was used without purification. To a well stirred solution of 3,4-difluorophenylacetyl chloride (2.21 g, 11.59 mmol) in THF (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.47 mL, 23.18 mmol) at room temperature and the solution was stirred for five minutes. Then methylisocyanoacetate (1.55 mL, 11.59 mmol) was added over a three minute period to the reaction mixture. After stirring for 18 hours at room temperature, the reaction mixture was partitioned between ether (100 mL) and water (50 mL). The organic layer was washed with 1N HCl (10 mL), water (15 mL) and saturated solution of sodium bicarbonate (15 mL), and dried over sodium sulfate. The solution was then filtered and concentrated. The residue was chromatographed (hexanes:EtOAc, 3:2) to yield 100 mg (3.4%) of the product; 1H-NMR (CDCl3) δ3.89 (s, 3H), 6.98 (s, 2H), 7.00-7.09 (m, 3H), 7.73 (s, 1H).
Reaction SMILES: [CH2:1]=[C:2]([C:7]([O:10]S(F)(=O)=O)([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[C:15](O[K])([C:21]([F:24])([F:23])[F:22])([C:17]([F:20])([F:19])[F:18])[F:16].[F-].[K+].FC(F)(F)C(C(F)(F)F)=O>O.COCCOCCOC>[CH2:1]=[C:2]([C:7]([O:10][C:15]([C:21]([F:24])([F:23])[F:22])([C:17]([F:20])([F:19])[F:18])[F:16])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(O[K])C(F)(F)F
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Agent: O=C(C(F)(F)F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: C=C(C(F)(F)F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)F
Reaction time: 2 h
Yield: 75 %

Procedure:
CH2═C(CF3)CF2OSO2F (10 g, 0.041 mole) is added at 20° C. to (CF3)2CFOK, prepared from freshly dried potassium fluoride (KF) (2.4 g, 0.041 mole), hexafluoroacetone (HFA) (9.3 g, 0.056 mole) and dry diglyme (10 ml). The reaction mixture is agitated for 2 hours and then poured into water, the organic layer separating. The organic layer is washed with dilute hydrochloric acid, then sodium bicarbonate solution, then water, after which it is dried over magnesium sulfate (MgSO4). Distillation of the reaction mixture gives CH2═C(CF3)CF2OCF(CF3)2 (10.2 g, 75% yield, b.pt. 87-88° C.).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.[F:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37](B(O)O)=[CH:36][C:35]=2[CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([C:9]3[C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[CH3:1])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=4)[N:10]=3)=[CH:36][C:35]=2[CH:42]=1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCC[C@@H]3C)nc2c1
Reactant: OB(O)c1cc2cc(F)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (240 mg, crude) in dioxane (5 mL) was added 5-fluorobenzofuran-2-ylboronic acid (337 mg, 1.87 mmol), K3PO4 (397 mg, 1.87 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol) and water (5 drops). The resulting solution was stirred for 1 hour at 90° C. and then concentrated under vacuum to give a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(5-fluorobenzofuran-2-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (135.0 mg, 59% 2 steps).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH:12][NH:13][C:14]([C:16]3[S:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[O:28][CH3:29])=[N:18][C:17]=3[CH3:30])=[O:15])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C=O.B.N1C=CC=C[CH:35]=1.Cl.[OH-].[Na+]>CO.C(O)(=O)C>[CH3:35][N:12]([CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2)[NH:13][C:14]([C:16]1[S:20][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[O:28][CH3:29])=[N:18][C:17]=1[CH3:30])=[O:15]
Reactant: c1ccncc1
Reactant: COc1cc(Cl)ccc1-c1nc(C)c(C(=O)NNCc2ccc3c(ccn3C)c2)s1
Agent: B
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(Cl)ccc1-c1nc(C)c(C(=O)NN(C)Cc2ccc3c(ccn3C)c2)s1
Reaction time: 0.33 h
Yield: 21 %

