Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:40]1[CH:45]=[CH:44][CH2:43][CH2:42][CH2:41]1.CO>O1CCOCC1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27][CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][O:40]4)[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: C1=COCCC1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 84 %

Procedure:
36.1 g (0.093 mole) of 3β-hydroxy-5-cholenic acid methyl ester was dissolved in 722 ml of dioxane at room temperature, and 1.81 g (0.05 mole of p-toluenesulfonic acid was added. Then, 26.83 ml (0.294 mole) of dihydropyrane was added dropwise over a period of 10 minutes. The temperature rose to 23°-27° C. The solution was stirred for two more hours at room temperature and then adjusted to pH 8 with 3.4 ml of a mixture of 1:1 methanol 29% ammonium hydroxide. An oily precipitate began forming. A semi-solid residue was obtained after the solvent was evaporated. The residue was dissolved in 1.1 liters of chloroform, washed with a 15% sodium bicarbonate solution, then with water. The chloroform solution was dried, decolorized with charcoal and evaporated. The solid residue was dissolved in 1.5 liters of boiling methanol, allowed to cool to room temperature and then filtered. The dried product weighed 34.5 g, mp 114°-115° C. (989-161-A). From the filtrate an additional amount of 8.0 g was isolated, which was recrystallized again from methanol and then from n-heptane. The second crop was 4.1 g, making a total of 38.6 g of 3β-(2-tetrahydropyranyloxy)-5-cholenic acid methyl ester, yield 84%. Anal. Calcd for C30H48O4, M. W. 472.715: C, 76.22; H, 10.24; O, 13.54. Found: C, 76.37; H, 10.21; O, 13.28 (989-161-A). NMR (989-157-A) (CDCl3): δ5.22-5.43 (m,1H, vinyl), ##STR17## 3.20-4.10 (br m, 3H, adjacent to oxygen), 3.63 (s, 3H, --OCH3), 1.00 (s, 3H, C-19 --CH3), 0.66 (s, 3H, C-18 --CH3). IR (989-157-A) (CHCl3) 2940, 2860, 1730, 1440, 1170, 1135, 1110, 1075, 1030, 1020 cm-1.
Reaction SMILES: [C:1]([N:8](C)[C@H:9]([C:17]([NH:19][CH2:20][C:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(OC(C)(C)C)=O.Cl>C(OCC)(=O)C>[NH:8]([CH3:1])[C@H:9]([C:17]([NH:19][CH2:20][C:21]([O:23][C:24]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25])=[O:22])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NCC(=O)OC(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN[C@@H](Cc1ccccc1)C(=O)NCC(=O)OC(=O)c1ccccc1
Yield: 95 %

Procedure:
Condensation of BocMePheOH (5.0 g.) and HGlyOBz (3.75 g.) by the mixed anhydride method using isobutyl chloroformate gave BocMePhe-GlyOBz in 52% yield. De-t-butoxycarbonylation of BocMePhe-GlyOBz (2.0 g.) using hydrogen chloride in ethyl acetate gave HMePhe-GlyOBz in 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.Cl.NC1C=NC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: Nc1cccnc1
Agent: Cl
Solvent: O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3cccnc3)nc21
Temperature: 210 °C
Reaction time: 1 h

Procedure:
A mixture of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one, 0.500 g (5.30 mmol) of 3-aminopyridine base, and 0.066 g (0.50 mmol) of 3-aminopyridine hydrochloride was heated with stirring in a 210° C. oil bath for 1 hour. Water (5 mL) was added to the cooled reaction mixture to precipitate a solid. The solid was filtered, washed well with water, and dried; wt 0.147 g. Purification was effected by silica gel chromatography by eluting with chloroform and then ethyl acetate. The ethyl acetate eluent containing the pure product was concentrated to 2 mL volume. The crystals that separated on inducement were filtered and washed with 0.5 mL of ethyl acetate and 1 mL of ether; wt 0.810 g; mp 247-248° C.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O>[Si:27]([CH:7]([OH:8])[C@H:6]1[O:9][C@@H:1]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@H:2]([OH:3])[C@@H:4]1[OH:5])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)C(O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred suspension of 1 gram of uridine in 20 ml dry N, N-dimethylformamide is added 2.4 molar equivalents of imidazole followed by 1.2 molar equivalents of t-butyldimethylchlorosilane. The mixture is stirred with protection from moisture at room temperature for 20 hours, at which time the solvent is removed at 50° C. in vacuo. The residue is dissolved in 15 ml of ethyl acetate, the solution is washed with 10 ml of water, and the extract is dried with magnesium sulfate and evaporated to give a syrup. Crystallization from 10 ml of hot chloroform, to which is added hexane to the point of opalescence, followed by slow cooling to room temperature, gives 5′-(t-butyldimethylsilyl) uridine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1>>[N:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: Sc1ccncc1
Product: O=c1[nH]nc(Sc2ccncc2)c2ccccc12

