Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[C:2]#[CH:3].C([N-]C(C)C)(C)C.[Li+].C([O-])(=O)C#C.[Li+].[C:24]([O:28][C:29]([N:31]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@@H:32]([CH2:40][CH2:41][CH:42]=[O:43])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:47]([O:46][C:44]([N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[C@H:32]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:40][CH2:41][CH:42]([OH:43])[C:3]#[C:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: C#CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@H](CCC=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: C#CC(=O)[O-]
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C#CC(O)CC[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.4 %

Procedure:
To a solution of tert-butyl propiolate (42.7 mg, 0.34 mmol) in a dry THF (1.5 mL) was slowly added lithium diisopropylamide (2.0 M in THF/ethyl benzene, 0.15 mL, 0.29 mmol) at −78° C. under nitrogen atmosphere. The resulting reaction mixture was continued stirring at the same temperature for 1.0 hour (to generate lithium propiolate anion), then slowly added (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (0.075 g, 0.193 mmol) in 1.0 mL THF solution. The mixture was stirred at the same temperature for 90 minutes (until finished by TLC). Then, the reaction was quenched with saturated aqueous NH4Cl (0.5 mL) solution and warmed to room temperature by removing the external acetone/dry ice bath. The reaction solution was diluted with ethyl acetate (20 mL) and an aqueous saturated solution of NH4Cl (15 mL) was added with stirring. The aqueous phase was extracted with ethyl acetate (50 mL) and the combined organic layers dried and concentrated under reduced pressure. The resulting residue was purified on 12 g silica gel column (eluent, hexanes to 40% ethyl acetate in hexanes) to afford (7S)-di-tert-butyl 7-(bis(tert-butoxycarbonyl)amino)-4-hydroxyoct-2-ynedioate (diastereomeric mixture, 40 mg, 40.3% yield) as an oil. 1H NMR (CDCl3) δ ppm: 4.76 (dt, J=9.2, 5.2 Hz, 1H), 4.53 (m, 1H), 2.27 (m, 1H), 2.04 (m, 1H), 1.83 (m, 2H), 1.52 (s, 18H), 1.50 (s, 9H), 1.46 (s, 9H). 13C NMR (CDCl3) δ ppm: 169.63, 169.52, 152.47, 152.40, 152.34, 84.96, 84.94, 83.63, 83.09, 83.04, 81.48, 81.46, 77.89, 77.84, 61.90, 61.37, 58.47, 58.31, 33.75, 33.70, 28.02, 27.96, 27.93, 25.13 and 24.72. MS (ESI+): 536 (M+Na)+.
Reaction SMILES: [C:1]1([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[I:32]I.Cl>C1COCC1.CCCCCC>[I:32][C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[C:1]([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[CH:2][CH:3]=1
Reactant: c1ccc2c(c1)oc1cccc(-c3cccc4oc5ccccc5c34)c12
Reactant: II
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Ic1ccc(-c2cccc3oc4ccccc4c23)c2c1oc1ccccc12
Temperature: -80 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
Into a 200-mL three-neck flask was put 3.0 g (9.0 mmol) of 4,4′-bidibenzofuran, and the air in the flask was replaced with nitrogen. To this flask was added 45 mL of THF to dissolve 4,4′-bidibenzofuran, and the mixture was cooled down to −80° C. Then, 5.6 mL (9.0 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped into this solution with a syringe. After that, the mixture solution was stirred for 2 hours while its temperature was increased to room temperature. After the stirring, this solution was cooled down to −80° C. Then, a solution in which 2.5 g (10 mmol) of iodine had been dissolved in 20 mL of THF was dripped into this solution with a dripping funnel, and the mixture was stirred for 18 hours while its temperature was returned to room temperature. After the stirring, approximately 10 mL of dilute hydrochloric acid (1.0 mol/L) was added to this solution, and the mixture was stirred for 2 hours. After the stirring, an aqueous layer of the mixture was extracted with ethyl acetate, and the extracted solution and an organic layer of the mixture were combined and washed with a saturated solution of sodium hydrogen carbonate and saturated brine. The organic layer was dried with magnesium sulfate and gravity-filtered. The obtained filtrate was concentrated to give a light brown solid. The obtained solid was purified by HPLC and washed with toluene to give 2.2 g of white powder, which was an objective substance, in 53% yield. Synthesis Scheme (c-2) of Step 2 is shown below.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([O:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7]2.[CH:19]([C:21]1[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[CH2:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCCCCC.CCOC(C)=O>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]1([CH3:27])[CH:24]=[CH:25][CH:26]=[C:21]([CH:19]=[CH:20][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]([O:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7]3)[CH:22]=1
Reactant: C=Cc1cccc(C)c1
Reactant: O=C(ON1CCc2c(Br)cccc2C1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cccc(C=Cc2cccc3c2CCN(OC(=O)C(F)(F)F)C3)c1

