Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)CCC.[Cl-].[Li+].C(OCC)(=O)C.O>O1CCOCC1.[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.[Cu]I>[CH3:20][C:19]1[C:14]([C:2]2[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Reactant: O=c1cc(Cl)cn[nH]1
Agent: [Cu]I
Agent: [Pd]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccnc1-c1cn[nH]c(=O)c1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a mixture of 5-chloropyridazin-3(2H)-one (0.135 g, 1 mmol) and 2-(tri-n-butylstannyl)-3-methylpyridine (0.42 g, 1.1 mmol) in anhydrous 1,4-dioxane (2 ml) was added tetrakis(triphenylphosphine)-palladium (0) (0.06 g, 0.051 mmol), copper(I)iodide (20 mg, 0.1 mmol) and lithium chloride (0.13 g, 3.1 mmol) and the mixture was irradiated in a Smith microwave reactor at 160° C. for 15 minutes. The mixture was allowed to cool to room temperature and poured onto a mixture of ethyl acetate/water (10 ml/5 ml). The phases were separated and the aqueous phase was extracted two times more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and adsorbed onto silica gel. Purification by flash chromatography (ethyl acetate) gave 5-(3-methylpyrid-2-yl)pyridazin-3(2H)-one (0.13 g, 69%) as a yellow solid which was suspended in phosphorous oxychloride (5 ml, 54 mmol) and the mixture was heated at 100° C. for 1 hour. After cooling to room temperature the homogeneous dark solution was evaporated under reduced pressure and repartitioned between chloroform and water (50 ml each). The pH was adjusted to 8 by portionwise addition of saturated aqueous sodium carbonate solution and the phases were separated. After two further extractions the combined organic extracts were washed with water and brine and dried over sodium sulfate. After filtration the compound was adsorbed onto silica gel and purified by flash column (50% ethyl acetate-iso-hexane) to yield the title compound (0.38 g, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[H-].[Na+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.CO>CN(C)C=O>[CH:25]1([CH2:24][N:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:20])[C:5]([C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][CH:10]=3)=[N:6]2)[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cn(CC2CC2)nc(-c2ccnn2-c2ccccc2)c1=O

Procedure:
Under an argon atmosphere, to a solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (2.0 g) in dimethylformamide (40 mL) was added 60% sodium hydride (596 mg) with stirring under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hr. Then, (bromomethyl)cyclopropane (1.085 mL) was added, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added methanol, and the mixture was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and crystallized from methanol/ethyl acetate to give the title compound (2.12 g) as white prisms.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C@@:7]2([CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:22]([O:24]C)=[O:23])[CH:19]=3)[CH2:14]2)[C:6]1=[O:26])(C)(C)C.[OH-].[Na+].Cl>CS(O)(=O)=O.O>[O:26]=[C:6]1[NH:5][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C@:7]21[CH2:21][C:20]1[C:15](=[CH:16][CH:17]=[C:18]([C:22]([OH:24])=[O:23])[CH:19]=1)[CH2:14]2
Reactant: COC(=O)c1ccc2c(c1)C[C@@]1(C2)C(=O)N(C(C)(C)C)c2ncccc21
Agent: CS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of (R)-methyl 1′-tert-butyl-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylate (53 g, 151 mmol) in methanesulfonic acid (196 mL) was heated at 90° C. for 1 h. Water (100 mL) was added and the solution was stirred for an additional 3 h at 90° C. The acidic mixture was cooled to 0° C., diluted with water (1 L), and basified to pH 14 with 50% aqueous NaOH solution. The basic mixture was then acidified to pH 3 by careful addition of concentrated aqueous HCl solution. The solids were collected by filtration and dried under nitrogen atmosphere to give the title compound which was used without further purification. MS: m/z=281.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22]O)[CH:7]=1)[CH3:2].P(Br)(Br)[Br:26]>COCCOC>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][Br:26])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CO)c1
Reactant: BrP(Br)Br
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To [3-(4-chloro-2-hydroxymethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.9 g 2.6 mmol) in DME was added phosphorus tribromide (0.37 mL, 3.9 mmol), and the reaction was stirred for 3 hours at room temperature. The mixture was worked-up to give the title compound.