Procedure:
4-chlorophthalazin-1(2H)-one and pyridine-4-thiol were processed using a method similar to that described in Example 57A to afford the title compound. MS (APCI) M/Z 256 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:9])[C:3]1[NH:7][N:6]=[C:5]([NH2:8])[CH:4]=1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.CCN(C(C)C)C(C)C>CCO>[Cl:10][C:11]1[N:16]=[C:15]([NH:8][C:5]2[CH:4]=[C:3]([CH:2]([F:9])[F:1])[NH:7][N:6]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cc(C(F)F)[nH]n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)c1cc(Nc2ccnc(Cl)n2)n[nH]1
Temperature: 70 °C
Reaction time: 30 h
Yield: 6.8 %

Procedure:
To a solution of 5-(difluoromethyl)-1H-pyrazol-3-amine (8.0 g, 60.1 mmol) in EtOH (350 mL) was added 2,4-dichloropyrimidine (10.7 g, 72.1 mmol) and DIPEA (10.9 g, 84.1 mmol). The reaction was stirred at 70° C. for 30 h. The reaction mixture was concentrated in vacuo. The crude product was purified by SiO2 chromatography to afford 2-chloro-N-(5-(difluoromethyl)-1H-pyrazol-3-yl)pyrimidin-4-amine (1.00 g, 7%). 1H NMR (400 MHz, DMSO) δ 13.23 (d, J. 68.6 Hz, 1H), 10.57 (s, 1H), 8.22 (d, J=4.9 Hz, 1H), 7.08 (m, 3H). MS (ESI) m/z: 246.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:3]=1[C:4](=[N:19][OH:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1ccc(O)c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccccc1)c1ccc(O)c(Cl)c1Cl

Procedure:
A solution of 18.0 g of 2,3-dichloro-4-hydroxybenzophenone and 9.3 g of hydroxylamine hydrochloride in 100 ml of pyridine is refluxed for 2 hours. Thereafter, the pyridine is evaporated under vacuum and the residual liquid is partitioned between 5% hydrochloric acid and ethyl acetate. The ethylacetate extract is washed with water, dried, and evaporated to give 2,3-dichloro-4-hydroxy-benzophenone oxime.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]3[S:26][CH:25]=[CH:24][C:16]=3[N:17]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>>[ClH:27].[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15]3[S:26][CH:25]=[CH:24][C:16]=3[N:17]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:18]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nn(CC(F)(F)F)c3ccsc23)CC1
Agent: Cl
Product: FC(F)(F)Cn1nc(C2CCNCC2)c2sccc21
Yield: 74 %

