Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:23]=[CH:22][C:15]([CH2:16]OS(C)(=O)=O)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25].C(=O)(O)[O-].[K+]>CN(C=O)C>[C:24]([O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:16][C:15]2[CH:22]=[CH:23][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[CH:13][CH:14]=2)[CH2:33][CH2:32]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CS(=O)(=O)OCc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 41.9 %

Procedure:
Methanesulfonic acid 4-benzyloxycarbonylamino-benzyl ester (0.35 g, 2.5 mmol) was added to a suspension of piperidin-4-yl-carbamic acid tert-butyl ester (0.15 g, 0.76 mmol) and potassium bicarbonate (0.35 g, 2.5 mmol) in DMF (10 ml) and the reaction heated to 60° C. and stirred at this temperature for 16 hours under a nitrogen atmosphere. After this time, the reaction mixture was cooled to room temperature and the solvent removed. The resulting residue was diluted with EtOAc (50 ml) and washed with water (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated and the resulting residue was triturated with EtOAc, the resulting precipitate collected by filtration and dried under vacuum to give the title compound (0.14 g, 37% yield) as a white solid. Tr=1.58 min, m/z (ES+) (M+H)+ 440.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1.[F:15][CH:16]([F:33])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[S:29](Cl)(=[O:31])=[O:30].N1C=C(C)C=C(C)C=1.Cl>C(#N)C.CS(C)=O>[F:33][CH:16]([F:15])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[C:20]=1[S:29]([NH:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1)(=[O:30])=[O:31]
Reactant: COc1cnc(OC)n2nc(N)nc12
Reactant: O=S(=O)(Cl)c1c(OCC(F)F)cccc1C(F)(F)F
Agent: Cc1cncc(C)c1
Agent: Cl
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1cnc(OC)n2nc(NS(=O)(=O)c3c(OCC(F)F)cccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
2-Amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine (19.5 g, 0.10 mol) and 2-(2,2-difluoro-ethoxy)-6-(trifluoromethyl)benzenesulfonyl chloride (32.5 g, 0.10 mol) were combined in acetonitrile (45 mL) and 3,5-lutidine (17 g, 93% technical, ˜0.16 mol) at room temperature. After 10 minutes, DMSO (0.20 g, 0.0026 mol) was added and the reaction slurry was stirred at room temperature for 24 hours. The mixture was then warmed to 48° C. and acidified by the addition of 2 N HCl (100 mL) over 30 minutes, during which the temperature was allowed to fall to ˜38° C. The warm mixture was stirred for one hour, then cooled to 10° C. The precipitated solids were filtered, washed with water (30 mL), washed with methanol (75 mL), and dried under vacuum to afford 44 g of product as a light tan solid assaying at 98 wt % (89% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[NH:5][C:6](=O)[C:7]=1[N+:8]([O-:10])=[O:9].O(Cl)[Cl:19].P(Cl)(Cl)(Cl)=O>C(N(CC)C1C=CC=CC=1)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:19])[N:5]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[N:3]=1
Reactant: ClOCl
Reactant: CC(C)C(=O)Nc1nc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Solvent: CCN(CC)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)C(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Yield: 72 %

