Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:20][C@@H:21]1[O:26][C@H:25]([CH3:27])[CH2:24][NH:23][CH2:22]1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([C:7]([N:23]2[CH2:22][C@@H:21]([CH3:20])[O:26][C@@H:25]([CH3:27])[CH2:24]2)=[O:9])[S:5][CH:6]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=C(O)c1nc(Br)cs1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)c2nc(Br)cs2)C[C@H](C)O1
Temperature: 0 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
To a solution of 4-bromothiazole-2-carboxylic acid (prepared according to the procedure given in WO200857336, 1.35 g, 6.49 mmol) in DMF (15 ml) was added HOBT (1.09 g, 7.14 mmol) at room temperature followed by the addition of (2S,6R)-2,6-dimethylmorpholine (0.75 g, 0.8 ml, 6.49 mmol). The reaction mixture was cooled to 0° C. and to this were added EDC (1.86 gm., 9.73 mmol) and triethylamine (2.63 g, 3.62 ml, 26.00 mmol). Mixture was stirred at room temperature for 15 hr. The progress of reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue so obtained was taken in ethyl acetate (150 ml) and washed with saturated sodium bicarbonate solution (1×40 ml) followed by brine (1×20 ml). The organic layer separated was dried over anhydrous sodium sulphate, filtered and concentrated at reduced pressure to get a crude product. The crude product was purified by column chromatography over silica gel (100-200 mesh) using 15% ethyl acetate in hexanes as an eluent to obtain the title compound (1.38 g, 69.7%). MS: m/z 306 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:20](=[O:37])[N:21]([C:28]2[O:36][C:32]3=[CH:33][CH:34]=[CH:35][C:31]3=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[C:39]1(B(O)O)[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCO.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:20](=[O:37])[N:21]([C:28]2[O:36][C:32]3=[CH:33][CH:34]=[CH:35][C:31]3=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=3)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(Cc2ccc(Br)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Reactant: OB(O)C1=CCCCC1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)c1ccc(CC(Cc2ccc(C3=CCCCC3)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Temperature: 125 °C

Procedure:
A solution consisting of 4-[2-(4-Benzofuran-2-ylphenylcarbamoyl)-3-(4-bromophenyl)-propyl]-benzoic acid methyl ester (200 mg, 0.35 mmol), dichlorobis(tri-o-tolyl phosphine)-palladium(II), 1-cyclohexenyl boronic acid (222 mg, 1.76 mmol) and sodium carbonate (373 mg, 3.5 mmol) in DME (8 mL), EtOH (4 mL) and water (2 mL) was heated at 125° C. for 7 min in the microwave. The crude reaction mixture was partitioned between EtOAc and water. Evaporation of the organic portion afforded crude 4-[2-(4-Benzofuran-2-ylphenylcarbamoyl)-3-(4-cyclohex-1-enylphenyl)-propyl]-benzoic acid methyl ester which was carried on as is for the next step. LC-MS m/z=570 [C38H35NO4+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[N+:20]([O-])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.CCN(CC)CC.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>CCO.C(Cl)Cl.[OH-].[Na+].[Zn]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[NH:20][C:32]2=[O:34])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)N1CCC(Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3ccc(Cl)cc32)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 0.50 g (1.52 mmol) of 4-(5-chloro-2-nitro-phenylamino)-piperidine-1-carboxylic acid ethyl ester in EtOH (15.0 mL) was added concentrated HCl (3.0 mL) followed by 0.99 g (15.2 mmol) of zinc powder. After 1 h, additional concentrated HCl (1.5 mL) followed by 0.99 g (15.2 mmol) of zinc powder was added and the reaction was stirred for 1.5 h. The mixture was filtered through a pad of celite and was washed with 5% MeOH/CH2Cl2. The mixture was diluted with saturated NaHCO3 and a precipitate formed. The layers were separated and the aqueous phase was extracted (3×5% MeOH/CH2Cl2). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure to afford a brown oil. The crude oil was diluted with CH2Cl2 (15.0 mL) and 0.64 mL (4.56 mmol) of Et3N was added followed by 0.45 g (1.52 mmol) of triphosgene. The reaction was allowed to stir overnight and was then diluted with 1 N NaOH (20 mL) and stirred for an additional 1 h. The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by flash chromatography (silica, 0-5% MeOH/CH2Cl2) afforded 0.33 g (67% over 2 steps) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.5. MS (electrospray): m/z calculated for C15H18ClN3O3 [M++Na] 346.10, observed 346.0. 1H NMR (400 MHz, CDCl3): 9.41 (s, 1H), 7.11 (d, J=2.0 Hz, 1H), 7.04 (d, J=1.8 Hz, 1H), 7.02 (s, 1H), 4.48-4.33 (m, 3H), 4.20 (q, J=7.1 Hz, 2H), 2.92 (t, J=12.5 Hz, 2H), 2.30 (dq, J=12.9, 4.6 Hz, 2H), 2.10 (d, J=12.6 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13](=[O:14])[NH:12][CH2:11][CH2:10][N:9]2[CH2:15][C:16]2[CH:17]=[C:18]([C:27]([O:29]CC)=[O:28])[C:19](=[O:26])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:35].[Li+].[OH-].Cl>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13](=[O:14])[N:12]([CH3:35])[CH2:11][CH2:10][N:9]2[CH2:15][C:16]2[CH:17]=[C:18]([C:27]([OH:29])=[O:28])[C:19](=[O:26])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(CN2CCNC(=O)C2c2cccc(F)c2)c2ccccn2c1=O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CS(C)=O
