Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)COC1C=CC(SC2C=C(OCCC3CCCCC3)C=C(Br)C=2)=CC=1C)C.C1(C#C)C=CC=CC=1.[CH2:40]([O:42][C:43](=[O:80])[CH2:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([S:52][C:53]2[CH:58]=[C:57]([C:59]#[C:60][C:61]3[CH:66]=[CH:65][C:64](CO)=[CH:63][CH:62]=3)[CH:56]=[C:55]([O:69][CH2:70][CH2:71][C:72]3[CH:77]=[CH:76][C:75](Cl)=[CH:74][CH:73]=3)[CH:54]=2)=[CH:48][C:47]=1[CH3:79])[CH3:41]>>[CH2:40]([O:42][C:43](=[O:80])[CH2:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([S:52][C:53]2[CH:58]=[C:57]([C:59]#[C:60][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH:56]=[C:55]([O:69][CH2:70][CH2:71][CH:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)[CH:54]=2)=[CH:48][C:47]=1[CH3:79])[CH3:41]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCC3CCCCC3)c2)cc1C
Solvent: C#Cc1ccccc1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCCC3CCCCC3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (300 mg; 0.58 mmol), phenylacetylen (181.1 mg; 1.8 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 110 mg (33%). HPLC-MS: m/z: 529.6 (M+H)+; Rt: 3.38 min.
Reaction SMILES: ClCCl.Br[C:5]1[S:9][C:8]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:11])=[CH:7][CH:6]=1.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.O>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:5]1[S:9][C:8]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14][CH:13]2[CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:11])=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)s2)C(COc2cccnc2)C1
Reactant: OB(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccccc3Cl)s2)C(COc2cccnc2)C1
Temperature: 80 °C

Procedure:
[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (7 mg, 0.008 mmol) was added to a mixture of tert-butyl 4-(5-bromothiophene-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (79 mg, 0.16 mmol), 2-chlorobenzeneboronic acid (51 mg, 0.33 mmol) and sodium carbonate (35 mg, 0.33 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), and water (1 mL). The reaction mixture was heated to 80° C. for 2 h. Upon cooling to room temperature, the reaction mixture was filtered, concentrated under reduced pressure, and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 75.9 mg (74%, ˜60% pure) of the TFA salt of the desired product. LC-MS: RT=9.60 min, [M+H]+=514.2.
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>CN(C=O)C.O.CCOC(C)=O>[Cl:15][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=1[O:14][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(Cl)c1
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 50.1 %

Procedure:
KOtBu (1.016 g, 9.05 mmol) was added to a solution of 4-amino-2-chlorophenol (1.00 g, 6.97 mmol) in DMF (35 mL) at RT and stirred 45 min. 2,4-Dichloropyridine (1.340 g, 9.05 mmol) was then added and the reaction was heated at 90° C. overnight. The mixture was cooled to RT, diluted with H2O and EtOAc, the layers separated and the aqueous layer was extracted with EtOAc (3×). The combined organics were washed with H2O (1×), then brine (2×), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (EtOAc/Hex) to afford 3-chloro-4-(2-chloropyridin-4-yloxy)benzenamine (0.89 g, 50%) as a waxy yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.24 (d, J=5.7 Hz, 1 H), 7.02 (d, J=8.7 Hz, 1 H), 6.87-6.82 (m, 2 H), 6.73-6.72 (m, 1 H), 6.58-6.56 (m, 1 H), 5.50 (br s, 2H); MS (ESI) m/z: 254.9 (M+H+); 256.9 (M+2+H+).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1.[Cl-].[NH4+].C([N:37](C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O.CCOC(C)=O>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[S:20][C:19]([N:21]4[CH2:22][CH2:23][CH:24]([C:27]([NH2:37])=[O:28])[CH2:25][CH2:26]4)=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1CCN(c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)C1CCN(c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.5 %