Procedure:
A mixture of 2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid N′-(1-methyl-1H-indol-5-ylmethyl)hydrazide (100 mg) prepared in the Step 17-1, a 37% formaldehyde solution (23 mg), pyridine borane (0.07 ml), acetic acid (2 ml) and methanol (4 ml) was stirred at a room temperature for 41 hours. To the reaction solution, 10% hydrochloric acid (0.5 ml) was added, and the resulting mixture was stirred for 20 minutes. Thereafter, the resulting mixture was neutralized with a 1-N sodium hydroxide aqueous solution. The neutralized mixture was concentrated under a reduced pressure. Then, water was added thereto, and the mixture was subjected to extraction twice with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated saline solution in order, dried over sodium sulfate, and concentrated under a reduced pressure. The concentrate was purified by a first thin-layer chromatography (chloroform:methanol=20:1) and then a second thin-layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (22 mg, 21%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H:36](C)[CH2:37][OH:38])[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].N[C@H:44](C)CO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([CH2:36][C@@H:37]([OH:38])[CH3:44])[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H](C)CO)c4)cc23)CC1
Reactant: C[C@@H](N)CO
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)C[C@H](C)O)c4)cc23)CC1
Yield: 36.1 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting (2S)-1-amino-2-propanol (1.20 mmol) for (2R)-2-amino-1-propanol to afford 15.3 mg of the title compound (36.1%)
Reaction SMILES: [OH-].[Na+].O.[SH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2.Cl[CH2:15][CH:16]([OH:37])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>CN(C=O)C>[OH2:37].[OH:37][CH:16]([CH2:17][N:18]1[CH2:19][CH2:20][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:22][CH2:23]1)[CH2:15][S:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2.[OH:37][CH:16]([CH2:17][N:18]1[CH2:19][CH2:20][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:22][CH2:23]1)[CH2:15][S:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 80 °C
Yield: 22.4 %

Procedure:
To DMF (6 mL), sodium hydroxide pellets (200 mg, 5 mmol) and 6-mercaptopurine monohydrate (0.85 g, 5 mmol) were added. The reaction mixture was stirred and heated to 80° C. for 30 min under nitrogen. The almost clear solution was cooled to room temperature and 1-(1-chloro-2-hydroxy-3-propanyl)-4-(diphenylmethyl)piperazine (1.72 g, 5 mmol) in DMF (10 mL) was added within 5 min. After stirring under nitrogen for 72 h, the mixture was filtered through Celite on a sintered glass funnel and the funnel was rinsed with DMF (2×5 mL). Evaporation of the solvent from the filtrate at 1.0 mm Hg at 50° C. gave a residue which was triturated with 10% methanol/methylene chloride. Filtration removed unreacted 6-mercaptopurine (0.5 g). The solution was purified using flash chromatography on silica gel using 10% methanol/methylene chloride as eluant. The product was isolated by concentration of the desired fractions and purified by trituration with n-pentane to give the title compound (0.35 g, 15.0%), mp 105°-110° C. (dec). DCI/MS M+1 461. 100 MHz 1H NMR (DMSO-d6) δ: 8.6 (s, 1H), 8.18 (s, 1H), 7.2-7.4 (m, 10H), 4.21 (s, 1H) 4.20 (m, 1H), 3.5 (m, 2H), 2.6 (m, 2H), 2.5-2.6 (m, 8H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]1[O:4][CH2:3]1.[OH-:14].[K+]>C(O)(=O)CCCCCCCCCCC.[OH-].[K+].O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]([CH2:3][OH:14])[OH:4]
Reactant: [OH-]
Reactant: CCCCCCCCOCC1CO1
Agent: CCCCCCCCCCCC(=O)O
Agent: [K+]
Solvent: O
Product: CCCCCCCCOCC(O)CO
Temperature: 140 °C
Reaction time: 5 h
Yield: 163.6 %