Product: CN1CCN(Cc2cc(C(=O)O)c(=O)n3ccccc23)C(c2cccc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 1-{[2-(3-fluorophenyl)-3-oxopiperazin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylate (0.050 g, 0.12 mmol) in 0.5 mL DMSO was added sodium hydride (6.1 mg, 0.15 mmol). After 15 minutes, iodomethane (0.010 mL, 0.15 mmol) was added and the reaction was stirred at room temperature for 15 hours. The mixture was then treated with saturated aqueous LiOH (0.3 mL). After 5 hours, 6 N HCl was added to pH ˜3, and the solution was purified by preparative reverse phase HPLC to afford the title compound that gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 409.9 for M+H+ [C22H2OPN3O4: 409.41]: 1H NMR (500 MHz, CD3OD) δ 9.37 (d, J=7.0 Hz, 1H), 8.37 (s, 1H), 7.93-7.89 (m, 2H), 7.60-7.56 (m, 1H), 7.28-7.25 (m, 1H), 7.15 (d, J=7.7 Hz, 1H), 7.08 (d, J=9.9 Hz, 1H), 7.00-6.95 (m, 1H), 4.16 (s, 1H), 3.88 (d, J=13.6 Hz, 1H), 3.77 (d, J=13.6 Hz, 1H), 3.67-3.60 (m, 1H), 3.34-3.31 (m, 1H), 3.10-3.06 (m, 1H), 2.97 (s, 3H), 2.78-2.71 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[CH3:22][N:23]([CH3:29])[CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([N:26]3[CH2:27][CH2:28][CH:24]([N:23]([CH3:29])[CH3:22])[CH2:25]3)=[N:16][CH:15]=2)[C:3]=1[CH3:21]
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: CN(C)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(N3CCC(N(C)C)C3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 19 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.32 mmol) in DMF (3.0 mL) was added 3-(dimethylamino)-pyrrolidine (0.041 mL, 0.32 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 100° C. and stirring continued for 19 h. After which, the reaction mixture was cooled to rt and water was added. The crude mixture was extracted with EtOAc and dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 1-(5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2-yl)-N,N-dimethylpyrrolidin-3-amine as a white solid. Mass Spectrum (ESI) m/e=403.1 (M+1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C([O-])(=O)C.[Na+].C[Si](C)(C)[O:16][C:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH:18]=1.O>C1COCC1.O.C(OCC)(=O)C>[Br:1][CH:18]1[CH:19]([CH3:23])[CH2:20][CH2:21][CH2:22][C:17]1=[O:16]
Reactant: CC1C=C(O[Si](C)(C)C)CCC1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1CCCC(=O)C1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-bromosuccinimide (0.48 mmol) and sodium acetate (0.04 mmol) in THF/water (1:1, 5.2 ml) is cooled to 0° C. and trimethyl-(3-methyl-cyclohex-1-enyloxy)-silane (0.4 mmol, 80% pure) is added dropwise. The reaction mixture is heated to room temperature and stirring is continued overnight. After addition of water extraction is carried out with ethyl acetate. The title compound is obtained from the combined organic phases after drying over sodium sulphate and evaporating-off of the solvent in a vacuum (JOC 1997, 62, 19, 6692-6696).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:14]#[N:15])[C:4]1[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH:16](Br)([CH3:18])[CH3:17]>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-]>[CH:16]([CH:3]([C:14]#[N:15])[C:4]1[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[C:6]([O:7][CH3:8])[CH:5]=1)([CH3:18])[CH3:17]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CC(C)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc(C(C#N)C(C)C)cc1OC
Temperature: 50 °C
Yield: 57.4 %

Procedure:
27.83 g of 50% NaOH solution, 5.84 g (145.95 mmol) of NaOH pellets and veratryl cyanide (8.9 g, 50.24 mmol) were placed in a 100 ml round-bottom flask. 2.05 g (9.02 mmol) of TEBAC was added and the mixture was stirred until homogenous while heating to 50° C. with a heating mantle. Isopropyl bromide (5.5 ml, 58.58 mmol) was added dropwise over 0.5 h at 50° C.±5° to the above mixture which was stirred at 50° C.±5° for 24 hours. The reaction mixture was partitioned between water and toluene and transferred to a separatory funnel. The aqueous layer was drawn off and extracted with ether. The toluene and ether fractions were combined and washed twice with water and dried over Na2SO4. The mixture was filtered and solvent removed by rotary evaporation. The combined fractions, following evaporation and recrystallization from 70 percent methanol/water yielded 6.32 g of the title compound (57% yield).