Procedure:
4-[1-(2,2,2-Trifluoro-ethyl)-1H-thieno[3,2-c]pyrazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.9 g, 4.87 mmol) was stirred at room temperature in a solution of HCl (6 mL, 4N HCl in dioxane) for 4 hours. The volatiles were removed in vacuo and the residue was triturated with ether (twice) to yield off white solids 2.1 g (74%) as the desired hydrochloride salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:37]=1[CH2:38][CH2:39][NH:40][CH2:41]2.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([N:40]4[CH2:39][CH2:38][C:37]5[C:42](=[CH:43][CH:44]=[CH:45][C:36]=5[F:35])[CH2:41]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: Fc1cccc2c1CCNC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(F)cccc5C4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB4) (170 mg, 0.358 mmol), 5-fluoro-1,2,3,4-tetrahydroisoquinoline (114 mg, 0.716 mmol), cupric acetate (65.7 mg, 0.358 mmol), pyridine (59 μL, 0.72 mmol), 4 Å molecular sieves (95 mg, 264 mg/mmol SM), and DCM (9 mL, 100 mmol) was stirred at rt under an atmosphere of air for 5 d. The mixture was diluted with DCM (50 ml), washed with EDTA solution (2%, 3×50 ml), water (3×50 ml) and brine (50 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a dark black oil that was purified by MDPS to give the title compound as a brown oil. 1H NMR (400 MHz, CDCl3): δ=1.48 (s, 9H), 1.87-1.99 (m, 2H), 2.12-2.19 (m, 2H), 2.84-2.98 (m, 2H), 3.00 (t, J=5.6 Hz, 2H), 3.34 (t, J=6.0 Hz, 2H), 4.17 (s, 2H), 4.22-4.36 (m, 3H), 6.90 (d, J=7.2 Hz, 1H), 6.98 (t, J=8.4 Hz, 1H), 7.18-7.24 (m, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.65 (s, 1H), 7.67 (d, J=1.6 Hz, 1H). MS(ES+): m/z=494.38 (100) [MH+]. HPLC: tR=2.84 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]([O:7][C:8]([N:10]1[C:19]2[C:14](=[N:15][C:16](Br)=[CH:17][CH:18]=2)[C@H:13]([N:21]([C:37](=[O:39])[CH3:38])[CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:12][C@@H:11]1[CH2:40][CH3:41])=[O:9])([CH3:6])[CH3:5]>O.CS(C)=O>[CH:4]([O:7][C:8]([N:10]1[C:19]2[C:14](=[N:15][C:16]([N:2]([CH3:3])[CH3:1])=[CH:17][CH:18]=2)[C@H:13]([N:21]([C:37](=[O:39])[CH3:38])[CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:12][C@@H:11]1[CH2:40][CH3:41])=[O:9])([CH3:6])[CH3:5]
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2nc(Br)ccc2N1C(=O)OC(C)C
Reactant: CNC
Solvent: O
Solvent: CS(C)=O
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2nc(N(C)C)ccc2N1C(=O)OC(C)C
Temperature: 100 °C
Yield: 57 %

Procedure:
Add N,N-dimethylamine 40% in water (0.5 mL) to a solution of (+/-)-cis-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-bromo-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (60 mg, 0.098 mmol) in dimethylsulfoxide (0.2 mL) and heat the mixture at 100° C. in a sealed tube for 15 h. Cool the reaction mixture to room temperature, add water and extract with ethyl acetate. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Chromatograph the residue overa silica gel cartridge, eluting with hexanes/ethyl acetate to provide the title compound (32 mg, 57%). MS (ES+): 575 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][OH:8].[CH:9]1([NH:12][C:13](=[O:31])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=3)[CH:15]=2)[CH2:11][CH2:10]1>>[CH:9]1([NH:12][C:13](=[O:31])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([NH:21][C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:8][CH2:7][C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:27][CH:28]=3)[CH:15]=2)[CH2:11][CH2:10]1
Reactant: OCc1ncccn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ncccn2)cc1
Yield: 58 %

Procedure:
The title compound was prepared from 2-pyrimidinemethanol and N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide according to the method used to prepared Example 8, to give the title compound as a solid (149 mg, 58%); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.67 (m, 2H), 2.24 (s, 3H), 2.84 (m, 1H), 5.37 (s, 2H), 7.09 (d, 2H), 7.31 (d, 1H), 7.47 (m, 1H), 7.61 (m, 1H), 7.78 (d, 1H), 7.93 (d, 2H), 8.35 (m, 1H), 8.83 (m, 2H), 9.80 (s, 1H); Mass Spectrum: M+H+ 403.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].CN(CCN(C)C)C.[Li]CCCC.[CH3:25][O:26]C=O.Cl>CC1CCCO1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[C:10]=1[CH:25]=[O:26])[C:5]([OH:7])=[O:6]
Reactant: COC=O
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC1CCCO1
Product: O=Cc1c(F)cc(C(=O)O)cc1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
To a solution of 3,5-difluorobenzoic acid (291 g, 1.84 mol) in 2-methyltetrahydrofuran (4.35 L) was added TMEDA (604 mL, 4.03 mol) at room temperature. The resulting solution was cooled to −78° C. Afterward, n-BuLi (2.5 M in hexane) (1.77 L, 4.43 mol) was added drop-wise, during which the temperature of the mixture remained at less than −65° C. The mixture was then stirred at −78° C. for 1.5 hr. Anhydrous MeOCHO (239 mL, 3.88 mol) was added dropwise at a rate that allowed the temperature to be maintained at less than −65° C. The resulting solution was allowed to warm at room temperature, and then maintained a room temperature while being stirred for 18 hr. The mixture was then cooled to 0-5° C., and excess base was quenched with 6M aqueous HCl (2.2 L, 13.2 mol). The phases were then separated, and the aqueous layer was extracted 3 times with 2-methyltetrahydrofuran (3×500 mL). The combined organic phases were washed with saturated brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was dissolved in ethyl acetate (350 mL) at reflux, and cooled to room temperature. Hexanes (480 mL) were then added, and the resulting mixture was further cooled to −15° C. The solid was collected by filtration, rinsed with hexanes, and dried under mechanical vacuum to form the title compound (122 g, 35%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.63-7.70 (m, 2H), 10.23 (s, 1H); MS m/z 187.17 [M+H]+ (ESI).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8](Cl)[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]1=[O:50])[CH2:2][CH2:3][CH3:4].[C:51]1([SH:57])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([S:57][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:18][CH:19]=2)[C:6]1=[O:50])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCn1c(=O)cc(Sc2ccccc2)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Yield: 69 %