Procedure:
A solution of 5-bromo-2-trifluoroacetoxy-1,2,3,4-tetrahydroisoquinoline (616 mg, 2 mmol), 3-vinyltoluene (330 mg, 2.5 mmol), tri-o-tolylphosphine (50 mg) and palladium acetate (20 mg) in triethylamine (1 mL) were heated in a pressure bomb at 100° C. for 8 h. Column chromatography of the dark mixture (silica gel; hexane/EtOAc 40:1 then 20:1) afforded the title compound. FAB ms (m+1) 346.18
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[C:20]([CH:32]([F:34])[F:33])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:32]([F:34])[F:33])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(OCc3ccccc3)c(C(F)F)c2)COC(C)(C)OC1
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(CCc2ccc(O)c(C(F)F)c2)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 89.4 %

Procedure:
Compound 30-3 (11.1 g) was dissolved in 1,4-dioxane (250 ml), 10% palladium carbon (3.5 g) was added, and the mixture was stirred at room temperature for 3.5 hr under a hydrogen atmosphere. The inside of the reaction container was displaced with nitrogen, the solution was filtrated, and the filtrate was concentrated. The residue was suspended in a mixed solution of diisopropyl ether and hexane, and collected by filtration to give the object product (8.17 g) as a white powder.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:37]2[CH2:36][CH2:35][N:34]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=3)[CH2:39][CH2:38]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Product: CCc1cc(NC(=O)N2CCN(c3cc(OC)c(OC)c(OC)c3)CC2)c(OC)nc1C
Yield: 52 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:21]>>[ClH:21].[CH3:20][S:17]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[CH:16][CH:15]=1)(=[O:19])=[O:18]
Reactant: CC(=O)N1CCC(Cc2ccc(S(C)(=O)=O)cc2)CC1
Agent: Cl
Product: CS(=O)(=O)c1ccc(CC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-acetyl-4-[4-(methylsulfonyl)benzyl]-piperidine (8.76 g) and concentrated hydrochloric acid (100 mL) was stirred for 4 hours under reflux with heat. The reaction mixture was concentrated under reduced pressure. 2-Propanol (100 mL) was added thereto and the mixture was concentrated under reduced pressure. To the residue was added 2-propanol (50 mL), and the mixture was stirred under reflux with heat for 30 minutes and cooled down to room temperature. The precipitate was filtered off, washed with 2-propanol (50 mL) and dried under reduced pressure to give the title compound as a white solid (7.51 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[NH2:31][CH2:32][CH2:33][OH:34]>>[Cl:27][C:26]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:31][CH2:32][CH2:33][OH:34])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: NCCO
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCNCCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 2-aminoethanol following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 8.70 (s, 2H), 7.86 (d, 1H), 7.01 (d, 1H), 4.70 (s, 1H), 4.52 (br, 1H), 3.95 (t, 2H), 3.89 (s, 3H), 3.43 (t, 2H), 2.58 (t, 2H), 2.53 (m, 2H), 1.74 (m, 2H), 1.48-1.28 (m, 6H) [NH's not seen]; MS (ESI): 495.3.
Reaction SMILES: [CH3:1][S:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13]([OH:15])=[O:14].[CH:20]1[CH:25]=CC=C[CH:21]=1.C(Cl)(=O)C(Cl)=O.C(=O)(O)[O-].[Na+]>CCOCC.C(O)(C)C>[CH3:1][S:2][C:3]([CH3:18])([CH3:19])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13]([O:15][CH:20]([CH3:25])[CH3:21])=[O:14]
Reactant: CSC(C)(C)CCCC(C)CC=CC(C)=CC(=O)O
Reactant: c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: CSC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C
Reaction time: 2 h