Reaction SMILES: C(OC([N:11]1[CH2:17][C@H:16]([OH:18])[C@@H:15]([NH:19][C:20](=[O:34])[C@@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C@H:12]1[CH3:35])=O)C1C=CC=CC=1.CO.[H][H]>CCOC(C)=O.[Pd]>[C:30]([O:29][C:27](=[O:28])[NH:26][C@H:21]([C:20](=[O:34])[NH:19][C@H:15]1[CH2:14][CH2:13][C@@H:12]([CH3:35])[NH:11][CH2:17][C@@H:16]1[OH:18])[CH2:22][CH:23]([CH3:25])[CH3:24])([CH3:32])([CH3:33])[CH3:31]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)NC[C@@H]1O
Reaction time: 8 h

Procedure:
(2R,5S,6S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (0.169 g, 0.344 mmol) was dissovled in EtOAc (3 ml), MeOH (1 ml). Then 10% Pd/C (0.183 g, 0.172 mmol) was added and the reaction was stirred overnight under a balloon filled with hydrogen gas. The reaction mixture was filtered through Celite, concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (0.126 g): Electrospray mass spec: M+H+=358.11.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1.Cl[CH2:29][C:30]1[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=1.C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+].[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:29][C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=4)=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][C:19]([CH3:24])([CH3:25])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reactant: CC(C)c1csc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1c(C)c2cc(OCc3nc(C(C)C)cs3)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A solution of methyl 3-[1-(4-chlorobenzyl)-3-methyl-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (Preparation 1) (50 mg), 2-chloromethyl-4-prop-2-ylthiazole (30 mg), K2CO3 (60 mg), and Cs2CO3 (10 mg) in 2 mL DMF was stirred at room temperature under nitrogen for 24 hours. The mixture was poured onto sat.'d NH4Cl solution, extracted 2× Et2O, washed 2× brine, dried (MgSO4), and evaporated. The residue was chromatographed on silica gel (hexane/EtOAc 4:1) to give the title compound.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:17]([Mg]Br)[CH3:18].[Mg].C(Br)C.[Cl-].[NH4+]>CCOCC>[CH2:17]([C:6]1([OH:16])[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[CH:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH3:18]
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Product: CCC1(O)c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5H-dibenzo[a,d]cyclohepten-5-one (15.5 g., 0.075 mole) is added in portion to a solution of ethyl-magnesium bromide, prepared from 3.64 g. (0.15 mole) of magnesium and 16.4 g. of ethyl bromide in ether. After stirring for one hour at room temperature, the mixture is heated to refluxing for 15 minutes, then cooled, and the Grignard adduct is hydrolyzed by cautiously adding ammonium chloride solution. The crude 5-ethyl-5-hydroxy-5H-dibenzo[a,d]cycloheptene is recovered from the ether layer in a yield of 16.78 g. (95%), m.p., 63°-65° (clearing at 70° C.). After recrystallization from petroleum ether, hexane and finally isopropyl alcohol, an analytical sample melted at 63°-65° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([CH3:28])[NH2:27])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16].CO.[BH4-].[Na+]>C1C=CC=CC=1>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH:27][CH2:11][CH:9]([OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)[CH3:28])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-trifluoromethylphenyl glyoxal (2.1 g) and 2-(4-carbomethoxyphenyl)-1-methylethanamine (2.0 g) in benzene (150 ml) was refluxed under Dean & Stark conditions for 2 hours. The solvent was replaced with methanol (150 ml), the mixture was cooled in ice and sodium borohydride (4.0 g) was added portionwise. The mixture was stirred at ambient temperature for 3 hours, the solvent was evaporated and the residue was partitioned between water (100 ml) and chloroform (100 ml). The aqueous phase was further extracted with chloroform (100 ml), the combined organic extracts were dried (Mg SO4) and evaporated to an oil which was crystallised from hexane to give the title compound, m.p. 80°-83° as a 25:75 mixture of diastereoisomers. (25% RR,SS:75% RS,SR). τ(CDCl3) 8.95 (3H,d,J=6 Hz) 6.6-7.6 (5H,m), 6.13 (3H,s), 5.3 (1H,m) 2.72 (2H,d,J= 8 Hz), 2.1-2.5 (4H,m), 1.92 (2H,d,J=8 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:43])[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])[CH2:24][CH2:23]3)=[C:18]([NH:35][C:36]([C:38]3[O:39][CH:40]=[CH:41][CH:42]=3)=[O:37])[CH:17]=2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.[CH2:54]([N:56]=[C:57]=[O:58])[CH3:55]>CO.N1C=CC=CC=1>[CH2:54]([NH:56][C:57]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:43])[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])[CH2:26][CH2:27]3)=[C:18]([NH:35][C:36]([C:38]3[O:39][CH:40]=[CH:41][CH:42]=3)=[O:37])[CH:17]=2)[CH2:9]1)=[O:58])[CH3:55]