Procedure:
The title compound of Example 23 (10.0 g, 38.37 mmol) was heated to reflux in phosphorus oxychloride oxychloride (200 ml) and N,N-diethylaniline (3-4 drops) for 5 hours under nitrogen. The solution was then cooled to room temperature, concentrated to dryness, and the syrup was dissolved in cold (~-10° C.) methylene chloride (200 ml). The organic layer was treated with saturated aqueous sodium bicarbonate (100 ml) with vigorous stirring, and the temperature was kept below 5° C. as solid sodium bicarbonate was added portionwise to elevate the pH to between 5 and 7. The layers were separated and the aqueous phase was extracted with methylene chloride. The combined organic layers were filtered over phase-separator paper, concentrated and dried under vacuum to give the title compound (7.71 g, 72%) as a yellow-white solid sufficiently pure to employ in the next step. Recrystallisation of the solid from hexane/methylene chloride provided an analytical sample, m.p. 166°-169° C.; 1H-NMR (DMSO-d6) δ 1.09 (d, J=6.9 Hz, 6H, (CH3)2CH), 2.79 (m, J=6.9 Hz, 1H, (CH3)2CH), 11.61 (s, 1H).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=1.CS(C)=O.CCOC(C)=O>O>[CH3:12][C:9]1[N:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: [C-]#N
Reactant: Cc1ccc(CCl)cn1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(CC#N)cn1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
Sodium cyanide (38.6 g, 787.7 mmol, 1.5 equiv), 5-(chloromethyl)-2-methylpyridine (74.37 g, 527.4 mmol, 1 equiv) and DMSO (750 mL, 10 vol) were charged into a reactor and placed under nitrogen. This exothermic mixture self-heated to ca. 45° C. and was heated to 60° C. After 15 min, TLC (eluent: EtOAc:heptanes 50/50) indicated that the reaction was completed. The mixture was cooled to RT and water (1500 mL, 20 vol) was added slowly; the exotherm was controlled by the addition rate. The solution was extracted with EtOAc (4×750 mL), and the combined organic layer was concentrated under reduced pressure. The resulting oil was purified by chromatography (eluent: EtOAc), to obtain 2-(6-methylpyridin-3-yl)acetonitrile.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:11])[CH2:6][S:7][C:8](=O)[CH3:9])(=[O:3])[CH3:2].[H-].[Na+].[H][H].C(Cl)[C:17]1[CH:22]=[CH:21]C=[CH:19][CH:18]=1>CN(C)C=O>[C:1]([NH:4][C:5](=[O:11])[CH2:6][S:7][CH2:8][C:9]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1)(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CC(=O)NC(=O)CSC(C)=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC(=O)CSCc1ccccc1

Procedure:
To a solution of 1.75 g. (0.01 mole) of N-acetyl-2-(acetylthio) acetamide in 20 ml. of dimethylformamide was added 0.5 g. of 50% sodium hydride. After evolution of hydrogen stopped, there was added 1.5 ml. of benzyl chloride and the reaction mixture was heated on a steam bath for 4 hours. The product was chromatographed by thin layer chromatography eluting with 40% ethylacetate/hexane, then 15 g. of silica gel was added and the product was stripped in vacuo. The prepack was chromatographed on 200 g. of silica gel, eluting with 15% ethylacetate/hexane. A yield of 0.65 g. of product was recrystallized from isopropanol, m.p. 86°-87° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:31](O)=[O:32])[CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[N:67]1([CH:78]2[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]2)[CH2:72][CH2:71][CH:70]([C:73]([O:75][CH2:76][CH3:77])=[O:74])[CH2:69][CH2:68]1>C1COCC1.CCOC(C)=O>[CH3:30][C:28]1[C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=[C:20]([CH2:19][C@@H:18]([O:17][C:15]([N:12]2[CH2:11][CH2:10][CH:9]([N:8]3[CH2:7][CH2:6][C:5]4[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=4[NH:3][C:2]3=[O:1])[CH2:14][CH2:13]2)=[O:16])[C:31]([N:81]2[CH2:82][CH2:83][CH:78]([N:67]3[CH2:68][CH2:69][CH:70]([C:73]([O:75][CH2:76][CH3:77])=[O:74])[CH2:71][CH2:72]3)[CH2:79][CH2:80]2)=[O:32])[CH:29]=1
Reactant: CCOC(=O)C1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c4[nH]c(=O)oc4c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 300 mg (0.59 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 210 mg (0.65 mmol) TBTU and 100 μL (0.72 mmol) triethylamine in 20 mL THF was stirred for 1 h at RT. Then 220 mg (0.70 mmol) ethyl [1,4′]bipiperidinyl-4-carboxylate (used as the bis-hydrochloride salt) and 400 μL (2.87 mmol) triethylamine were added. The reaction mixture was stirred for 24 h at RT. The mixture was diluted with EtOAc, the organic phase was washed with saturated NaHCO3 solution and dried on Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (Alox, activity grade II-III, gradient DCM/EtOH 20:1 to DCM/EtOH 10:1). The fractions containing the product were combined, evaporated down i. vac., the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [CH:1]1([N:6]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]([CH3:18])[C:12]3[C:7]2=[N:8][C:9]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=2[O:29][CH3:30])=[N:10][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:64][CH:65]1[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][CH3:73])[CH2:67][CH2:66]1>CC(N(C)C)=O.CO>[CH:1]1([N:6]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]([CH3:18])[C:12]3[C:7]2=[N:8][C:9]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:64][CH:65]4[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][CH3:73])[CH2:67][CH2:66]4)=[O:25])=[CH:22][C:21]=2[O:29][CH3:30])=[N:10][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CCC(=O)N4C)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Example 111; 231 mg, 0.56 mmol), DIPEA (0.3 mL, 1.68 mmol) and HATU (283 mg, 0.75 mmol) were stirred together in DMA (4 mL) at ambient temperature for 10 minutes. 4-amino-1-propylpiperidine (Fluorochem; 100 mg, 0.70 mmol) was added and the mixture stirred at room temperature for 4 hours. The reaction mixture was loaded onto an SCX-2 (10 g) column pre-wet with MeOH. The column was washed with MeOH (×2) and the product eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC. Product containing fractions were combined and evaporated to yield the title compound as a gum (194 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:28](OC1C=CC([N+]([O-])=O)=CC=1)=[O:29].[C:40]1([C:46]2([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH:50]3[CH2:51][NH:52][CH2:53][CH2:54][N:49]3[C:48](=[O:55])[O:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1.C(OCC)(=O)C>[O:55]=[C:48]1[N:49]2[CH2:54][CH2:53][N:52]([C:28]([NH:1][C:2]3[C:10]4[N:9]=[CH:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]=4[CH:5]=[CH:4][CH:3]=3)=[O:29])[CH2:51][CH:50]2[C:46]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[O:47]1
Reactant: CC(C)(C)OC(=O)n1cnc2c(N)cccc21
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cnc2c(NC(=O)N3CCN4C(=O)OC(c5ccccc5)(c5ccccc5)C4C3)cccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.2 %

