Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH2:20]([O:19][C:15]1[CH:14]=[C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=1)[CH3:21]
Reactant: C1CNCCN1
Reactant: CCOc1cccc(-n2c(Cl)c(C=O)c3ccccc32)c1
Product: CCOc1cccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)c1
Yield: 37 %

Procedure:
2-Chloro-1-(3-ethoxyphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(3-ethoxyphenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (37% yield) as a light yellow solid. ESI/MS 350 (M+H); RT 2.69 min; NMR (CDCl3) 10.26 (1H, s); 8.26 (1H, d, J=6 Hz); 7.28 (3H, m); 7.21 (3H, m); 6.95 (1H, d, J=9 Hz); 4.15 (2H, q); 3.29 (4H, m); 2.79 (4H, m); 1.49 (3H, t).
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:65][C:66]1[O:67][C:68]2[C:74]([C:75]([F:78])([F:77])[F:76])=[CH:73][CH:72]=[CH:71][C:69]=2[N:70]=1>>[F:76][C:75]([F:78])([F:77])[C:74]1[C:68]2[O:67][C:66]([S:65][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]4[C:39]([N:50]5[CH2:51][CH2:52][CH2:53][CH2:54]5)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=4[N:44]4[CH2:45][CH2:46][CH2:47][CH2:48]4)=[O:36])[CH2:32][CH2:33]3)=[N:70][C:69]=2[CH:71]=[CH:72][CH:73]=1
Reactant: FC(F)(F)c1cccc2nc(S)oc12
Reactant: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCSc3nc4cccc(C(F)(F)F)c4o3)CC2)c(N2CCCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercapto-7-trifluoromethylbenzoxazole, to thereby yield the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1.OS(O)(=O)=O.[BH4-].[Na+].[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([N:8]2[CH2:13][CH2:17][CH2:16][CH2:15]2)[CH:7]=1
Reactant: CSc1ccc(Cl)cc1N
Reactant: COC1CCC(OC)O1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CSc1ccc(Cl)cc1N1CCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
To a tan solution of 5-chloro-2-methylsulfanyl-phenylamine (5.4 g, 31 mmol.) in THF (35 mL) and MeOH (35 mL) was added dropwise a solution of 2,5-dimethoxy-tetrahydro-furan (5.3 mL, 40 mmol) and 2.5 M H2SO4 (31 mL, 78 mmol) in THF (45 mL) via addition funnel over 1 h. The reaction was cooled to 0° C. and NaBH4 (4.7 g, 124 mmol) was added portionwise over 1 h with vigorous stirring. The reaction mixture was allowed to slowly warm to room temperature, stirred at room temperature overnight, diluted with water (60 mL), stirred at room temperature overnight, slowly basified with NaOH (˜7 g) until pH˜10 while cooling with an ice bath, and extracted with Et2O. The combined organic extracts were extracted with 6 N HCl (100 mL). The aqueous phase was basified with NaOH (˜30 g, 0.75 mmol) until pH˜10, and extracted with Et2O. The organic extract was dried with Na2SO4 and concentrated to give 2 g of the crude product. The crude product was purified by flash chromatography using 40 g of silica gel and 5-50% EtOAc in hexanes as eluant to afford 0.55 g of 1-(5-chloro-2-methylsulfanyl-phenyl)-pyrrolidine. M+H 228.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22]Cl)[CH:15]=1)[CH:10]=2.[CH2:24]([NH2:27])[CH2:25][CH3:26]>>[ClH:2].[ClH:1].[ClH:2].[CH2:24]([NH:27][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22][NH:17][CH2:16][CH2:15][CH3:14])[CH:15]=1)[CH:10]=2)[CH2:25][CH3:26]
Reactant: CCCN
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Agent: Cl
Product: CCCNCCOc1ccc2cc3ccc(OCCNCCC)cc3nc2c1

Procedure:
The compound is prepared from 3,6-bis(2-chloroethoxy)acridine hydrochloride and n-propylamine as described in Example 15, giving 1.20 g. of the desired product as yellow crystals, m.p. 250°-252° C.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24].Cl>CN(C=O)C>[CH2:24]([O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: Cc1ccc(Oc2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccc(C)cc2)cc1

