Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]Cl.[H-].[Na+]>CN(C)C=O>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][N:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][S:1][C:5]=2[C:6]1=[O:10]
Reactant: CN(C)CCCCl
Reactant: O=c1[nH]ccc2ccsc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCn1ccc2ccsc2c1=O
Temperature: 80 °C
Yield: 95.2 %

Procedure:
To a solution of thieno[2,3-c]pyridin-7(6H)-one (1.82g, 12 mmol) in dry dimethylformamide (18 ml), under a nitrogen atmosphere, was added 3-(dimethylamino)propyl chloride hydrochloride (2.25 g, 14.4 mmol). Sodium hydride in mineral oil (60%, 1.35 g, 33 mmol) was carefully added to this solution and the mixture was warmed at 80° C. for 3 hours. The cooled reaction mixture was diluted with ice-water and the crude product was extracted into methylene chloride. This organic layer was extracted with dilute hydrochloric acid and the acid layer was made basic with sodium hydroxide solution. After extraction of the product into methylene chloride, this solution was dried over anhydrous sodium sulfate, filtered and evaporated to give an oily product (2.7 g, 95% yield) which contained less than 12% of the by-product resulting from O-alkylation. Some of this material was further purified by formation of the hydrochloride salt upon treatment with ethanolic HCl. Recrystallization from hot ethanol gave pure salt, m.p. 185°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30][Cl:31])=[O:10])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@H:15]3[S:14](=[O:42])[CH2:13][C:12]=2[CH2:30][Cl:31])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(CCl)CS(=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To an ice cold solution of 7β-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (3.0 g; 6.16 mMol.) in dichloro-methane (50 ml) is added m-chloroperbenzoic acid (1.32 g: 1 Eq.), and the mixture is stirred for 1 hour under ice cooling. The reaction mixture is diluted with aqueous 5% sodium thiosulfate and extracted with dichloromethane. The extract is washed with aqueous sodium hydrogen carbonate, dried, and concentrated in vacuum to give 7β-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide (1.66 g). Yield: 53.5%.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)CCCC#CCBr
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCC#CCN1C(=O)c2ccccc2C1=O
Yield: 44.1 %

Procedure:
A mixture or potassium phthalimide (2.31 g) and methyl 7-bromohept-5-ynoate (3.0 g) in dimethylformamide (35 ml) was heated at 110° C. for 4.5 hours. The cooled solution was poured into water (75 ml) and the pH of the solution was adjusted to 6. The resulting solution was extracted with ether (4×200 ml) and the combined ether extracts were dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with chloroform to give the title compound (1.56 g) m.p. 62°-63° C.
Reaction SMILES: [OH-].[Na+].C(O)C.[CH2:6]([O:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([O:27]CC)=[O:26])[C:19]=3[N:18]=[C:17]2[CH3:30])=[C:13]([Cl:33])[CH:12]=1)[CH2:7][CH2:8][CH3:9].Cl>O>[CH2:6]([O:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][N:16]2[C:20]3[CH:19]=[C:24]([C:25]([OH:27])=[O:26])[CH:23]=[CH:22][C:21]=3[N:18]=[C:17]2[CH3:30])=[C:13]([Cl:33])[CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1ccc(Cn2c(C)nc3c(C(=O)OCC)cccc32)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc(Cn2c(C)nc3ccc(C(=O)O)cc32)c(Cl)c1
Reaction time: 4 h
Yield: 72.8 %