Procedure:
To a solution of 1,1-dimethylethyl 4-amino-1H-benzimidazole-1-carboxylate (0.12 g, 0.50 mmol) in tetrahydrofuran (10 ml) were added diisopropylethylamine (90 μL, 0.50 mmol) and 4-nitrophenyl chloroformate (0.11 g, 0.50 mmol), and the mixture was stirred at room temperature for 4 hours. Hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (88 mg, 0.30 mmol) and diisopropylethylamine (90 μL, 0.50 mmol) were sequentially added thereto, and the mixture was stirred at room temperature overnight. To the reaction solution were added ethyl acetate (50 mL) and a 0.5 M aqueous sodium hydrogen carbonate solution (50 mL), and the obtained crystals were collected by filtration. The crude crystals were sequentially washed with a 0.5 M aqueous sodium hydrogen carbonate solution, water and ethyl acetate to obtain the title compound (0.11 g, yield 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[NH:7][CH3:8]>C1COCC1.CO.[Ni]>[Br:1][C:2]1[CH:9]=[C:6]([NH:7][CH3:8])[C:5]([NH2:10])=[C:4]([CH3:13])[CH:3]=1
Reactant: CNc1cc(Br)cc(C)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(Br)cc(C)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a solution of 5-bromo-N,3-dimethyl-2-nitroaniline (Step 85.1) (2.7 g, 11.02 mmol) in THF (100 mL) and MeOH (100 mL) was added Raney Nickel (189 mg, 2.203 mmol) and the resulting mixture was stirred under hydrogen atmosphere at RT for 16 hr. The reaction was filtered through a pad of Celite and the resulting filtrate was concentrated under reduced pressure to afford the title product (2.5 g, 10.56 mmol, 96% yield) as off-white solid. tR: 0.94 min (LC-MS 2); ESI-MS: 214 [M+H]+ (LC-MS 2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.[OH-].[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[N:2]1
Reactant: COC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Yield: 104.3 %