Procedure:
A solution of 4-(4′-methylphenoxy)phenol (4.75 g, 23.30 mmol), potassium carbonate (4.17 g, 30.30 mmol) and allyl bromide (2.22 mL, 25.60 mmol) in DMF (50 mL) was stirred for 5 h at 60° C. After cooling, the reaction mixture was neutralized with 1 N HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate/ hexane) to afford 4-(4′-methylphenoxy)phenyl allyl ether.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12]
Reactant: Cc1c(F)cccc1CC(O)CCl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1c(F)cccc1CC(=O)CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
0.867 g (35.67 mmol) of magnesium turnings were dried and suspended in 17 ml of anhydrous THF under argon. A solution of 1,2-dibromoethane (0.14 ml, 1.62 mmol) and 2-bromo-6-fluoro-toluene (6.74 g, 35.67 mmol) in 17 ml of anhydrous THF was then added dropwise so as to maintain a gentle reflux. Once the magnesium had been consumed, copper(I) iodide (0.432 g, 2.27 mmol) was then added, followed by a solution of epichlorohydrine (3.00 g, 32.42 mmol) in DMF (8 ml). The mixture was stirred for 3.5 h at room temperature and then quenched with a saturated solution of ammonium chloride (120 ml). The organic layer was separated, and the aqueous phase was extracted twice with EA. The combined organic phases were washed twice with a saturated solution of ammonium chloride, dried over sodium sulfate, filtered and evaporated to dryness. The product was purified by chromatography on silica gel (cyclohexane/EA, from 100:0 to 90:10) to give 6.89 g of 1-chloro-3-(3-fluoro-2-methyl-phenyl)-propan-2-ol. 3.92 g (16.23 mmol) of this alcohol were dissolved in DCM under argon, and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane reagent; 7.57 g, 16.23 mmol) was added. The mixture was stirred at room temperature overnight and then diethyl ether (150 ml) was added. The mixture was washed three times with 1 N hydrochloric acid (70 ml) and twice with a saturated solution of sodium chloride, and extracted with ether. The extracts were dried over sodium sulfate, filtered and evaporated to dryness. 2.69 g of the title compound were obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([F:14])[CH:8]=1)([CH3:6])[CH3:5].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:17]=[O:19])=[C:9]([F:14])[CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(N)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1ccc(N=C=O)c(F)c1

Procedure:
In analogy to the procedure described in example 9.1, 2-(4-amino-3-fluoro-phenyl)-2-methyl-propionic acid methyl ester (Chung, Jae-Uk; Kim, Su Yeon; Lim, Ju-Ok; Choi, Hyun-Kyung; Kang, Sang-Uk; Yoon, Hae-Seok; Ryu, HyungChul; Kang, Dong Wook; Lee, Jeewoo; Kang, Bomi; Choi, Sun; Toth, Attila; Pearce, Larry V.; Pavlyukovets, Vladimir A.; Lundberg, Daniel J.; Blumberg, Peter M. Bioorganic & Medicinal Chemistry (2007), 15(18), 6043-6053) was reacted with triphosgene in the presence of Et3N in CH2Cl2 under reflux conditions for 16 h to give the title compound as brown oil which was used in the next step without further purification. MS: m/e=255.4 [M+NH4+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.C(N(CC)CC)C.C1(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([N:34]=[N+:35]=[N-:36])=[O:12])=[CH:2]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC(=O)c1c[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1H-indole-3-carboxylic acid (500 mg) in tetrahydrofuran (10 mL) were added triethylamine (0.519 mL) and diphenylphosphoryl azide (0.802 mL) at ambient temperature. The mixture was stirred at 60° C. for 2 hours. Ethyl acetate (10 mL) was added to the mixture at room temperature, and then the organic layer was washed with saturated sodium bicarbonate aqueous solution×2, water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residual solid was recrystallized from ethyl acetate (2 mL). The crystals were washed with n-hexane/chloroform (3:1, 1 mL). The crystals were recrystallized from ethyl acetate again to afford 1H-indole-3-carbonyl azide (192 mg) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1>Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH2:7][CH2:8][C:9](=[O:10])[CH2:14][CH2:15]1
Reactant: Fc1ccc(CN2CCC3(CC2)OCCO3)cc1F
Agent: Cl
Product: O=C1CCN(Cc2ccc(F)c(F)c2)CC1
Yield: 81.5 %