Procedure:
In an autoclave, 208 g of the resulting crude octyl glycidyl ether, 104.8 g of water, 5.82 g of lauric acid and 18.5 g of potassium hydroxide were charged. The resulting mixture was stirred at 140° C. for 5 hours. The reaction mixture was dehydrated at 100° C. under reduced pressure (6.67 kPa), followed by the addition of 9.7 g of lauric acid and 2.72 g of potassium hydroxide. After reaction at 160° C. for 15 hours, the reaction mixture was purified by distillation under reduced pressure (53 to 67 Pa, 120 to 123° C.), whereby 110.2 g of monooctyl glyceryl ether was obtained. As a result of GLC, it was found that the resulting product had a purity not less than 99% and the content of organochlorine compounds was not greater than 100 ppm.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](Cl)=[N:12][CH:13]=1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C(OCC)(=O)C>CN(C=O)C>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:11]2[CH:10]=[CH:9][C:8]([Br:7])=[CH:13][N:12]=2)=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Clc1ccc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1
Temperature: 110 °C

Procedure:
Potassium tert-butoxide (7 g, 62 mmol) is added to a solution of 5-bromo-2-chloro-pyridine (10 g, 52 mmol) and 4-benzyloxy-phenol (10.4 g, 52 mmol) in DMF (104 mL). The mixture is heated to 110° C. for 3.5 hours then cooled. The solution is then poured into water/ethyl acetate, and the organic layer is collected. The aqueous layer is extracted twice with EtOAc, and the combined organic layers are washed with brine. The organic layer is then dried over Na2SO4, filtered and concentrated. The resulting residue is purified on SiO2 (EtOAc/heptanes) to provide Intermediate D.
Reaction SMILES: Br/[C:2](=[CH:35]\[CH:36]=[C:37]1\[N:38]([CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[C:39]2[CH:40]=[CH:41][C:42]3[C:51]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:50][C:49]([S:56]([O-:59])(=[O:58])=[O:57])=[CH:48][C:43]=3[C:44]=2[C:45]\1([CH3:47])[CH3:46])/[CH:3]=[CH:4]/[C:5]1[C:13]([CH3:15])([CH3:14])[C:12]2[C:11]3[CH:16]=[C:17]([S:24]([O-:27])(=[O:26])=[O:25])[CH:18]=[C:19]([S:20]([O-:23])(=[O:22])=[O:21])[C:10]=3[CH:9]=[CH:8][C:7]=2[N+:6]=1[CH2:28][CH2:29][CH2:30][S:31]([O-:34])(=[O:33])=[O:32].[Na+:67].[Na+].[Na+].[Na+].[Na+].[C:72]([CH2:75][CH2:76][CH2:77][CH2:78][C:79]1[CH:80]=[C:81](B(O)O)[CH:82]=[CH:83][CH:84]=1)([OH:74])=[O:73].C(=O)([O-])[O-].[Cs+].[Cs+].O>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>[C:72]([CH2:75][CH2:76][CH2:77][CH2:78][C:79]1[CH:80]=[C:81](/[C:2](=[CH:35]\[CH:36]=[C:37]2\[N:38]([CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[C:39]3[CH:40]=[CH:41][C:42]4[C:51]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:50][C:49]([S:56]([O-:59])(=[O:57])=[O:58])=[CH:48][C:43]=4[C:44]=3[C:45]\2([CH3:47])[CH3:46])/[CH:3]=[CH:4]/[C:5]2[C:13]([CH3:14])([CH3:15])[C:12]3[C:11]4[CH:16]=[C:17]([S:24]([O-:27])(=[O:25])=[O:26])[CH:18]=[C:19]([S:20]([O-:23])(=[O:21])=[O:22])[C:10]=4[CH:9]=[CH:8][C:7]=3[N+:6]=2[CH2:28][CH2:29][CH2:30][S:31]([O-:34])(=[O:32])=[O:33])[CH:82]=[CH:83][CH:84]=1)([OH:74])=[O:73].[Na+:67].[Na+:67].[Na+:67].[Na+:67].[Na+:67]
Reactant: O=C(O)CCCCc1cccc(B(O)O)c1
Reactant: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
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: [Cs+]
Solvent: O
Solvent: CCO
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21