Procedure:
To 0.6 g. of 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoic acid in 10 ml. of dry benzene is added 0.23 ml. of oxalyl chloride at room temperature with stirring. After 2 hours, isopropanol (2ml.) is added and the mixture allowed to stand at room temperature for about 2 hours. Ether and saturated sodium bicarbonate is added and the organic phase separated. The organic phase is washed with aqueous sodium bicarbonate, saturated sodium chloride, dried over calcium sulfate and evaporated to yield isopropyl 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:10][C:11]([C@@H:13]1[CH2:15][C@@H:14]1[C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.B(Br)(Br)Br>ClCCl>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([C@H:14]2[CH2:15][C@H:13]2[C:11]([NH:10][CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][OH:1])=[O:12])=[CH:21][CH:20]=1
Reactant: COc1ccc([C@H]2C[C@H]2C(=O)NC(CO)c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NC(CO)c1ccccc1)[C@@H]1C[C@@H]1c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.8 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with 100 mL of dichloromethane. To the stirred solvent was added (1R,2S)—N-(2-hydroxy-1-phenylethyl)-2-(4-methoxyphenyl)cyclopropanecarboxamide (1.9 g, 6 mmol). The reaction mixture was brought to 0° C. and boron tribromide (0.86 mL, 9 mmol) was added drop wise. The reaction mixture was allowed to stir at room temperature for 45 minutes. The reaction mixture was quenched with ethanol (5 mL), the reaction mixture was concentrated to distill off the solvent; water (25 mL) was added and extracted with ethyl acetate (25 mL). The organic layer was washed with saturated NaHCO3 solution (10 mL) and brine solution (10 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as white solid (0.55 g, yield: 58.7%). 1H NMR (300 MHz, DMSO-d6): δ 9.20 (s, 1H), 8.47-8.50 (d, 1H), 7.21-7.30 (m, 5H), 6.88-6.91 (d, 2H), 6.63-6.66 (d, 2H), 4.86-4.90 (t, 2H), 3.52-3.56 (t, 2H), 2.05-2.11 (m, 1H), 1.87-1.93 (m, 1H), 1.24-1.29 (m, 1H), 1.04-1.10 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)=[CH:3][C:2]([C:33]2[CH:34]=[C:29]([Cl:28])[C:30]([OH:45])=[C:31]([Cl:44])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Product: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 72.2 %

Procedure:
Following general procedure F, (6-bromo-4-{4-[(dimethylamino)methyl]phenylamino}quinolin-3-yl)(cyclopropyl)methanone (44 mg, 0.104 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (45 mg, 0.156 mmol) to afford the desired product (38 mg, 73%) as a yellow solid: 1H NMR (300 MHz, CD3OD+Acetic Acid-d4) δ 9.26 (s, 1H), 7.99 (d, J=10.0 Hz, 2H), 7.94 (s, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.29 (s, J=9.9 Hz, 3H), 7.25 (s, 1H), 4.32 (s, 2H), 2.94-2.85 (m, 1H), 2.82 (s, 6H), 1.17-1.01 (m, 4H); ESI MS m/z 506 [C28H25Cl2N3O2+H]+; HPLC 94.4% (AUC), tR=11.19 min.
Reaction SMILES: [CH3:1][CH:2](C(O)=O)C(O)=O.O1C=CCCC1.S(=O)(=O)(O)O.[OH-].[Na+].[N:22]1[O:23][C:24]([C:31]([OH:33])=O)=[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12.S(Cl)(Cl)=O>C1C=CC=CC=1.O.C(O)(=O)C>[C:31]([C:24]1[O:23][N:22]=[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=12)(=[O:33])[CH2:1][CH3:2]
Reactant: O=C(O)c1onc2ccccc12
Reactant: CC(C(=O)O)C(=O)O
Agent: C1=COCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CCC(=O)c1onc2ccccc12
Reaction time: 1 h

Procedure:
Added to 75 ml of dry benzene were 5.3 g (45 mmol) of methylmalonic acid and 11.4 g (0,135 mmol) of 3,4-dihydropyran, followed by the addition of 1 droplet of concentrated sulfuric acid under stirring over a water bath. After one hour, 6 g of sodium hydroxide were added. After the resultant mixture was stirred for 5 minutes, an insoluble material was filtered off. Then, 1.8.g of 60% sodium hydride was added in small portions to the filtrate. After evolution of hydrogen gas subsided, a solution of the acid chloride, which had been prepared from 6.5 g (0.04 mol) of 2,1-benzisoxazole-3-carboxylic acid prepared above in the procedure (1) and 30 ml of thionyl chloride in benzene, was added dropwise under ice cooling. After the resultant solution was stirred for 2 hours at room temperature, 6 ml of acetic acid were added, followed by heating under reflux for 8 hours. After ice cooling, water was added and the reaction product was extracted with ethyl acetate. The extract was purified by silica gel chromatography (eluent: 30:1 n-hexane/ethyl acetate), so that 3-propionyl-2,1-benzisoxazole was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1C(O)=C(NC(=O)C2C=C(OC)C=C(OC)C=2)C=C(Cl)C=1C.Cl.Cl.[CH2:26]([N:28]([CH2:37][CH3:38])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[C:31]([CH3:36])N=1)[CH3:27].C(N(CC)CC)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O.CO>[CH3:27][CH2:26][N:28]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[C:31]([CH3:2])[CH:36]=1)[CH2:37][CH3:38]
Reactant: COc1cc(OC)cc(C(=O)Nc2cc(Cl)c(C)c(Cl)c2O)c1
Reactant: CCN(CC)c1ccc(N)c(C)n1
Agent: Cl
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(CC)c1ccc(N)c(C)c1
Temperature: 5 °C