Procedure:
A solution of D3 (7.9 g, 29.4 mmol) in hydrochloric acid (5N, 150 ml) was heated at 50° C. for 2 h. After this period, the reaction mixture was washed with diisopropyl ether (100 ml) and then a saturated solution of sodium hydrogen carbonate (100 ml). The mixture was then extracted with dichloromethane and the extracts dried (MgSO4) and the solvents evaporated in vacuo to give D4 (5.4 g, 82%). C12H13F2NO requires 225; Found 226 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:39]=[CH:38][C:13]([CH2:14][N:15]([C:25]3[CH:37]=[CH:36][C:28]4[O:29]C(C)(C)[O:31][C:32](=[O:33])[C:27]=4[CH:26]=3)[C:16](=[O:24])[CH2:17][CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][N:15]([C:16](=[O:24])[CH2:17][CH2:18][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[C:25]3[CH:37]=[CH:36][C:28]([OH:29])=[C:27]([CH:26]=3)[C:32]([OH:33])=[O:31])=[CH:38][CH:39]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(N(Cc3ccc(C#Cc4ccc(Cl)cc4)cc3)C(=O)CCC3CCCC3)ccc2O1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(N(Cc2ccc(C#Cc3ccc(Cl)cc3)cc2)C(=O)CCC2CCCC2)ccc1O