Procedure:
Sodium hydroxide (0.17 g), ethanol (8 ml), and water (4 ml) were added to 1-(4-butyloxy2-chlorobenzyl)(ethoxycarbonyl)-2-methylbenzimidazole (0.62 g) and the whole was s d for 4 hours at 80° C. The pH was adjusted to about 5 with 35% hydrochloric acid. Deposited crystals were filtered and dried to obtain crystals (0.42 g) of 1-(4-butyloxy-2-chlorobenzyl)-6-carboxy-2-methyl-benzimidazole. [Physicochemical properties of the compound]
Reaction SMILES: [C:1]1([CH2:7][Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[CH3:11][N+:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19]>CCOCC>[CH2:7]([CH:17]1[CH:16]=[C:15]([CH3:18])[CH:14]=[C:13]([CH3:19])[N:12]1[CH3:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Cc1cc[n+](C)c(C)c1
Agent: [I-]
Solvent: CCOCC
Product: CC1=CC(Cc2ccccc2)N(C)C(C)=C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
PhCH2MgCl (1 M in Et2O, 180 mL) is added dropwise to a solution of 1,2,4-trimethyl-pyridinium iodide (24.3 g) in Et2O(90 mL) chilled in an ice bath. After stirring in the ice bath for 2 h, the solution is poured into a mixture of 72% aqueous HClO4 (40 mL) and crushed ice (ca. 900 mL). The resulting mixture is stirred for 1 h and the precipitate formed is separated by filtration. The precipitate is washed with methanol and dried to afford the HClO4 salt of the title compound.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:7]([NH:6][CH:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[CH2:4][OH:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(C)c(OC)c1)NC(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CC(CO)NCc2ccccc2)ccc1C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
55.5 gm (0.16 mol) of N-benzoyl-3-(3'-methoxy-4'-methyl-phenyl)-alanine ethyl ester (m.p. 133° C) were dissolved in 550 ml of absolute tetrahydrofuran, and the resulting solution was slowly added dropwise to a stirred suspension of 37 gm (0.98 mol) of lithium aluminum hydride in 1850 ml of tetrahydrofuran at room temperature in an atmosphere of nitrogen. The resulting mixture was refluxed for five hours, then allowed to stand overnight, and subsequently slowly admixed with water. The inorganic precipitate formed thereby was collected by vacuum filtration, washed with tetrahydrofuran, and the wash solution was combined with the filtrate. The tetrahydrofuran was distilled in vacuo out of the combined solution, the residue was taken up in ether, and the ethereal mixture was extracted with water. The ether phase was dried over sodium sulfate, the ether was distilled off, and the residue was recrystallized from petroleum ether, yielding 45.0 gm (97.5% of theory) of the free base 2-benzylamino-3-(3'-methoxy-4'-methyl-phenyl)-1-propanol.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]2[CH:28]=[C:11]([CH:12]=[CH:13][N:14]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][C:3]1=[O:29].C1C(=O)N([Br:37])C(=O)C1>C(#N)C>[Br:37][C:8]1[CH:7]=[CH:6][C:5]2[NH:4][C:3](=[O:29])[C@H:2]([CH3:1])[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:15]3[CH:28]=[C:11]([CH:12]=[CH:13][N:14]=3)[C:10]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccccc2NC1=O
Solvent: CC#N
Product: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2cc(Br)ccc2NC1=O
Temperature: 75 °C
Yield: 89.8 %