Procedure:
To a solution of 1-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylic acid (15 mg, 0.033 mmol) in N,N-dimethylformamide (0.33 mL) was added ammonium chloride (5.4 mg, 0.10 mmol), diisopropylethylamine (23 μL, 0.13 mmol) and then (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (35 mg, 0.067 mmol). After stirring for 90 minutes at room temperature, the mixture was diluted with EtOAc (30 mL), then washed with 1:1 saturated aqueous sodium bicarbonate:brine (2×30 mL). The aqueous fractions were further extracted with EtOAc (30 mL). The combined organic extracts were dried over sodium sulfate, and concentrated under reduced pressure. Purification by reverse phase HPLC provided 7 mg (0.016 mmol, 47% yield) of 1-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxamide. MS APCI: [M+H]+ m/z 449.1. 1H NMR (400 MHz, DMSO): δ 10.26 (s, 1H); 8.84 (d, J=4.9 Hz, 1H); 8.01 (s, 1H); 7.57-7.49 (m, 2H); 7.35-7.26 (m, 3H); 7.16 (d, J=7.7 Hz, 1H); 6.85 (s, 1H); 3.93 (d, J=12.8 Hz, 2H); 3.14-2.98 (m, 2H); 2.42-2.31 (m, 1H); 1.91-1.69 (m, 2H); 1.69-1.55 (m, 2H). rhSyk=+++.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>ClCCl.O>[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of alpha-bromo-4-tolunitrile (86.6 g) in dichloromethane (1000 mL) is mixed with imidazole (68.0 g). The mixture is stirred at ambient temperature for 15 hours and then diluted with water (1000 mL). Any undissolved solid is removed by filtration and the separated organic solution is then repeatedly washed with water (5×200 mL) to remove excess imidazole, and then dried (MgSO4). The crude product obtained upon evaporation of the solvent can be purified by trituration with cold diethyl ether (200 mL) to obtain 4-(1-imidazolylmethyl)-benzonitrile, m.p. 99°-101°; HCl salt, m.p. 142°-144°.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]([O:7][C:8](=[O:11])[CH2:9]Br)[CH3:6]>CCO>[CH2:5]([O:7][C:8](=[O:11])[CH2:9][NH:4][CH:1]1[CH2:3][CH2:2]1)[CH3:6]
Reactant: NC1CC1
Reactant: CCOC(=O)CBr
Solvent: CCO
Product: CCOC(=O)CNC1CC1
Reaction time: 1 h

Procedure:
To a solution of 10 g (0.18 mol) of cyclopropylamine in 50 ml of EtOH was added 7 g (0.04 mol) of ethylbromoacetate and the reaction stirred for 1 h. The reaction was then evaporated to dryness, redissolved in CH2Cl2 washed with water, dried over sodium sulfate and concentrated to afford 6 g (quant.) of the title compound as a colorless oil. MS: 144.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@@H:5]([C@H:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[OH:8])[OH:6])[CH3:2].BrN1C(=O)CCC1=O.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N>C(O)(=O)C>[O:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[C:7](=[O:8])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(=O)C(=O)OCC
Temperature: 55 °C
Reaction time: 3 h

Procedure:
L-Tartaric acid diethyl ester (10.0 g), acetic acid (100 ml), N-bromosuccinimide (34.5 g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (0.15 g) were mixed, and the reaction solution was stirred at 55° C. for 3 hours. The reaction solution was concentrated under reduced pressure until its volume became 50 ml to afford a solution of diethyl dioxobutanedioate in acetic acid as a yellow liquid.
Reaction SMILES: [CH3:1][N:2]([N:6]=O)[C:3](N)=[O:4].[N+:8](=[CH2:10])=[N-:9].[CH3:11][CH2:12][O:13][CH2:14][CH3:15].[CH2:16](Cl)[CH2:17][CH2:18]C>>[N+:2](=[CH2:1])=[N-:6].[CH3:11][CH2:12][O:13][CH2:14][CH3:15].[N+:8](=[CH:10][C:3](=[O:4])[CH2:16][CH2:17][CH3:18])=[N-:9]
Reactant: CN(N=O)C(N)=O
Reactant: CCCCCl
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCC(=O)C=[N+]=[N-]
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