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-chlorophenyl)ethynyl]benzyl}-3-cyclopentyl-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)propanamide and NaOH as a white powder (95%). 1H NMR (DMSO-d6, 300 MHz) δ 7.56 (m, 2H), 7.48 (m, 5H), 7.30-7.19 (m, 3H), 6.93 (m, 1H), 4.82 (brs, 2H). 2.08-1.99 (m, 2H), 1.69-1.33 (m, 9H), 0.99-0.82 (m, 3H). HPLC, Rt: 5.76 min (Purity: 88.5%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([CH:35]=O)=[CH:4]1)[CH3:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl.C(Cl)Cl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([CH2:35][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:4]1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCn1cc(C=O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c(F)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCn1cc(CN2CCCC2)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c(F)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
To a solution of 1-ethyl-8-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (6.5 g, 13.22 mmol) in 1,2-Dichloroethane (DCE) (100 mL) was added pyrrolidine (1.637 mL, 19.84 mmol), sodium triacetoxyborohydride (5.61 g, 26.4 mmol) and AcOH (0.076 mL, 1.322 mmol). The reaction mixture was stirred at 25° C. for 3 h. LCMS indicated completion of the reaction. The mixture was diluted with DCM and washed with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The crude material was purified by normal phase automatic silica column chromatography (Combiflash RF, 40 g golden column) eluting with MeOH/DCM (0-20%), and purified again with reverse phase automatic silica column chromatography (Combiflash RF, 150 g golden column) eluting with acetonitrile/Water (0-60%) to afford 1-ethyl-8-fluoro-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (4.3 g, 7.87 mmol, 59.5% yield) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([Br:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:1]([O:8][C:9]1[C:16]([Br:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cccc(Br)c1OCc1ccccc1
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(Br)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 8 (8.6 g, 29.55 mmol, 1.0 equiv) in THF (220 mL) was cooled to ˜10° C. and 1M PhMgBr in THF (45 mL, 45 mmol, 1.5 equiv) was added slowly via syringe at <10° C. A pale yellow color initially developed that changed to light blue then back to pale yellow. The mixture was allowed to warm to room temperature and stirred 2 hr. The mixture was recooled to ˜0° C. and quenched by addition of saturated NH4Cl solution (100 mL). The mixture was partitioned between EtOAc (300 mL) and H2O (25 mL). The organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure to give a yellow oil. The crude product was absorbed onto silica gel using DCM and dry-loaded on a column of silica gel (100 g) packed in heptanes. The column was eluted with heptanes (1 L), 5% EtOAc/heptanes (1 L) and 10% EtOAc/heptanes (2 L). Product fractions were concentrated under reduced pressure to give 8.7 g (80%) of 9 as a nearly colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14](O)([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:12]C)[C:8]=1[CH:9]([CH3:11])[CH3:10].B(Br)(Br)Br.O.[OH-].[Na+]>C(Cl)Cl>[CH2:22]([C:14]([C:5]1[CH:4]=[C:3]([OH:2])[C:8]([CH:9]([CH3:10])[CH3:11])=[C:7]([OH:12])[CH:6]=1)=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc(C(O)(Cc2ccccc2)Cc2ccccc2)cc(OC)c1C(C)C
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)c1c(O)cc(C(=Cc2ccccc2)Cc2ccccc2)cc1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 2-(3,5-dimethoxy-4-i-propylphenyl)-1,3-diphenylpropan-2-ol (0.63 g, 1.6 mmol) in CH2Cl2 (10 mL) at −78° C. under N2 was added BBr3 (1M in CH2Cl2, 5.0 mL, 5.0 mmol) dropwise. After the reaction was stirred at −78° C. for 1 h, the temperature was allowed to rise to room temperature and the reaction mixture was stirred at room temperature over night. Water (50 mL) was added followed by 20% NaOH to adjust pH>12. The organic layer was removed and the aqueous layer was washed with hexane (2×10 mL). The aqueous layer was acidified with 6N HCl to pH 1 and extracted with ether (3×50 mL). The extract was washed with water (10 mL) and brine (10 mL) and dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using ethyl acetate:hexane (1:9) gave 5-(1-benzyl-2-phenylethenyl)-2-i-propyl-1,3-benzenediol (1).(0.26 g, 47%) as a liquid, which solidified on standing at 0° C. 1HNMR (CDCl3, ppm): δ 1.38 (d, J=7.1 Hz, 6H), 3.52 (hept, J=7.1 Hz, 1H), 4.08 (s, 2H), 6.51 (s, 2H), 7.13 (s, 1H), 7.2-7.4 (m, 10H).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(C)([O-])C.[K+].S(O[CH:25]([CH2:37][CH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)[CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O.O1CCCC1>[O:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]1[O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]([CH2:37][CH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)[S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CS
Reactant: Cc1ccc(S(=O)(=O)OC(CCCCOC2CCCCO2)CCCc2cccnc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CSC(CCCCOC1CCCCO1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.125 mL (1.1 mmol) ethyl 2-mercapto-acetate in 2.4 mL dimethylformamide is added 0.68 mL (1.1 mmol) of 1.61 M potassium t-butoxide in tetrahydrofuran. The solution is stirred at room temperature for 30 minutes and then a solution of 0.402 g (0.87 mmol) 5-tosyloxy-8-(3-pyridyl)-1-(2-tetrahydropyranyloxy)-octane in 1 mL dimethylformamide is added. The mixture is stirred at room temperature for 18 hours, poured into water and then extracted with ethyl acetate. The organic phase is washed with water, brine, dried, filtered and evaporated to give an orange oil which is purified by preparative thin layer chromatography using ether, hexane (4:1) as the eluent to give ethyl 8-(2-tetrahydropyranyloxy)-4-[3-(3-pyridyl)propyl]-3-thia-octanoate; IR (CH2Cl2): 1729, 1134 cm-1.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5].O[CH2:9][NH:10][C:11](=[O:13])[CH3:12]>FC(F)(F)C(O)=O>[C:11]([NH:10][CH2:9][S:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5])(=[O:13])[CH3:12]
Reactant: CC(CS)C(=O)O
Reactant: CC(=O)NCO
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCSCC(C)C(=O)O
Reaction time: 1 h