Reaction SMILES: [CH2:1]([O:8][P:9]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:22].[K+].Cl.S(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH2:1]([O:8][P:9]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:22])[OH:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OP(CCCCc1ccccc1)OCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=P(O)(CCCCc1ccccc1)OCc1ccccc1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-phenylbutylphosphonous acid benzyl ester (1.0 gm, 0.0035 moles) in 10 ml acetone and 5 ml water was added a solution of potassium permanganate (0.16 gm, 0.0021 moles) in 5 ml water at 20° C. After the addition (2 minutes), the reaction mixture was stirred at 20° C. for 5 minutes and acidified to pH 1 using concentrated HCl acid. Saturated sodium bisulphite solution was added to the reaction mixture to get a cloudy white solution, which on extraction with ethyl acetate followed by solvent evaporation produced the title compound as a pale yellow oil in 87% (0.92 gm) yield.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:32])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@H:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:8][C@@H:9]([C:14]([O:16]C)=[O:15])[CH2:10][CH2:11][S:12][CH3:13].O.CC(O)=O>CO.[OH-].[Na+]>[CH3:1][NH:2][C:3](=[O:32])[C@H:4]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[NH:5][C:6](=[O:22])[C@H:7]([CH2:18][CH:19]([CH3:20])[CH3:21])[NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)[C@H](CC(C)C)N[C@H](CCSC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)[C@H](CC(C)C)N[C@H](CCSC)C(=O)O
Yield: 20.6 %

Procedure:
N[1-(R)-Carbomethoxy-3-methylthiopropyl]-L-leucyl-O-methyl-L-tyrosine N-methylamide (100 mg, 0.2 mM) was dissolved in MeOH (10 ml) and treated with IN NaOH (0.25 ml, 0.25 mM). After 18 h another portion of IN NaOH (0.5 ml, 0.5 mM) and H2O (2 ml) were added. After a further 18 h the reaction mixture was acidified with AcOH and evaporated in vacuo. The resulting white solid was chromatographed on C18 -Silica eluting with a gradient of 10% to 40% MeOH in H2O. The relevant fractions were pooled and evaporated in vacuo; the residue was recrystallised from hot H2O to yield the title compound (20 mg); m.p. 170-180; (Found: C,56.88; H,7.49; N,9.05; calculated for C22H35N3O5S,.0.6H2O: C,56.90; H,7.86; N,9.0 5%); νmax (Nujol) 3340, 1650 and 1625 cm-1 ; δ (d6DMSO) 0.82 (6H,t,J=7 Hz, (CH3)2CH), 1.17 and 1.5-1.9 (5H, m, CHCH(CH3)2 and SCH2CH2), 2.04 (3H, s,CH3S), 2.3 (2H, m, --SCH2), 2.6 (3H, d, J=5 Hz, NHCH3), 2.6-2.95 (3H, m, CH2C6H4 and α-CH),), 3.14 (1H, t, J=7 Hz, α-CH), 3.7 (3H, s, OCH3), 4.25 (1H, m, --CH), 6.8 and 7.12 (2×2H, each d, each J=9 Hz, C6H4), 7.88 (1H, q, J=5 Hz, NHCH3) and 8.18 (1H, d, J=9 Hz, NHCH); m/e 454 (100%, [m+1]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.[P:11]([OH:14])([OH:13])[OH:12].P(Cl)(Cl)Cl.C>C1(OC2C=CC=CC=2)C=CC=CC=1.CO.C1(C)C=CC=CC=1.O>[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH2:7][C:8]([P:11]([OH:14])([OH:13])=[O:12])([P:11]([OH:14])([OH:13])=[O:12])[OH:10])[CH:4]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: OP(O)O
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 70 °C

Procedure:
The suspension of (3-pyridyl)ethanoic acid (10.0 g) and phosphorous acid (17.9 g) in diphenyl ether (50 ml) was heated up to 70° C. for 1 hour. Phosphorous trichloride (19.1 ml) was slowly added to reaction mass at 70° C. temperature and maintained reaction temperature for another 6 hours. Reaction mass was cooled to 25° C. followed by addition of water (150 ml) and toluene (30 ml). The reaction mixture was again heated to 70° C. and charged charcoal in hazy biphasic solution, stirred, filtered through Hyflo bed, washed the bed with hot water (30 ml). Layers was separated from filtrate, aqueous layer was washed with toluene (20 ml) and combined organic layer was then back extracted with water (20 ml) and mixed with main aqueous layer. The water (140 ml) was distilled out from combined aqueous layer at atmospheric pressure in 2 hours and then refluxed the concentrated mass for 13 hours. Reaction mass was cooled to 25° C. followed by addition of methanol (150 ml) in 1 hours, stirred and again cooled to 0° C., filtered, washed with chilled 1:2 mixture (30 ml) of water and methanol and dried at 60° C. to get Risedronic acid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: OC1CCNCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CCC(O)CC1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.20 g, 1.0 eq.) was dissolved in DCM (10 mL). Piperidin-4-ol (0.07 g, 1.2 eq.) was added and the reaction mixture was cooled to −60° C. T3P (propyl phosphonic anhydride) (0.40 mL, 1.2 eq.) and DIPEA (0.19 mL, 2.0 eq.) were added. Reaction mixture was stirred for 30 min. The reaction mixture was then transferred into water (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford crude product, which was purified by chromatography (0-3% MeOH in DCM) to obtain 0.025 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(4-hydroxypiperidin-1-yl)prop-2-en-1-one (Yield: 10%). 1H NMR (400 MHz, CDCl3) δ, 8.75 (s, 1H), 8.58 (s, 7.93 (s, 1H), 7.08-7.11 (d, J=10.4 Hz, 1H), 6.01-6.04 (d, J=10.4 Hz, 1H), 4.02-4.14 (m, 1H), 3.98-4.01 (m, 1H), 3.78-3.85 (m, 1H), 3.47-3.52 (s, 1H), 3.32-3.38 (s, 1H), 1.96 (s, 1H), 1.83 (s, 1H), 1.27 (s, 1H), 0.90 (s, 1H); LCMS for Chemical Formula: C18H17F6N4O2 [M+H]+ 435.34 found 435.24 at RT 2.408 min.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][N:8]=2)=[N:4][CH:3]=1.[CH3:13][C:14]1[CH:30]=[C:17]2[N:18]=[C:19]([CH3:29])[CH:20]=[C:21]([CH:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[N:16]2[N:15]=1.C([O-])(=O)C.[K+].O>CN1CCCC1=O.CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(C1C=C(C(C)(C)C)C=CC=1P(C1C=CC(C(C)(C)C)=CC=1C(C)(C)C)C1C=CC(C(C)(C)C)=CC=1C(C)(C)C)(C)(C)C>[CH3:13][C:14]1[C:30]([C:2]2[S:6][C:5]([C:7]3[N:11]([CH3:12])[N:10]=[CH:9][N:8]=3)=[N:4][CH:3]=2)=[C:17]2[N:18]=[C:19]([CH3:29])[CH:20]=[C:21]([CH:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[N:16]2[N:15]=1
Reactant: CCCC(CCC)c1cc(C)nc2cc(C)nn12
Reactant: Cn1ncnc1-c1ncc(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc(P(c2ccc(C(C)(C)C)cc2C(C)(C)C)c2ccc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCC(CCC)c1cc(C)nc2c(-c3cnc(-c4ncnn4C)s3)c(C)nn12
Temperature: 125 °C
Yield: 341.8 %

Procedure:
Combine 5-(5-bromo-thiazol-2-yl)-1-methyl-1H-[1,2,4]triazole (6.5 g, 23 8 mmol) and 2,5-dimethyl-7-(1-propyl-butyl)-pyrazolo[1,5-a]pyrimidine (6 g, 24 5 mmol) in N-methylpyrrolidinone (58 mL) and stir to complete solution under nitrogen. Then add tetra-N-butylammonium bromide (5.47 g, 16.7 mmol) and potassium acetate (11.8 g, 119 mmol) and heat the mixture to 100° C. under a nitrogen atmosphere. Degas the hot mixture by three cycles of vacuum/nitrogen purge. Then add palladium acetate (216 mg, 0.94 mmol) and tris(2,4-di-tert-butyl-phenyl)-phosphane (787 mg, 1.2 mmol). Heat the mixture 4 h at 125° C. under nitrogen. Cool the mixture to 22° C. and add to water (750 mL). Extract the aqueous layer with methyl-t-butyl ether (3×200 mL), combine the organic portions, and evaporate. Purify the residue by filtration through a silica gel pad eluting with hexanes/ethyl acetate (4/1). Combine the product containing fractions and evaporate the solvent to afford the title compound (7 g, 72%). ES/MS m/z 410 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([F:43])=[C:19]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:30]=[C:31]4[CH2:42][CH2:41][NH:40][CH2:39][C:32]4=[N:33][C:34]=3[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:25][CH2:24]2)=[O:22])[CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([F:43])=[C:19]([CH:20]=1)[C:21]([CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:30]=[C:31]3[CH2:42][CH2:41][N:40]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:39][C:32]3=[N:33][C:34]=2[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:25][CH2:24]1)=[O:22].[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCNC2
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCN(C(=O)N(C)C)C2
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (3.2 mg, 0.029 mmol) was added to a solution of (5-chloro-2-fluorophenyl)(1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone TFA salt (8.0 mg, 0.015 mmol) and triethylamine (6 μL, 0.044 mmol) in DCM (150 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (3.9 mg, 43.1%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.31 (d, J=6.6 Hz, 6H), 1.85-2.05 (m, 4H), 2.77-2.84 (m, 2H), 2.91 (s, 6H), 2.93-3.01 (m, 2H), 3.36-3.41 (m, 1H), 3.51-3.59 (m, 4H), 4.07-4.15 (m, 1H), 4.31 (s, 2H), 7.28 (dd, J=10.4, 8.8 Hz, 1H), 7.61 (ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.76 (dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 504.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([CH2:33][O:34][CH3:35])[CH:32]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:14]([CH:22]=[CH:23][CH:24]=1)[O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[NH:36]1[C:44]2[C:39](=[CH:40][C:41](B(O)O)=[CH:42][CH:43]=2)[CH:38]=[CH:37]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:27]([CH2:26][CH2:25][C:13]1[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]2[CH:30]=[C:31]([CH2:33][O:34][CH3:35])[CH:32]=[C:2]([C:41]3[CH:40]=[C:39]4[C:44](=[CH:43][CH:42]=3)[NH:36][CH:37]=[CH:38]4)[CH:3]=2)=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([OH:29])=[O:28]
Reactant: COCc1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: COCc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3[nH]ccc3c2)c1
Yield: 68.6 %

Procedure:
A similar procedure as described in step 3, method B was used, starting from 4-[3-[6-(3-bromo-5-methoxymethyl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (175 mg, 0.31 mmol), 5-indoleboronic acid (104 mg, 0.64 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (51 mg, 0.07 mmol), and cesium carbonate (417 mg, 1.28 mmol) to obtain 4-[2-(2-carboxy-ethyl)-3-{6-[3-(1H-indol-5-yl)-5-methoxymethyl-phenoxy]-hexyl}-phenoxy]-butyric acid (125 mg, 69%) as a light brown solid: ES(+)-HRMS m/e calcd for C35H41NO7 (M+Na)+ 610.2775. found 610.2774.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.C1COCC1.[CH:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17](Br)[CH:16]=1.S(=O)(=O)(O)O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:21][C:20]1[CH:19]=[CH:18][C:17]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc([Mg]Cl)cc1
Reactant: Clc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
0.5 mol of a 25% strength by weight 4-methylphenylmagnesium chloride/THF solution is added dropwise in the course of 30 minutes to a boiling solution of 0.5 mol of 1,4-bromochlorobenzene and 0.0025 g of Pd(dppf)Cl2 *CH2Cl2 in 100 ml of THF. After stirring under reflux for four hours, the mixture is hydrolyzed with dilute sulfuric acid (conversion 99%, selectivitity 97%). The organic phase is freed from the solvent by distillation. The crude 4-chloro-4'-methylbiphenyl thus obtained is recrystallized from ethanol.