Procedure:
To a suspension of 45G (616 mg, 1.558 mmol) in acetonitrile (15.200 ml) in a sealed vial was added NBS (277 mg, 1.558 mmol). The reaction was sealed and heated at 75° C. overnight. Additional NBS (300 mg, 1.686 mmol) was added and heat at 75° C. overnight. The mixture was concentrated and purified by silica gel chromatography to afford 137A as a white solid (664 mg, 90%). MS (ESI) m/z: 476.0 (M+H)+.
Reaction SMILES: Cl.C([S:5][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[CH2:28][CH2:27]2)=[O:25])[CH2:7]1)(=O)C>O1CCOCC1>[SH:5][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C@H:8]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:36])[CH2:30][CH2:31]2)=[O:25])[CH2:7]1
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
600 ml of a 10% w/v methanolic solution of hydrogen chloride were added to a solution of 140 g of (2S,4S)-4-acetylthio-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine [prepared as described in step 90(b)(ii) or 90(c)(ii) above] in 150 ml of 1,4-dioxane, and the resulting mixture was stirred at 50° C. for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with 1500 ml of ethyl acetate. The dilute solution was neutralized with an aqueous solution of sodium hydrogencarbonate and washed, in turn, with 300 ml of water and with 300 ml of an aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol ranging from 30:1 to 20:1 by volume as the eluent, to give 96.44 g of the title compound, as a colorless powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>C(#N)C.CN(C1C=CN=CC=1)C>[O:7]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1CCCCN1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCCC1=O
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
A solution of piperidin-2-one (25 g, 252.2 mmol) in acetonitrile (250 ml) was cooled to 0° C. and added DMAP (6.1 g, 50.4 mmol) and triethyl amine (25.5 g, 252.2 mmol) and stirred for 10 min at same temperature then added (BOC)2O (66 g, 302.6 mmol) and continue stirring for 2 h at room temperature. After completion of starting material, solvent was removed and residue was re-dissolved in ethyl acetate and washed with water, brine and dried over Na2SO4 and concentration to afford crude product as brown liquid (31.8 g) which was used directly for the next step. 1H NMR (300 MHz, CDCl3) δ 3.66-3.62 (2H, m), 2.52-2.47 (2H, m), 1.83-1.79 (4H, m), 1.52 (9H, s) ppm.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>O1CCCC1>[Cl:14][CH2:15][CH2:16][C:17]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:18]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(CCCl)N(c1ccccc1)c1ccccc1
Yield: 48.1 %

Procedure:
To a solution of 40.6 g (0.240 mole) of diphenylamine in 150 ml of tetrahydrofuran (THF) was added dropwise a solution of 20.0 g (0.160 mole) of 3-chloropropionyl chloride in 100 ml of THF. The reaction mixture was stirred mechanically and the temperature maintained between 5° and 15° C. throughout the addition. After the final addition, the solution was filtered to remove solid precipitates, and the filtrate was concentrated under reduced pressure. The residue was partitioned between methylene chloride and water (200 ml each). The methylene chloride layer was washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give an amorphous solid. The solid was recrystallized from THF to yield 20.0 g (48%) of the title compound as a white, crystalline solid, mp 93°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:16]([OH:18])=O)=[N:9][NH:8][C:7]2=[O:23].[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:15]([C:16]([N:29]3[CH2:30][CH2:31][CH:26]([O:25][CH3:24])[CH2:27][CH2:28]3)=[O:18])[CH:19]=[C:20]([F:22])[CH:21]=1)=[N:9][NH:8][C:7]2=[O:23]
Reactant: O=C(O)c1cc(F)cc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Reactant: COC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CCN(C(=O)c2cc(F)cc(Cc3n[nH]c(=O)c4cccc(Cl)c34)c2)CC1
Reaction time: 1 h