Procedure:
Methyl (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoate (0.71 g, 2.54 mmol) obtained in Step 5 was dissolved in methanol (2.6 mL), and the solution-was added with an aqueous sodium hydroxide solution (1 mol/L, 5.00 mL), followed by heating under reflux for 1.5 hours. Methanol was evaporated under reduced pressure, the pH of the residue was adjusted to 3 or below with 6 mol/L hydrochloric acid under ice-cooling. The resulting precipitates were collected by filtration to obtain (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.70 g, quantitative yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15](=O)(O)[O-:16].[Na+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1.[CH3:31][O:32][CH:33]([O:36][CH3:37])[CH2:34][NH2:35]>ClCCl>[CH3:31][O:32][CH:33]([O:36][CH3:37])[CH2:34][NH:35][C:15](=[O:16])[NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: O=C([O-])O
Reactant: COC(CN)OC
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(CNC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1)OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
4-Amino-1-Boc-piperidine (1.02 g, 5.09 mmol) was dissolved in dichloromethane (25 mL). Aqueous sodium bicarbonate solution was added to the mixture followed by 20% phosgene in toluene (3.2 mL, 6.08 mmol). Mixture stirred vigorously at room temperature for 45 minutes. Aminoacetaldehyde dimethyl acetal (760 μl, 6.98 mmol) was added to the mixture. Reaction stirred vigorously at room temperature for 30 minutes. Reaction layers were partitioned. Aqueous layer was back extracted with dichloromethane and the aqueous phase was discarded. Organic phases were combined. Mixture was dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as pale yellow oil in 96% yield. MS (M−H)−=330.2.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10](Cl)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:17][C:16](=[O:24])[CH:15]=1>>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:15]2[C:16](=[O:24])[O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:14]=2[OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: O=C(Cl)CCCC1CCCCC1
Product: O=c1oc2ccccc2c(O)c1CCCCC1CCCCC1

Procedure:
The title compound was prepared from 4-cyclohexylbutyryl chloride and 4-hydroxycoumarin following the same procedure used in Example 13, m.p. 160°-161° C.; NMR (CDCl3) δ0.82 (m, 2H), 1.15 (m, 5H), 1.38 (m, 2H), 1.51-1.66 (m, 8H), 2.62 (t, 2H), 7.21 (bs, 1H), 7.26-7.34 (m, 2H), 7.53 (m, 1H), 7.87 (dd, 1H).
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Cl-:1].[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:6]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCOc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(OC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]
Temperature: 100 °C

Procedure:
Into a 100 ml round-bottom flask was added 5 g (28.8 mmol, 1.0 equiv) of α,4-dichloroanisole, 7.8 g (30 mmol, 1.05 equiv) triphenylphosphine, and 50 ml toluene (over sieves). The resulting solution was heated to 100° C. for 24 hours, cooled down to room temperature, and filtered to afford the product as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[OH:14][C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=1[C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=2[OH:35])[N:25]=[C:24]([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][C:37]=2[OH:43])[N:23]=1.[OH-:44].[K+]>COCCOCCOC>[OH:14][C:15]1[CH:20]=[C:19]([O:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:18]=[CH:17][C:16]=1[C:22]1[N:23]=[C:24]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:44])=[CH:38][C:37]=2[OH:43])[N:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:30][C:29]=2[OH:35])[N:27]=1
Reactant: [OH-]
Reactant: OCCCCCCCCCCCBr
Reactant: Oc1ccc(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(O)c1
Agent: [K+]
Solvent: COCCOCCOC
Product: OCCCCCCCCCCCOc1ccc(-c2nc(-c3ccc(OCCCCCCCCCCCO)cc3O)nc(-c3ccc(OCCCCCCCCCCCO)cc3O)n2)c(O)c1
Temperature: 100 °C
Yield: 53 %