Reactant: CCN=C=O
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2NC(=O)c2ccco2)CC1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N1CCC[C@@H](NC(=O)c2ccc(N3CCN(c4ccccc4C)CC3)c(NC(=O)c3ccco3)c2)C1
Temperature: 45 °C
Reaction time: 6 h
Yield: 17.5 %

Procedure:
(R)-3-[3-[(Furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.204 mmol) was stirred with a mixture of DCM (1.0 mL) and TFA (1.0 mL) for 4 h. LC-MS indicated the completion of deprotection. The mixture was concentrated and dissolved in pyridine (5.0 mL). EtNCO (29 mg, 0.41 mmol) was added and the reaction mixture was stirred at 45° C. for 6 h. Pyridine was rotavaped out and the crude was dissolved in methanol and purified on preparatory HPLC using water/methanol as eluent to give desired product (0.02 g, 18%).
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[CH3:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl>[CH3:8][N:9]([CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(=O)Cl
Reactant: CNCc1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)N(C)Cc1ccncc1
Yield: 28.2 %

Procedure:
A solution of methyl chlorooxoacetate (2.01 g, 16.37 mmol), N-methyl-N-(4-pyridinylmethyl)amine (2.0 g, 16.37 mmol) and pyridine (1.6 mL, 19.64 mmol) in anhydrous dichloromethane (10 mL) was stirred at 50° C. for 2 h. The mixture was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (40%-100% EtOAc in hexanes) to afford methyl 2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoacetate (77) as a pale yellow oil (0.96 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1>[Cl:11][C:9]1[C:10]2[C:2]([CH:20]=[O:21])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CN(C)C=O
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.33 g, 10.0 mmol, 1.0 eq) in anhydrous THF (100 mL) at −78° C. under argon, n-BuLi solution (2.5 M in THF, 8.8 mL, 22.0 mmol, 2.2 eq) was added dropwise (over 10 min). The resulting mixture was stirred at −78° C. for 1 h and then DMF (2.0 g, 11.0 mmol, 1.1 eq) was added dropwise (over 10 min). The mixture was stirred at −78° C. for an additional 30 min and then stirred at RT overnight. The reaction mixture was quenched with H2O (50 mL) and then concentrated in vacuo. The residue was triturated with saturated aqueous NH4Cl solution. The solid was collected by filtration, rinsed with ethyl acetate, and dried in vacuo to afford 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (1.17 g, 65% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.C(#N)C>[Pt].CO>[N:15]1([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: C1CCNCC1
Agent: [Pt]
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(N2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.9 %

Procedure:
A mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (1.05 g, 5.00 mmol), piperidine (0.592 ml, 6.00 mmol), diisopropylethylamine (1.31 ml, 7.50 mmol) and acetonitrile (10 ml) was refluxed for 8 hours. Methanol (10 ml) and 10% platinum on activated carbon (0.10 g) were added to the residue obtained by evaporation of the solvent of the reaction mixture under reduced pressure, and the mixture was stirred at room temperature for 12 hours under hydrogen atmosphere. The reaction mixture was filtered through celite. The residue obtained by concentration of the filtrate under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (1.11 g, 91%) as a colorless liquid.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=[O:2].S(Cl)(Cl)=O.[C:26]1(C)C=CC=CC=1>>[CH3:26][O:2][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:8]=1)[CH3:5])=[O:3]
Reactant: Cc1ccccc1
Reactant: CC(Oc1ncn(-c2cccc(C(F)(F)F)c2)n1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)Oc1ncn(-c2cccc(C(F)(F)F)c2)n1

Procedure:
A 2.5 g portion of the compound of Example 24 was added to 50 ml of toluene, and 3 ml of thionyl chloride was added to the mixture. It was heated under reflux for 2 hours, and was then cooled and evaporated under vacuum. Fifty ml of toluene was added to the residue and was removed under vacuum, and the residue was then taken up in methanol and heated under reflux for 3 hours. The solvent was then removed under vacuum, and the residue was recrystallized from methanol to obtain 2.0 g of the desired product, m.p. 135°-137°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[F:43])[CH:38]=[O:39].[Cl-].[NH4+]>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C(Cl)Cl>[F:34][C:35]1[CH:36]=[C:37]([C:38](=[O:39])[CH:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:40]=[CH:41][C:42]=1[F:43]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)C(NC(=O)OC(C)(C)C)c2ccc(F)cc2)cc1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(F)c(F)c1)c1ccc(F)cc1