Procedure:
3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-5-fluorobenzoic acid (128), 4-methoxypiperidine and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate were dissolved in DMF (10 mL), to this was added DIPEA and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white foam (67.0 mg); 1H NMR (400.132 MHz, CDCl3) δ 1.89-1.40 (4H, m), 3.17-3.06 (1H, m), 3.34 (3H, s), 3.58-3.42 (3H, m), 4.00-3.84 (1H, m), 4.67 (2H, s), 6.97-6.89 (3H, m), 7.67 (1H, t), 7.81 (1H, d), 8.49 (1H, d), 10.29 (1H, s); m/z (LC-MS, ESI+), RT=1.93 (M+H 430).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][CH2:8][CH2:9]2)=[CH:4][NH:3]1.I[CH2:16][CH2:17][CH2:18][CH3:19].[H-].[Na+].Cl>CN(C=O)C>[CH2:16]([N:3]1[C:2](=[O:1])[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][CH2:8][CH2:9]2)=[CH:4]1)[CH2:17][CH2:18][CH3:19]
Reactant: N#Cc1c2c(c[nH]c1=O)C(=O)CCC2
Reactant: CCCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cc2c(c(C#N)c1=O)CCCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
3,8-Dioxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-010) (770 mg, 4.1 mmol) was dissolved in DMF (15 mL) and to the reaction mixture was added 1-iodobutane (0.51 mL, 4.5 mmol) and sodium hydride (60% oil suspension, 180 mg, 4.5 mmol), and the reaction mixture was stirred at room temperature for 3 h. To the reaction mixture was added dilute hydrochloric acid (1 mol/L, 60 mL) and the reaction mixture was extracted with ethyl acetate (150 mL), washed with brine (50 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (toluene/ethyl acetate) to give 2-butyl-3,8-dioxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-011) (610 mg, 61%) as a white crystal.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]2[C:14]([C:27]([F:30])([F:29])[F:28])=[CH:13][C:12](Br)=[CH:11][C:10]=2[S:9]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:84][N:85]1[CH2:90][CH2:89][NH:88][CH2:87][CH2:86]1>>[CH3:84][N:85]1[CH2:90][CH2:89][N:88]([C:12]2[CH:13]=[C:14]([C:27]([F:30])([F:29])[F:28])[C:15]3[N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:17]4[C:8]([S:9][C:10]=3[CH:11]=2)=[CH:7][C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:19][CH:18]=4)[CH2:87][CH2:86]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1c2ccc(N3CCCC3)cc2Sc2cc(Br)cc(C(F)(F)F)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: CN1CCN(c2cc3c(c(C(F)(F)F)c2)N(C(=O)OC(C)(C)C)c2ccc(N4CCCC4)cc2S3)CC1

Procedure:
To a stirred solution of 7-(pyrrolidin-1-yl)-3-bromo-1-trifluoromethyl-10-Boc-phenothiazine (30 mg, 0.058 mmol) in xylenes (5 mL) Pd(dba)2 (1.7 mg, 0.003 mmol), BINAP (1.3 mg, 0.002 mmol), Cs2CO3 (94.5 mg, 0.29 mmol) and 1-methylpiperazine (8.7 mg, 0.01 mL, 0.087 mmol) were added. The mixture was refluxed for 48 h. After that reaction mixture was filtered, solvent was removed under vacuum. Product was used without additional purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([Br:11])=[CH:9][CH:10]=1)=O.[CH:12]1([CH2:15][NH:16][C:17]([NH2:19])=[S:18])[CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(O)C>[Br:11][C:8]1[N:7]=[CH:6][C:5]([C:3]2[N:19]=[C:17]([NH:16][CH2:15][CH:12]3[CH2:14][CH2:13]3)[S:18][CH:2]=2)=[CH:10][CH:9]=1
Reactant: O=C(CBr)c1ccc(Br)nc1
Reactant: NC(=S)NCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2csc(NCC3CC3)n2)cn1
Yield: 61 %

Procedure:
Slurry crude 2-bromo-1-(6-bromo-pyridin-3-yl)-ethanone (11.5 g, ca. 48%), N-cyclopropylmethyl thiourea (2.2 g, 16.9 mmol) and sodium bicarbonate (1.7 g, 20 mmol) in ethanol (100 mL) at room temperature. Stir the mixture at reflux for 1 h under a nitrogen atmosphere. Turn off heat and stir the mixture for an additional 16 h at room temperature. Filter the slurry, then wash the solids with ethanol (50 mL), water (2×50 mL) and hexane (excess). Dry the solid in a vacuum oven for 20 h at 50° C. to obtain the title compound as a tan solid (3.2 g, 61% yield over 2 steps). MS (ES+) m/z: 312 (M+2)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1.[Br:15]Br>C(Cl)Cl.[Fe]>[Br:15][C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1
Reactant: BrBr
Reactant: CC1Cc2cc(S(C)(=O)=O)ccc2O1
Agent: [Fe]
Solvent: ClCCl
Product: CC1Cc2cc(S(C)(=O)=O)cc(Br)c2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.6 %