Procedure:
3-Mercapto-2-methylpropanoic acid (2.4 g.) and N-hydroxymethylacetamide (1.8 g.) are dissolved in trifluoroacetic acid and the solution is stored at room temperature for 1 hour. The trifluoroacetic acid is removed in vacuo and the residue is dried in vacuo over potassium hydroxide to yield 3-acetamidomethylthio-2-methylpropanoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][CH2:23][OH:24])[N:18]=[C:17]([O:25][CH3:26])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27](OC(N1CCC(NC2N=C(Cl)N=C(OC)N=2)CC1)=O)(C)(C)C.COCCN.COC1N=C(NC2CCNCC2)N=C(NCCO)N=1>>[CH3:26][O:25][C:17]1[N:18]=[C:19]([NH:21][CH2:22][CH2:23][O:24][CH3:27])[N:20]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:16]=1
Reactant: COc1nc(Cl)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: COc1nc(NCCO)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: COCCN
Agent: COc1nc(NCCO)nc(NC2CCNCC2)n1
Product: COCCNc1nc(NC2CCNCC2)nc(OC)n1

Procedure:
The compound was prepared in analogy to the synthesis of 4-[4-(2-hydroxy-ethylamino)-6-methoxy-[1,3,5]triazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (intermediate C26/step 2) from 4-(4-chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (intermediate C26/step 1) and 2-methoxy-ethylamine, followed by BOC cleavage in analogy to the procedure described for 2-[4-methoxy-6-(piperidin-4-ylamino)-[1,3,5]triazin-2-ylamino]-ethanol (intermediate C26/step 3). MS (ISP): 283.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][C:10]([CH2:21][CH2:22][O:23][CH3:24])(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH:10]([CH2:21][CH2:22][O:23][CH3:24])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCOC)(CC(=O)c1ccc(Br)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)C(CCOC)CC(=O)c1ccc(Br)cc1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
To a 150 mL flask was added diethyl 2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-methoxyethyl)malonate (1.59 g, 3.59 mmol) dissolved in acetone (16 mL) and ethanol (16 mL), followed by addition of 1N aqueous sodium hydroxide solution (3.6 mL). The reaction mixture was then heated at 55° C. for 3 h. The reaction mixture was concentrated in vacuo to remove solvents, the residue redissolved in dimethoxyethane (32 mL), and the reaction mixture heated at 80° C. for 3 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (50 mL) and water (50 mL), and stirred for 15 minutes until almost all color was extracted into the organic layer. The layers were separated, the aqueous layer was extracted with additional ethyl acetate (50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo, to afford ethyl 4-(4-bromophenyl)-2-(2-methoxyethyl)-4-oxobutanoate (1.06 g, 86%). No further purification of this material was required. LC-MS ret. time 3.18 min, m/z 342.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.35 (t, 3H), 1.77–1.92 (m, 1H), 1.94–2.10 (m, 1H), 3.05–3.2 (m, 2H), 3.35–3.50 (m, 3H), 4.09–4.25 (m, 2H), 7.60 (d, 2H), 7.83 (d, 2H).
Reaction SMILES: CN(C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:19]3[CH:24]=[CH:23][C:22](N(C)C)=[CH:21][CH:20]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)C(=O)O2)=[CH:5][CH:4]=1.CN(C)C1C=CC(C2(C3C=CC(N(C)C)=CC=3)C3C(=CC(N(C)C)=CC=3)C(=O)O2)=CC=1.CN(C)C1C=CC(C2(C3C=CC(N(C)C)=CC=3)C3C(=CC(N(CC)CC)=CC=3)C(=O)O2)=CC=1.CN(C)C1C=CC(C2(C3C=CC(N(C)C)=CC=3)C3C(=CC(OC)=CC=3)C(=O)O2)=CC=1>>[C:6]1([CH:9]([C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3ccccc32)cc1
Agent: CCN(CC)c1ccc2c(c1)C(=O)OC2(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Agent: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Agent: COc1ccc2c(c1)C(=O)OC2(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Product: c1ccc(C(c2ccccc2)c2ccccc2)cc1

Procedure:
3,3-Bis-(p-dimethylaminophenyl)phthalide, 3,3-bis-(p-dimethylaminophenyl)-6-dimethylaminophthalide, 3,3-bis-(p-dimethylaminophenyl)-6-diethylaminophthalide, 3,3-bis-(p-dimethylaminophenyl)-6-methoxyphthalide, 4-hydroxy-4'-dimethylaminotriphenylmethane lactone and 4,4'-bis-dihydroxy-3,3'-bis-diaminotriphenylmethane lactone.