A 100 ml quantity of diazomethane ether solution (containing 2.8 g of diazomethane) is prepared from 10 g of N-methyl-N-nitrosourea. To the diazomethane ether solution is added dropwise 1.7 g of n-butyl chloride with ice-cooling, and the mixture is thereafter stirred for 30 minutes. Nitrogen gas is passed through the reaction mixture at room temperature to remove the excess of diazomethane therefrom. The ethereal solution is distilled in a vacuum, and the residue is purified by column chromatography (silica gel, developed with chloroform) to give 1.75 g of light yellow oily 1-diazo-2-pentanone (yield 97.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:19]([CH3:20])=[C:15]([C:16]([OH:18])=[O:17])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:26]O.O>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:11]2[C:19]([CH3:20])=[C:15]([C:16]([OH:18])=[O:17])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)=[O:26])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1c(Sc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c(O)c1C(=O)O
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(S(=O)c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c(O)c1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 5-(4-nitrophenylthio)-3-t-butyl-6-methylsalicylic acid (2.0 g.) in acetic acid (200 ml.) is mixed with 30% w/v aqueous hydrogen peroxide solution (11 ml.). The mixture is stirred at room temperature for 6 hours and then added to water (700 ml.). The precipitated solid thus formed is separated by filtration and crystallised from acetic acid to give 5-(4-nitrophenylsulphinyl)-3-t-butyl-6-methylsalicylic acid, m.p. 201°-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:24]=[N:23][CH:22]=[CH:21][C:11]=1[C:12]([NH:14][O:15][CH2:16][C@H:17]([OH:20])[CH2:18][OH:19])=[O:13].CN(C=O)C.C[Si]([C:34]#[CH:35])(C)C.[F-].[Cs+]>CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:34]#[CH:35])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:24]=[N:23][CH:22]=[CH:21][C:11]=1[C:12]([NH:14][O:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[O:13]
Reactant: O=C(NOC[C@H](O)CO)c1ccncc1Nc1ccc(I)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: C#Cc1ccc(Nc2cnccc2C(=O)NOCC(O)CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.43 mmol of 3-[(2-chloro-4-iodophenyl)amino]-N-{[(2R) -2,3-dihydroxypropyl]oxy}isonicotinamide (synthesis described above), 0.02 mmol of dichlorobis(triphenylphosphine)palladium(II), and 0.03 mmol of copper (I) iodide were dissolved and DMF and TEA. 0.93 mmol of trimethylsilylacetylene was added to the stirring solution and the resultant orange mixture was vigorously stirred for 18 h at ambient temperature. The solvent was then removed under reduced pressure and the residue was diluted with EtOAc, washed with water (2×) and saturated brine (2×). The organics were dried over Na2SO4, filtered, and then concentrated under reduced pressure to give a brown solid, which was then dissolved in methanol. 3.10 mmol of CsF was added and the mixture was stirred at ambient temperature. After stirring for 16 h, the solution was concentrated, taken up in EtOAc, and then the organic phase was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (Flashmaster) on silica gel using EtOAc/MeOH (0-100%) to afford the desired product LC/MS [5.29 min; 362 (M+1)]
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:9]=[C:8]([CH3:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:6]=1.[N:19]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C)C=O>[Cl:18][C:13]1[CH:12]=[C:11]([N:7]2[C:8]([CH3:10])=[CH:9][C:5]([O:4][CH2:3][CH2:2][N:22]3[CH2:21][CH2:20][N:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23]3)=[N:6]2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Cc1cc(OCCCl)nn1-c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(CCOc2cc(C)n(-c3ccc(Cl)c(Cl)c3)n2)CC1
Temperature: 85 °C
Yield: 24.8 %