Procedure:
Under nitrogen, 42.9 g (170 mmol) of 11-bromo-1-undecanol are added at 80° C. to a solution of 20.3 g (50 mmol) of 2,4,6-tris(2,4-dihydroxyphenyl)-1,3,5-triazine, 9.3 g (141 mmol) of potassium hydroxide and 150 ml of diglyme. The mixture is heated at 100° C. for 16 hours and filtered while hot, and the filtrate is cooled to 0° C. The crystallized solid is filtered off, pressed and dried for 48 hours under reduced pressure (60 mmHg, 70° C.), giving 24.3 g (53% yield) of 2,4,6-tris[2-hydroxy-4-(11-hydroxyundecyloxy)phenyl]-1,3,5-triazine as a pale yellow, resin-like solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C(O)(=O)C>C(O)C.O.[Zn]>[CH3:14][S:13][C:4]1[N:3]=[CH:2][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(SC)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
Commercially available ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.00 g, 21.5 mmol) was dissolved in ethanol (72 mL) and water (14 mL), and zinc powder (14.0 g, 214 mmol) was added to the solution. Then, the mixture was added with acetic acid (2.95 mL, 51.5 mmol) in three portions, followed by stirring at room temperature for 2 hours. After removing the insoluble material by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, and the organic layer was separated from the aqueous layer. The organic layer was sequentially washed with water and saturated brine, and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20) to obtain ethyl 2-(methylthio)pyrimidine-5-carboxylate (1.54 g, 36%).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+]=[N-]>CO.C(O)(=O)C.[Pd]>[NH2:1][CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(N)C1
Yield: 69.4 %

Procedure:
A solution of the title compound of Example 3 (37.1 g, 164 mmol) in a mixture of MeOH (100 mL) and acetic acid (25 mL) was added 10% Pd-C (3.7 g) and the reaction mixture was hydrogenated (50 psi) for 24 h at rt in a Parr apparatus. Analysis of the reaction by TLC (solvent system A) and IR (to look for presence or absence of N3 str peak at 2100 cm-1) indicated the reaction to be complete. The solution was filtered through celite to remove catalyst and the filtrate was evaporated in vacuo to give the crude product as an oily residue. The residue was dissolved in 500 mL of 10% aqueous acetic acid and the solution was extracted with Et2O (3×200 mL). The combined ethereal extract was discarded and the aqueous solution was basified by addition of excess concentrated aqueous NH3 solution. The basified mixture was extracted with Et2O (3×200 mL) and the combined organic extract was dried (Na2SO4) and evaporated to give the title compound (22.8 g, 69%) as a pale yellow oil. The fumarate salt crystallized from 2-propanol: mp 197°-198° C., 1H-NMR (CDCl3) ∂ 3.93 (br s, 1H), 3.82 (dm, Jgem =3 Hz, 1H), 1.46 (s, 9H), 1.29-1.41 (complex m, 3H), 1.24 (m, 1H); CIMS (MH+ calcd for C10H20N2O2): 201. Found (MH+): 201; Anal. (calc'd for C10H20N2O2 ·0.5 C4H4O4):C,H,N.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[C:18]([O:22][C:23]([N:25]1[CH2:28][C:27](=O)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:18]([O:22][C:23]([N:25]1[CH2:28][CH:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC1C(=O)NN=C2COc3ccc(N)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1C(=O)NN=C2COc3ccc(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A solution of 6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #2, Step E; 5 g, 21.6 mmol) and 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (7.37 g, 43.1 mmol) in MeOH (90 mL) and HOAc (10 mL) was stirred at rt for 2 h. Sodium cyanoborohydride (2.7 g, 43.1 mmol) was added in portions and the resulting dark solution was stirred at rt for 2 h. The solvent was removed in vacuo and the residue was washed with aqueous Na2CO3 (100 mL) and extracted with EtOAc (4×100 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10-50% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (4.48 g, 54%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.28 (brs, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.15 (s, 1H), 6.13 (d, J=8.4 Hz, 1H), 4.70 (m, 1H), 4.58 (d, J=13.2 Hz, 2H), 4.30 (m, 2H), 4.17 (m, 1H), 4.01 (m, 1H), 3.75 (m, 2H), 1.51 (d, J=6.8 Hz, 3H), 1.47 (s, 9H).