Procedure:
Compound 6 (80 mg), 3-(4-carboxybutyl)phenylboronic acid (40 mg), and cesium carbonate (20 mg) are stirred into 1:1 water:ethanol (10 ml) under nitrogen at room temperature. Tetrakis(triphenylphosphine)palladium(0) (10 mg) is added to the reaction mixture. The mixture was refluxed for 4 hours, and the solvent and volatile compounds are evaporated under vacuum. The crude product is purified by flash chromatography on reverse-phase C18-functionalized silica by eluting with a 1:4 acetonitrile:water mixture. The purified product 8 has UV/vis absorption max of λMeOH=680 nm, ε=229,000; λPBS676 nm, ε=239,000.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>>[OH:10][CH2:9][CH2:8][N:6]1[CH:7]=[C:2]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)[CH:3]=[CH:4][C:5]1=[O:11]
Reactant: OB(O)c1cccs1
Reactant: O=c1ccc(Br)cn1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1ccc(-c2cccs2)cn1CCO
Reaction time: 0.33 h

Procedure:
To a microwave vial with 5-bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one (0.400 g, 2 mmol), 2-thiopheneboronic acid (0.800 g, 6 mmol), Potassium Carbonate (2 mL, 4 mmol) and 1,4-Dioxane (2.5 mL, 29 mmol) was added Palladium-Fibrecat. The vial was equipped with a stir bar and capped. The vial was placed into the CEM microwave for 20 minutes at 140° C., while 50 Watts of energy was supplied via Powermax. The progress of the reaction was monitored by LC/MS, which showed mostly desired product in the mixture. The mixture was diluted with CH2Cl2 (3 mL) and Water (2 mL). The organic layer was extracted with 3:1 CH2Cl2/MeOH (3×16 mL). Combined organics, dried over Sodium sulfate, filtered and concentrated in-vacuo. The crude was recrystallized from 5:1 CH2Cl2/MeOH and Hexanes to give the desired product as a light-yellow crystalline solid (0.280 g, 69% yield). MS (ESI pos. ion) m/z (MH+): 222. Calc'd exact mass for C11H11NO2S: 221. 1H NMR (300 MHz, CDCl3): 7.60 (s, 3H), 7.06 (s, 3H), 4.16 (s, 2H), 3.98 (s, 2H).
Reaction SMILES: CN.[CH2:3]([N:5]([CH2:26][CH3:27])[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH3:4].[C:28](O)(=O)/C=C/C(O)=O>C(O)C>[CH2:26]([N:5]([CH2:3][CH3:4])[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23](=[S:25])[NH:24][CH3:28])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH3:27]
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: O=C(O)/C=C/C(=O)O
Agent: CN
Solvent: CCO
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=S)NC)cc21
Temperature: 60 °C
Reaction time: 24 h
Yield: 88.8 %

Procedure:
A mixture of a 33% strength solution (10 cc) of methylamine in absolute ethanol and 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (2 g) in absolute ethanol (15 cc) is brought for 24 hours to a temperature in the region of 100° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (100° C.), washed with distilled water (2×50 cc), dried over magnesium sulphate in the presence of charcoal 3S, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil (1.7 g) is purified by chromatography on a column (height: 25 cm; diameter: 2.5 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting successively with ethyl acetate (750 cc) and with a mixture (90:10 by volume) (500 cc) cf ethyl acetate and ethanol and collecting 50-cc fractions. Fractions 2 to 7 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual brown oil (1.3 g) is dissolved at 50° C. in ethanol (3 cc) and the solution obtained is poured into a solution of fumaric acid (0.39 g) in ethanol (3 cc), with stirring and at a temperature in the region of 60° C. After 1 hour with stirring at a temperature in the region of 5° C., the solid formed is drained, washed with ethanol (3×1 cc) and dried in the air. This solid is redissolved in ethanol (20 cc) under reflux and then stored for 1 hour at a temperature in the region of 5° C. The solid formed is drained, washed with ethanol (3×1 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-[(2RS)-1-diethylamino-2-propyl]-N-methyl-2-phenothiazinecarbothioamide acid fumarate (1.15 g) is thereby obtained in the form of a yellow solid, m.p. 224° C.;