Procedure:
To a mixture of the title compound from Step 1 (300 mg, 1.42 mmol) in DCM (10 mL) was added Fe (159 mg, 2.84 mmol) and Br2 (454 mg, 2.84 mmol) in one portion under N2. The mixture was stirred at room temperature for 6 h. The reaction mixture was washed with saturated aqueous Na2SO3 (200 mL) and extracted with DCM (30 mL×2). The combined organic layers were washed with brine (20 mL×2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA=3/1) to give the title compound (300 mg, 73%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.90 (d, J=1.6 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 5.20-5.14 (m, 1H), 3.53-3.47 (m, 1H), 3.01-2.95 (m, 1H), 3.04 (s, 3H), 1.56 (d, J=6.4 Hz, 3H). LCMS: 291.0 (M+1)+; 293.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].Cl>O1CCCC1>[OH:1][C:2]1[C:7]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(C)=CCCl
Reactant: CC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 120 h
Yield: 45.4 %

Procedure:
In 750 ml of tetrahydrofuran was dissolved 149.95 g of 2',4'-dihydroxyacetophenone, and 409.26 g of anhydrous potassium carbonate and 150 ml of 1-chloro-3-methyl-2-butene were added to the solution and the mixture was stirred at room temperature in a nitrogen current for 5 days. After the reaction, 3 N hydrochloric acid was added to the reaction liquid under cooling to make the aqueous layer acidic, and the aqueous layer was extracted with ether. The ether extract was washed with water and dried with anhydrous sodium sulfate and the solvent was removed by distillation. Then, 800 ml of hexane was added to the obtained residue and the hexane-soluble substances were removed by decantation to obtain 98.55 g (yield=45.4%) of 2',4'-dihydroxy-3'-(3-methyl-2-butenyl)acetophenone in the form of a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH2:23])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:23][O:34]2)=[CH:18][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.7 %

Procedure:
To a solution of 291 (4.1 g, 12.1 mmol) in dry CHCl3 (60 mL) was added m-CPBA 70% (3.6 g, 14.5 mmol). The reaction mixture was stirred at room temperature for 5 h then additional me CPBA (0.6 g, 2.4 mmol) was added and the stirring continued for 1 h. A further amount of m-CPBA (0.6 g, 2.4 mmol) was added and the reaction mixture was stirred for 16 h. Chloroform and a 10% solution of NaHCO3 were added and the phases were separated. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/Hexane: 1/3) to afford the title compound 292 (2.86 g, 8.07 mmol, 66% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.20 (s, 1H), 7.95 (d, J=8.1 Hz, 2H), 7.86-7.75 (m, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.26-7.10 (m, 3H), 6.84-6.70 (m, 1H), 3.93 (t, J=3.0 Hz, 1H), 3.20 (t, J=5.0 Hz, 1H), 2.80 (dd, J=5.0, 3.0 Hz, 1H), 1.52 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=1[Cl:12]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Nc1c(OC(=O)c2ccc(Cl)cc2Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a 500 mL, round-bottomed, one-necked flask equipped with a magnetic stir bar and a septum was added 2-amino-3-nitrophenol (4.25 g, 27.6 mmol), anhydrous CH2Cl2 (140 mL), 4-(dimethylamino)pyridine (3.37 g, 27.6 mmol) and 2,4-dichlorobenzoyl chloride (5.78 g, 3.87 mL, 27.6 mmol). The reaction mixture was allowed to stir at room temperature overnight. TLC analysis indicated the complete consumption of starting material. The reaction mixture was diluted with CH2Cl2 (300 mL) and the mixture was washed with H2O (2×200 mL), dried (Na2SO4), and concentrated to give 8.91 g (98.7%) of a yellow-orange solid. 1H NMR analysis indicated the material, I-113 was pure enough to carry on to the next step. 1H NMR (500 MHz, CDCl3).