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
30.0 g (79 mmol) of tert-butyl [(4-fluorophenyl)(toluene-4-sulfonyl)methyl]carbamate, 5.9 g (23 mmol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, 164 ml (1.2 mol) of triethylamine and 11.2 g (79 mmol) of 3,4-difluorobenzaldehyde were mixed in 700 ml of methylene chloride at room temperature and then heated at 35° C. for 6 h. After reaction of the aldehyde was complete, saturated ammonium chloride solution was added, and the reaction mixture was stirred for 15 minutes. After removal of the aqueous phase, the organic phase was washed with 0.5 M sodium hydroxide solution and saturated sodium chloride solution to result in 29.0 g of tert-butyl [2-(3,4-difluorophenyl)-1-(4-fluorophenyl)-2-oxoethyl]carbamate, which was reacted further without purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:6][C:7]=1[C:13]([F:16])([F:14])[F:15])#[N:10]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C(F)(F)F
Product: COC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized in a manner similar to step B of example 1 using 4-[(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and methyl bromoacetate: 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.8 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.88 (dd, J=8.8, 2.6 Hz, 1H), 4.24 (s, 2H), 4.06 (q, J=8.5 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:29]=1)[CH:25]=O>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:29]=1)[CH2:25][N:1]1[CH:2]([C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: O=Cc1cc(Cl)cc(-c2ccccn2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cc(Cl)cc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-chloro-5-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.76 min.; [M+H]+: 437.09 g/mol.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[OH-].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:11]1[C:12]2[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: BrCCCCCCBr
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Sc1ccccc1N2CCCCCCN1c2ccccc2Sc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of phenothiazine (0.15 mol), 0.1 mol of 1,6-dibromohexane, 0.15 mol of potassium hydroxide and 1% w/w of tetra-n-butyl ammonium hydrogen sulfate in 300 ml of dry toluene was stirred and refluxed for 48 hours. The reaction mixture was cooled to room temperature, filtered, and washed thoroughly with water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The crude product was purified by column chromatography using a mixture of ethyl acetate and hexane in a volume ratio of 1:6 as eluent. The yield of 1,6-di(10H-10-phenothiazinyl)hexane was 85%. The 1H-NMR spectrum of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 1.35-1.50(m, 4H), 1.55-1.90(m, 4H), 3.82(t, 4H), and 6.73-7.19(m, 16H).
Reaction SMILES: [F:1][C:2]([F:28])([C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH2:3][CH2:4][CH:5]([CH2:11]CCCCC=C)[C:6]([O:8]CC)=[O:7].C(OCC)(=O)CC(OCC)=O.ICCCCCC=C.ICCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F.[CH2:64]([C:66]1([C:103]2[CH:108]=[CH:107][C:106]([OH:109])=[CH:105][CH:104]=2)[CH:75]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82]CCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:74]2[C:69](=[CH:70][C:71]([OH:102])=[CH:72][CH:73]=2)[O:68][CH2:67]1)[CH3:65]>>[CH2:64]([C:66]1([C:103]2[CH:104]=[CH:105][C:106]([OH:109])=[CH:107][CH:108]=2)[CH:75]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:11][CH:5]([CH2:4][CH2:3][C:2]([F:1])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:22])([F:21])[F:23])[C:6]([OH:8])=[O:7])[C:74]2[C:69](=[CH:70][C:71]([OH:102])=[CH:72][CH:73]=2)[O:68][CH2:67]1)[CH3:65]
Reactant: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Agent: C=CCCCCCI
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Solvent: CCOC(=O)CC(=O)OCC
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared from diethyl malonate, 7-iodo-1-heptene and 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane as in Example 9 and the allyl compound prepared in Example 21, the same procedure as shown in Example 21 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid.