Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].O1CCCC1.[CH:9]1([N:12]2[C:17](=[O:18])[C:16]3[C:19]([NH:26][C:27]4[CH:28]=[C:29]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:30]=[CH:31][CH:32]=4)=[C:20]([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:15]=3[N:14]([C:38]3[CH:43]=[CH:42][C:41]([I:44])=[CH:40][C:39]=3[F:45])[C:13]2=[O:46])[CH2:11][CH2:10]1.C(O)(=O)C>CO>[CH:9]1([N:12]2[C:17](=[O:18])[C:16]3=[C:15]([NH:14][C:38]4[CH:43]=[CH:42][C:41]([I:44])=[CH:40][C:39]=4[F:45])[N:22]([CH3:23])[C:21](=[O:24])[C:20]([CH3:25])=[C:19]3[N:26]([C:27]3[CH:28]=[C:29]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:30]=[CH:31][CH:32]=3)[C:13]2=[O:46])[CH2:10][CH2:11]1
Reactant: Cc1c(Nc2cccc(NS(C)(=O)=O)c2)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(=O)n(C)c(Nc2ccc(I)cc2F)c2c(=O)n(C3CC3)c(=O)n(-c3cccc(NS(C)(=O)=O)c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Under a nitrogen atmosphere, to a solution (18.5 g) of 28% sodium methoxide in methanol was added tetrahydrofuran (284 ml), N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide 45 (28.4 g) obtained in Step 1 was added, and the mixture was stirred at room temperature for 1 hr. Acetic acid (12.5 ml) was added, and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. A 9:1 mixed solvent (426 mL) of 1-butanol and water was added to the obtained solid, and the mixture was stirred with heating under reflux for 3 hrs. The mixture was allowed to return to room temperature and stirred overnight, and the crystals were collected by filtration and dried. A 9:1 mixed solvent (426 mL) of 1-butanol and water was added again to the obtained crystals, and the mixture was stirred with heating under reflux for 3 hrs. The mixture was allowed to return to room temperature and stirred overnight. The crystals were collected by filtration and washed with a 9:1 mixed solvent of methanol and water and dried to give N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide 46 (26.35 g, yield 93%) as white crystals.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]=[O:22])[CH2:17][CH2:16]1>CN(C)C=O>[CH2:1]([C:3]1[N:4]([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([CH:21]=[O:22])[CH2:19][CH2:20]2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C)c[nH]1
Reactant: O=CN1CCC(CCCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(C)cn1CCCC1CCN(C=O)CC1
Reaction time: 4 h
Yield: 51.3 %

Procedure:
2-Ethyl-4-methyl-1H-imidazole (3.3 g, 30 mM) and sodium hydride (50% by weight in mineral oil, 80 mM) in dimethylformamide (20 ml) was heated at 50° C. for 1/2 hour. The solution of 4-(3-bromopropyl)-1-piperidinecarboxaldehyde (7 g, 30 mM) in dimethylformamide (20 ml) was added at 50° C. and stirred at that temperature for 4 hours. After the reaction, solvent was removed in vacuo and water (100 ml) was added and then extracted with ethyl acetate (2×100 ml). The extracts, dried over Na2SO4, was stripped to dryness and purified on silica gel column, eluted with 2% by volume MeOH, 98% by volume CH2Cl2, to give 4-[3-(2-ethyl-4-methyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde as an oil (4.04 g, 51% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[OH2:11].[C:12]([O:18][CH2:19]Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.C(N(CC)CC)C>[C:12]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:19][O:18][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[O:6])(=[O:11])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: O
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=Cc1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOc1ccc(C=O)cc1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 120 h

Procedure:
3,4-Dihydroxybenzaldehyde (27.6 g, 0.2 mol) was dissolved in 100 mL of DMF with 45 mL of triethylamine and 40 mL of pivalyloxymethyl chloride. The mixture was stirred at room temperature for five days. After one day 20 mL of pivalyloxymethyl chloride and 20 ml of triethylamine were added to the mixture. The mixture was then poured into 600 mL of water. The water was extracted with 600 mL of CH2Cl2 and twice with 500 mL of ether. The organic layers were concentrated and that residue was chromatographed on silicAr CC-7 using petroleum ether bp 30°-60°, acetone (1:1) as the eluent to give the desired compound: mp 58°-60°.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([CH:25]=[CH:26][CH:27]=1)[CH:10]([C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=1)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])Cl)(C)(C)C.[CH3:30][C@H:31]1[CH2:36][NH:35][CH2:34][C@@H:33]([CH3:37])[NH:32]1.[CH2:38](Br)[CH:39]=[CH2:40]>>[CH3:30][CH:31]1[NH:32][CH:33]([CH3:37])[CH2:34][N:35]([CH:10]([C:12]2[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=2)[C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])[C:9]2[CH:25]=[CH:26][CH:27]=[C:7]([OH:6])[CH:8]=2)[CH2:36]1.[CH2:40]([N:32]1[C@@H:33]([CH3:37])[CH2:34][N:35]([CH:10]([C:12]2[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=2)[C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])[C:9]2[CH:25]=[CH:26][CH:27]=[C:7]([OH:6])[CH:8]=2)[CH2:36][C@H:31]1[CH3:30])[CH:39]=[CH2:38]
Reactant: CCN(CC)C(=O)c1cccc(C(Cl)c2cccc(O[Si](C)(C)C(C)(C)C)c2)c1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: C=CCBr
Product: C=CCN1[C@H](C)CN(C(c2cccc(O)c2)c2cccc(C(=O)N(CC)CC)c2)C[C@@H]1C
Product: CCN(CC)C(=O)c1cccc(C(c2cccc(O)c2)N2CC(C)NC(C)C2)c1

Procedure:
(±)-3-(α-(3,5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide was prepared from (3-(3-((tert-butyldimethyl-silyl)oxy)-α-chlorobenzyl)-N,N-diethylbenzamide (Example 1, infra) and cis-2,6-dimethylpiperazine according to the methods of Example 1. This material was then alkylated with allyl bromide and deprotected by methods similar to that in Example 4 to give (±)-cis-3-(α-(4-allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N -diethylbenzamide.
Reaction SMILES: O[N:2]=[CH:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:20])([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[CH3:11])[C:6](=[O:21])[C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl>[C:3]([C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:20])([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[CH3:11])[C:6](=[O:21])[C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[N:2]
Reactant: CC(C)(c1cc(Cl)cc(Cl)c1)N1COC(C=NO)=C(c2ccccc2)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(c1cc(Cl)cc(Cl)c1)N1COC(C#N)=C(c2ccccc2)C1=O
Yield: 82 %

Procedure:
6-Hydroxyiminomethyl-3-[1-methyl-1-(3,5-dichlorophenyl)ethyl]-5-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one (Compound No. 135, 0.50 g), triphenylphosphine (0.33 g), carbon tetrachloride (0.19 g) and triethylamine (0.13 g) were mixed, and dichloromethane (5 ml) was added thereto. The mixture was refluxed for two and one-half hours. The reaction mixture was rinsed with water and dried with magnesium sulfate, then the solvent was removed by evaporation and the crude product was purified by silica gel chromatography to afford the captioned compound (0.39 g, yield 82%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C.CCCP(=O)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:8][C:5]1[N:4]=[N:3][C:2]([NH:1][C:19](=[O:20])[CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:10]([F:22])([F:9])[F:23])[CH:13]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Reactant: Nc1ccc(Cl)nn1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(OC(F)(F)F)c1)Nc1ccc(Cl)nn1
Reaction time: 0.08 h

Procedure:
3-Amino-6-chloropyridazine (55.5 g, 0.428 mol) and 3-(Trifluoromethoxy)phenylacetic acid (1.1 equiv., 0.471 mol, 104 g) were dissolved in DMF (30.0 vol., 1.66 L) in a 3000 mL three neck round-bottom flask. Addition of DIEA (1.1 equiv., 0.471 mol, 82 mL) via addition funnel was done over 5 minutes. Propylphosphonic anhydride solution (300 mL of a 50% solution in DMF, 1.1 equiv., 0.471 mol,) was charged into a 500 mL addition funnel and added dropwise to reaction solution (keeping reaction temperature≦+30° C.). The reaction usually goes to completion after 3 hours (TLC: 6:4 hexanes-ethyl acetate). Reaction mixture was then poured into 7.5% sodium bicarbonate (80.0 vol., 4.4 L) which was chilled in an ice bath. Off-white crystalline powder was filtered through a Büchner funnel, rinsed with water (20.0 vol., 1.1 L). Dried in a 50° C. vacuum to a constant weight to afford N-(6-chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide 1117: yield of 119.6 g (77%). 1H NMR (300 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.38 (d, J=9.4 Hz, 1H), 7.88 (d, J=9.4 Hz, 1H), 7.52-7.27 (m, 4H), 3.90 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[S:21](Cl)(=[O:23])=[O:22].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[S:21]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)(=[O:23])=[O:22]
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)Cl)c3cc(F)ccc32)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)N3CCOCC3)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
A solution of 5-fluoro-3-chlorosulfonyl-1-(toluene-4-sulfonyl)-1H-indole (1 g) in DCM is added to a solution of morpholine (2.26 mL) in water (50 mL) and stirred at rt for 5 h. The organic phase is separated and washed water, brine and dried (MgSO4), filtered and concentrated in vacuo to afford 5-fluoro-3-(morpholine-4-sulfonyl)-1-(toluene-4-sulfonyl)-1H-indole (1.3 g, 100%). MS: 439 (M+H).
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].[CH2:9]([N:13]1[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[S:15]/[C:14]/1=[N:22]\[C:23](=[O:35])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1F)[CH2:10][CH2:11][CH3:12]>C1COCC1>[CH2:9]([N:13]1[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[S:15]/[C:14]/1=[N:22]\[C:23](=[O:35])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:4][CH2:3][C:2]([OH:6])([CH3:5])[CH3:1])[CH2:10][CH2:11][CH3:12]
Reactant: CC(C)(O)CO
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ccncc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OCC(C)(C)O)sc2ccncc21
Reaction time: 4 h
Yield: 35.3 %

Procedure:
The product from Example 21A (91 mg, 1.01 mmol) in THF (2 mL) was treated with NaH (60%) (40.3 mg, 1.01 mmol) at room temperature for 20 minutes. To the above mixture was added the product from Example 20B (200 mg, 0.5 mmol) in THF (2 mL). After 4 hrs, the reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 82.4 mg (35%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.04 (t, J=7.63 Hz, 3H) 1.38 (s, 6H) 1.48-1.55 (m, 2H) 1.89-1.97 (m, 2H) 4.03 (s, 2H) 4.54 (t, J=7.32 Hz, 2H) 4.62 (brs, 1H) 7.08 (d, J=8.85 Hz, 1H) 7.66 (d, J=4.58 Hz, 1H) 7.70 (dd, J=8.54, 2.14 Hz, 1H) 8.51 (d, J=5.19 Hz, 1H) 8.51 (s, 1H) 8.74 (s, 1H); MS (ESI+) m/z 468 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][CH2:20][C:21]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3][C:2]2([CH3:14])[CH3:1])=[O:22]
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)CCl)ccc21
Reaction time: 8 h

Procedure:
A solution of 68 g (0.36 mole) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 200 ml of methylene chloride was added dropwise at 0°-5° C. to a solution of 72 g (0.55 mole) of anhydrous aluminum chloride and 40.7 g (0.36 mole) of chloroacetyl chloride in 270 ml of dry methylene chloride. Stirring was then carried out overnight at room temperature. The mixture was poured onto ice/water and extracted with methylene chloride, and the organic phase was washed several times with water, dried over sodium sulfate and evaporated down. 92.2 g of 6-chloroacetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene remained as an oil. The structure was determined by H-NMR spectroscopy.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@H:8]([CH2:12][C@H:13]([CH3:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CSC.B.CSC>C1COCC1>[C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:9][OH:10])[CH2:12][C@H:13]([CH3:18])[CH2:14][CH2:15][CH2:16][CH3:17])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of the crude acid 139 (6.14 mmol) in 30 mL THF at 0° C. was added borane-dimethyl sulfide complex (2.0 M solution in THF, 4.6 mL, 9.2 mmol), and the mixture was allowed to warm slowly to ambient temperature overnight. Additional BH−DMS was added until the acid was completely consumed (ca. 5 mL). The reaction was quenched by addition of MeOH, then partitioned between Et2O and sat. NaHCO3 (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated to provide alcohol 140. LRMS: m/z 226.1; 1H NMR (CDCl3): □3.63 (dd, J=11.0, 4.2 Hz, 1H), 3.42 (dd, J=11.0, 6.8 Hz, 1H), 2.30 (dd, J=14.9, 7.6 Hz, 1H), 2.20 (dd, J=14.9, 5.6 Hz, 1H), 2.03 (m, 2H), 1.42 (s, 9H), 1.24 (m, 6H), 1.02 (m, 2H), 0.85 (m, 6H). The crude product was used without purification.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.Cl.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][NH2:19].C(N(CC)CC)C>C1COCC1.O>[Cl:9][C:6]1[N:5]=[C:4]([S:10][CH3:11])[N:3]=[C:2]([NH:19][CH2:18][C:14]2[S:13][CH:17]=[CH:16][N:15]=2)[C:7]=1[F:8]
Reactant: NCc1nccs1
Reactant: CSc1nc(Cl)c(F)c(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc(Cl)c(F)c(NCc2nccs2)n1
Reaction time: 96 h
Yield: 117 %

Procedure:
4,6-Dichloro-5-fluoro-2-(methylthio)pyrimidine (see Intermediate E) (0.422 g, 1.991 mmol), commercially available (1,3-thiazol-2-ylmethyl)amine hydrochloride (0.300 g, 1.992 mmol) and triethylamine (0.61 mL, 4.3765 mmol) were dissolved in THF (3 mL) and left to stir for 4 days. The reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organics were dried (MgSO4) and concentrated to produce 6-chloro-5-fluoro-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine as a yellow-orange solid (0.6773 g). LCMS: (M+H)+=291.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[O:24]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25]1.C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][CH2:25][CH:26]([OH:24])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C1=C(c2ccccc2)O1
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCC(O)c1ccccc1)c1ccc(-c2ccc(OCCCCCCO)cc2)cc1

Procedure:
A solution of 26.6 g of 4'-(6-hydroxyhexyloxy)(1,1')-biphenyl-4-carboxylic acid, 16 g of epoxystyrene and 16 g of triethylamine in 300 ml of tetrahydrofuran is heated at the boiling point for 140 hours. It is diluted with 1000 ml of methylene chloride, washed twice with 2N hydrochloric acid and dried over sodium sulfate. After concentration under reduced pressure, the residue is crystallized from ethanol. 2-Hydroxy-2-phenylethyl 4'-(6-hydroxyhexyloxy)-(1,1')-biphenyl-4-carboxylate is obtained; melting point: 148°-150°.
Reaction SMILES: [NH2:1][C@@:2]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])([CH3:8])[CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].ClCCl.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C([O-])(O)=O.[Na+].O.[Cl-].[Na+].O.C(OCC)(=O)C>[Br:15][C:13]1[CH:12]=[CH:11][C:10]([F:16])=[C:9]([C@:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])([CH3:8])[CH2:3][C:4]([OH:6])([CH3:5])[CH3:7])[CH:14]=1
Reactant: CC(C)(O)C[C@](C)(N)c1cc(Br)ccc1F
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)C[C@](C)(NC(=O)CCl)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a vigorously stirred mixture of (S)-4-amino-4-(5-bromo-2-fluoro-phenyl)-2-methyl-pentan-2-ol (intermediate A14A) (2.22 g; 7.7 mmol) in sat. aqueous NaHCO3-sol. (25 ml) and dichloromethane (DCM) (35 ml) at 0° C. was added chloroacetyl chloride (672 μl, 8.5 mmol) and the mixture was stirred at 0° C. for 30 min Diluted with water, brine and ethyl acetate (EtOAc), separated phases, dried organic layer over sodium sulphate. Removal of the solvent in vacuum left the crude product as a colourless oil (3.11 g, 111%), which was used in the next step without further purification. MS (ISP): m/z=366.0 [(M+H)+], 368.0 [(M+2+H)+] and 370.0 [(M+4+H)+].
Reaction SMILES: C(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17](=[O:20])[CH:18]=[CH2:19].[CH2:21]([OH:23])C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[N:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:21](=[O:23])[CH2:19][CH2:18][C:17](=[O:20])[CH3:16]
Reactant: O=Cc1cccnc1
Reactant: C=CC(C)=O
Reactant: CCO
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Product: CC(=O)CCC(=O)c1ccccn1
Temperature: 80 °C
Yield: 58 %