Procedure:
Into a 250 ml erlenmeyer flask was placed 4 g (11.4 mmoles) of N-(3,5-dichloro-2-hydroxy-4-methylphenyl)-3,5-dimethoxybenzamide, 3.15 g (12.5 mmoles) N2,N2-diethyl-6-methyl-2,5-pyridinediamine dihydrochloride and 100 ml of methanol. A suspension resulted. To this suspension was added 7.84 g (77.5 mmoles) of triethylamine. The suspension became a solution. The reaction flask was cooled via an ice/water bath to about 5° C. While the reaction mixture was cooling, 5.7 g (25 mmoles) of ammonium persulfate was dissolved in 12 mL of water. This solution was added dropwise to the reaction vessel. The mixture got so thick during the addition that an additional 100 ml of methanol needed to be added. After complete addition of the ammonium persulfate, the mixture was stirred at 5° C. for 2½ hours. The solid was collected on a medium sintered glass funnel, rinsed with methanol then 2 times with 45° C. water and finally ligroin and then air dried by sucking air through the funnel overnight. 5.2 g of desired product was collected. The collected product was returned to a 125 ml erlenmeyer flask 75 ml of ethanol was added. The mixture was heated to reflux on a hot plate for 5 minutes and allowed to cool to 45° C. A solid was then collected on a medium sintered glass funnel and dried by sucking air through the funnel overnight. The yield was 4.8 g (85% purified yield) of desired dye, with an absorbance maximum of 630 nm, and an extinction coefficient of 24,565.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[OH:21][C@H:22]1[CH2:26][CH2:25][NH:24][C:23]1=[O:27].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].[Al]>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]>[OH:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([CH:9]4[CH2:12][CH:11]([N:13]5[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[C:23]1=[O:27]
Reactant: O=C1NCC[C@@H]1O
Reactant: Brc1ccc2nc([C@H]3C[C@H](N4CCCCC4)C3)sc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=C1[C@@H](O)CCN1c1ccc2nc(C3CC(N4CCCCC4)C3)sc2c1
Temperature: 150 °C
Yield: 40.4 %

Procedure:
To a microwave vial equipped with magnetic stir bar, 50 mg (0.14 mmol) of 6-bromo-2-[trans-3-(1-piperidinyl)cyclobutyl]benzothiazole (prepared as described in Cowart, et al. Benzothiazole cyclobutylamine derivatives, US Patent Publication No. 2007/0066588(A1)) was added, followed by (S)-3-hydroxypyrrolidin-2-one (50 mg, 0.50 mmol), Pd2(dba)3 (4.0 mg, 0.0044 mmol), xantphos (6.9 mg, 0.012 mmol) and Cs2CO3 (68 mg, 0.21 mmol). The reaction vial was sealed with an aluminum cap, and purged with N2, then dioxane (2 mL) was introduced via a syringe. The reaction mixture was then heated in a microwave oven at 150° C. for 60 minutes. The reaction mixture was cooled to room temperature, filtered, and the solvent was removed under vacuum, after which the residue was purified via chromatography on silica gel, eluting with a gradient of 0-10% methanol in dichloromethane, to give the desired product (21 mg, 40%). 1H NMR (300 MHz) δ 8.34 (d, J=2.2, 1H), 7.97 (d, J=8.9, 1H), 7.61 (dd, J=2.2, 8.9, 1H), 4.51 (dd, J=8.2, 9.7, 1H), 3.86 (m, 3H), 3.13 (m, 1H), 2.66 (m, 1H), 2.58 (m, 4H), 2.32 (m, 3H), 2.15 (ddd, J=9.5, 12.6, 19.1, 1H), 1.61 (m, 6H), 1.48 (m, 2H). MS (ESI) m/z=372.0 (M+H)+
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:26]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine6-carboximidate and 2-trifluoromethylbenzoyl chloride, there is obtained ethyl N-(o-trifluoromethylbenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m,p. 122°-125° C.;
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:51][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][CH:48]=1)[CH2:44][NH:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:54])[CH2:24][O:23][C:22]3[CH:55]=[CH:56][C:19]([OH:18])=[CH:20][CH:21]=3)=[CH:53][CH:52]=2)[CH2:40][CH2:39]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4cccc(F)c4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1cccc(F)c1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 66.7 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(3-fluorobenzyl)-1-piperidinecarboxamide (0.174 g, 0.225 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.085 g, 0.15 mmol).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
(S)-Tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10 g, 53.4 mmol) was dissolved in 1-fluoro-4-nitrobenzene (13.94 g, 99 mmol). An aqueous solution of 5.9N potassium hydroxide (77 ml, 452 mmol) was added followed by addition of tetrabutylammonium bromide (2.238 g, 6.94 mmol). The reaction mixture was stirred at 40° C. for 24 hours and then cooled, diluted with water and extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered and concentrated to give the title compound.