Procedure:
A mixture of 3-(2-chloroethoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole (0.2 g, 0.65 mmol), ethyl piperazine-1-carboxylate (0.113 g, 0.72 mmol), K2CO3 (270 mg, 1.96 mmol) and NaI (98 mg, 0.65 mmol) in dry dimethylformamide (6 ml) was warmed overnight at 85° C., and then an additionally 16 hrs at 95° C., in a dry nitrogen atmosphere. Solvents were evaporated in vacuo and the crude residue partitioned in water/ethyle acetate. The combined organic extracts were washed with water, dried on Na2SO4 and concentrated in vacuo to obtain a crude oil, which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether 8:2) yielding 69 mg of ethyl 4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazine carboxylate as a colourless oil
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:24][C:25]([F:31])([F:30])[S:26](O)(=[O:28])=[O:27]>N1C=CC=CC=1>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:16][CH:15]=2)=[CH:18][CH:19]=1)[S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27]
Reactant: CCCCCCCCCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Product: CCCCCCCCCCc1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 0 °C
Yield: 98.9 %

Procedure:
1.00 g (3.22 mM) of 4-(4-decylphenyl)phenol, 1.6 ml of pyridine were mixed and stirred on a common salt-ice bath. To the mixture, 0.60 ml (3.57 mM) of anhydrous trifluoromethanesulfonic acid was added dropwise and stirred for 18 minutes, followed by further stirring for 70 minutes at room temperature. After the reaction, the reaction mixture was poured into ice water, followed by extraction with isopropyl ether. The isopropyl ether layer was successively washed with a common salt aqueous solution, 12%-HCl and a common salt aqueous solution, followed by drying with anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated into a solid product, whereby 1.41 g of 4-(4-decylphenyl)phenyl triflate (Yield: 98.9%).
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:4]2[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: CSc1ccccc1
Reactant: O=C(O)Cc1ccc(F)cc1
Product: CSc1ccc(C(=O)Cc2ccc(F)cc2)cc1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
Thioanisole (10.1 g, 81.5 mmol) and 4-fluorophenylacetic acid (10.0 g, 65 mmol) were combined in a round bottom 3-neck flask. Polyphosphoric acid (PPA) (160 g), warmed to 60° C., was added and the mixture was heated to 120°-125° C. under nitrogen with vigorous stirring for 20 minutes. Upon cooling to 40° C., ice water and ice were added with vigorous stirring. The temperature was kept below 85° C. during the quench and dissolution of PPA. After cooling to 25° C., the white solids were filtered off, washed with two portions of water and dried. Recrystallization from ethyl acetate-hexane afforded the ketone (10.7 g, 63% mp 139°-140° C. Elemental analysis Calc'd. for C15H13FOS: C, 69.21, H, 5.03, S, 12.32. Found: C, 68.74, H, 5.09, S, 12.15.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH2:16][N:17]([CH3:25])C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)=O)=[N:6][CH:7]=1.[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)[CH2:29][CH3:30]>>[CH3:25][NH:17][CH2:16][CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:5]2[N:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH3:30])=[CH:27][CH:26]=1
Reactant: CCC(=O)c1ccccc1
Reactant: CN(CCOc1ccc(C(=O)c2ccc(O)cn2)cc1)C(=O)OC(C)(C)C
Product: CCC(=C(c1ccc(OCCNC)cc1)c1ccc(O)cn1)c1ccccc1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, tert-butyl 2-(4-(5-hydroxypicolinoyl)phenoxy)ethyl(methyl)carbamate (1.0 eq) was reacted with propiophenone (3.0 eq) to give the desired product (Z/E=1/1). m/z=375[M+1]+.
Reaction SMILES: [NH3:1].CO.[Br:4][C:5]1[C:6]([F:17])=[C:7]2[C:11](=[C:12]([C:14](O)=[O:15])[CH:13]=1)[NH:10][CH:9]=[CH:8]2>C(Cl)Cl>[Br:4][C:5]1[C:6]([F:17])=[C:7]2[C:11](=[C:12]([C:14]([NH2:1])=[O:15])[CH:13]=1)[NH:10][CH:9]=[CH:8]2
Reactant: O=C(O)c1cc(Br)c(F)c2cc[nH]c12
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cc(Br)c(F)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A solution of 2 M NH3/MeOH (0.6 mL, 1.2 mmol) was added to a solution of 5-bromo-4-fluoro-1H-indole-7-carboxylic acid (20 mg, 0.078 mmol) in DCM. The reaction was stirred at room temperature overnight. The mixture was washed with water, and the organic layer was concentrated. The residue was purified by flash chromatography, giving 4 mg (20%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:6](Cl)=[O:7])[C:3](Cl)=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[O:32])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>S1CCCC1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[C:6](=[O:7])[C:2]([CH3:9])([CH3:1])[C:3](=[O:4])[NH:33][C:31]4=[O:32])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Reactant: COc1ccc(N2CCN(c3ccc(NC(N)=O)cc3)CC2)cc1
Solvent: C1CCSC1
Product: COc1ccc(N2CCN(c3ccc(N4C(=O)NC(=O)C(C)(C)C4=O)cc3)CC2)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
2,2-Dimethylmalonyl chloride (0.057 mol) was added to a solution of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]urea (0.057 mol) in tetrahydrothiophene, 1,1-dioxide (200 ml). After stirring for 15 minutes, the reaction mixture was heated to 40° C. for 3 hours and at 50° C. for 2 hours. The reaction mixture was allowed to stand overnight at 25° C. The product was precipitated with diethyl ether and crystallized by trituration. The product was recrystallized from 2-propanol, yielding 20.1 g of 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl)phenyl]-5,5-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione (interm. 16).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23]CC)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.CO.O[Li].O.Cl>O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.2 %

Procedure:
To a solution of ethyl 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetate (1.0 g, 0.02 mol) in 1:1 MeOH:THF (20 mL) was added LiOH.H2O (1.76 g, 0.008 mol). The reaction mixture was then stirred at RT for 16 h and then concentrated in vacuo to obtain the crude product. The crude material was diluted with water and adjusted to pH 4 using 1N HCl. The mixture was then filtered and the residue was dried in vacuo to afford 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetic acid (800 mg, 86%) as a solid.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)=[O:4].[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(#N)C>[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)=[O:4])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1ccc(C(=O)CCl)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: COC(=O)Cc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of methyl 4-chloroacetylphenylacetate (260 mg) in acetonitrile (4 ml) was added dropwise over 15 minutes to a stirred solution of 1-(4-pyridyl)piperazine (375 mg) in acetonitrile (10 ml) and the mixture stirred overnight. The supernatent was decanted from the solid formed, concentrated in vacuo and purified by flash chromatography on neutral alumina, eluting with dichloromethane then 0.25% v/v methanol/dichloromethane and finally 0.5% v/v methanol dichloromethane. Concentration of the fractions in vacuo gave the title compound, 96 mg, as a white crystalline solid: m.p. 127°-129° C.; NMR (d6 DMSO) δ 8.15(2H,d), 7.98(2H,d), 7.41(2H,d), 6.81(2H,d), 3.91(2H,s), 3.78(2H,s), 3.53(3H,s), 3.33(4H,t), 2.64(4H,t); m/e 354(M+H)+ ; calculated for C20H23N3O3 : C, 68.0; H, 6.6; N, 11.9. found: C, 68.2; H, 6.6; N, 11.9%.