Procedure:
In a sealable vial were added nicotinaldehyde (4.7 g, 43.9 mmol), triethylamine (12.17 mL, 87 mmol), but-3-en-2-one (3.97 mL, 43.7 mmol), and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium bromide (2.202 g, 8.73 mmol) in ethanol (10 mL). The reaction mixture was heated at 80° C. for 16 h. The reaction was then concentrated. The residue was treated with 1N HCl and extracted with DCM (3×20 mL). The organic layer was dried with Na2SO4. The crude product was added to a 80 g ISCO silica gel column and was purified with a gradient of 0% to 100% ethyl acetate in hexanes. Collection and concentration of pertinent fractions resulted in isolation of 1-(pyridin-2-yl)pentane-1,4-dione (4.5 g, 58%) as a tan liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH3:2].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl.C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C@@H:5]1[CH2:9][C@@H:8]([O:10][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-CBZ-trans-4-hydroxy-L-proline ethyl ester (5.6 g, 19 mmol) and anhydrous pyridine (4.6 mL, 4.5 g, 57 mmol) in CHCl3 (30 mL) was added p-toluenesulfonyl chloride (7.2 g, 38 mmol) in one portion. After stirring at room temperature for 72 h, the reaction was diluted with CH2Cl2 (70 mL) and pyridine removed by repeated extraction with 10% HCl (4×10 mL). The organic layer was dried (MgSO4) and concentrated to a golden oil which was purified by silica gel flash chromatography (gradient elution, using 1:1, 2:1 ethyl ether-petroleum ether) to yield 8.2 g (98%) of pure 2 as a colorless oil: TLC Rf 0.27 (3:3:1 ethyl ether-petroleum ether-CH2CL2); [α]24D -29° (c 1.5, CHCl3); 1H NMR (250 MHz, CDCl3 δ 7.79-7.74 (m, 2 H), 7.37-7.26 (m, 7 H), 5.18-5.00 (m, 3H, phCH2 and H-4), 4.44 (app q, J=7.5 Hz, 1 H, H-2), 4.19-3.99 (q, J=7.1 Hz, 2H, CO2CH2CH3, two rotamers), 3.76-3.60 (m, 2 H, H-5), 2.62-2.38 (m, 1 H, H-3), 2.45+2.43 (s, 3 H, PhCH3), 2.23-2.08 (m, 1 H, H-3), 1.25+1.08 (t, J=7.1 Hz, 3 H, CO2CH2CH3); 13C NMR (75.5 MHz, CDCl3) δ 171.59, 171.39, 154.12, 153.64, 145.10, 135.96, 135.81, 133.14, 133.08, 129.88, 129.86, 128.25, 128.17, 127.85, 127.60, 127.48, 78.66, 78.00, 67.14, 67.11, 61.25, 61.17, 57.39, 57.07, 52.25, 51.87, 36.99, 35.86, 21.41, 13.84, 13.69; IR (CHCl3) 1740, 1705, 1420, 1355, 1175 cm-1 ; LRMS (EI, 70 eV) m/e 447 (M+, 0.23), 374 (2), 202 (2), 158 (24), 91 (100); HRMS (EI, 40 eV) m/e 447.1337 (447.1351 calcd for C22H25NO7S).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH:6]=[CH2:7].Cl[C:10]1[N:15]=[C:14](Cl)[N:13]=[C:12](Cl)[N:11]=1.[OH2:18]>O1CCCC1>[CH2:3]([O:8][C:10]1[N:15]=[C:14]([O:18][CH2:7][CH2:6][CH2:5][CH:4]=[CH2:3])[N:13]=[C:12]([O:8][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[N:11]=1)[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCO
Reactant: O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCOc1nc(OCCCC=C)nc(OCCCC=C)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To 10.5 g of sodium hydride (purity: 60% or more), 200 mL of tetrahydrofuran was added and the resultant reaction mixture was cooled down to 0° C., followed by dropping 22.58 g of 4-penten-1-ol into the reaction mixture at 4° C. or less to be added. After the completion of the dropping, the resultant reaction mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was cooled down again to 0° C. and into the reaction mixture, 11.9 g of 2,4,6-trichloro-1,3,5-triazine dissolved in 85 mL of tetrahydrofuran was slowly dropped at 15° C. or less to be added. At room temperature, the reaction was effected over one night and to the reaction mixture, water was added, followed by extracting the resultant reaction mixture with ethyl acetate. The extract was washed with water and was dried over anhydrous sodium sulfate and from the extract, the solvent was distilled off to obtain 21.9 g of a crude product. The crude product was purified with a column (ethyl acetate:hexane=1:10) to obtain 13.15 g of 2,4,6-tri(4-pentene-1-oxy)-1,3,5-triazine which is the objective substance as a transparent oil. Yield: 60%, Purity: 99.2% (GC)
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C:23](O)=[O:24])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C([O-])(=[O:28])C.[Na+]>CC(O)=O>[OH:24][C:23]1[C:22]([C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)=[C:4]([C:2]([OH:28])=[O:3])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: CC(=O)[O-]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-c2c(O)nc3ccccc3c2C(=O)O)cc1OC
Temperature: 200 °C

Procedure:
A mixture of isatin (2.21 g, 15 mmol), 3,4-dimethoxyphenylacetic acid (4.91 g, 25 mmol) and sodium acetate (0.3 g) was heated at 200° C. for 3 hrs (TLC monitoring). After cooling, the mixture was added with AcOH (100 mL), and the precipitate was collected, washed with H2O, and dried to give 2-hydroxy-3-[(3,4-dimethoxy)phenyl]quinoline-4-carboxylic acid as a crude intermediate, which was used in the next step without further purification.