Procedure:
A mixture of 3-butyl-6-chloro-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.52 g), thiophenol (0.1 ml) and potassium carbonate (0.15 g) in acetonitrile (10 ml) was heated under reflux for 4 hours with stirring. The reaction mixture was allowed to cool and the insoluble material was removed from the reaction mixture by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and 1N hydrochloric acid (1 ml) and the mixture stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness and the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.27 g, 69%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:41])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]3[CH2:26][CH2:25]3)=[CH:18][C:17]=2[S:27]CCC(OCC(CC)CCCC)=O)=O)[O:10][N:9]=1)(=[O:3])[CH3:2].[O-]CC.[Na+].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C1COCC1>[CH:24]1([CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]3[N:15]=[C:13]([C:11]4[O:10][N:9]=[C:8]([O:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:41])[CH:12]=4)[S:27][C:17]=3[CH:18]=2)[CH2:26][CH2:25]1
Reactant: CCCCC(CC)COC(=O)CCSc1cc(OCC2CC2)ccc1NC(=O)c1cc(OC[C@H](C)NC(C)=O)no1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H](C)COc1cc(-c2nc3ccc(OCC4CC4)cc3s2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
A mixture of 2-ethylhexyl 3-{[2-{[(3-{[(2S)-2-(acetylamino)propyl]oxy}isoxazol-5-yl)carbonyl]amino}-5-(cyclopropylmethoxy)phenyl]sulfanyl}propanoate (935 mg), sodium ethoxide (20% ethanol solution, 1.08 g) and THF (10 mL) was stirred at room temperature for 30 min. To the reaction mixture was added trifluoroacetic acid (0.611 mL) at 0° C., and the obtained mixture was stirred at 70° C. overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (ethyl acetate) to give the title compound as white crystals (71.6 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:10]=2[C:11]#[N:12])[CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:10]=2[C:11]#[N:12])[CH:7]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(Br)cnc12
Reactant: Nc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(-c3ccccc3N)cnc12
Temperature: 80 °C
Yield: 62 %

Procedure:
A mixture of 6-bromo-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (500 mg, 1.28 mmol), 2-aminophenylboronic acid (175 mg, 1.28 mmol), Cs2CO3 (623 mg, 1.92 mmol) and Pd(PPh3)4 (74 mg, 0.06 mmol) in 1,4-dioxane (30 mL) and water (1.0 mL) was heated to 80° C. for 16 hr under N2. The mixture was filtered and the filtrate was concentrated and purified by chromatography column on silica gel using 50% of EA in PE as eluant to give the crude product (320 mg, 59.1%) as a yellow solid. MS (ESI, m/e) [M+1]+ 403.9.
Reaction SMILES: [CH2:1]([C:5]1([CH2:24][CH2:25][CH2:26][CH3:27])[C:17]2[CH:16]=[C:15]([C:18](=O)[CH3:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([N+:21]([O-:23])=[O:22])=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].Cl.[NH2:29][OH:30].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:5]1([CH2:24][CH2:25][CH2:26][CH3:27])[C:17]2[CH:16]=[C:15]([C:18](=[N:29][OH:30])[CH3:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([N+:21]([O-:23])=[O:22])=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCC1(CCCC)c2cc(C(C)=O)ccc2-c2ccc([N+](=O)[O-])cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCC1(CCCC)c2cc(C(C)=NO)ccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
After 5.0 g of 1-(9,9-di-n-butyl-7-nitrofluorene-2-yl)-ethanone (6) (13.7 mmol) was dispersed in 150 ml of ethanol and 1.04 g of hydroxylamine hydrochloride (15.1 mmol) and 1.24 g of sodium acetate (15.1 mmol) were added thereto, the reaction mixture was slowly heated and refluxed for 1 hour. The reaction mixture was cooled to room temperature and 100 ml of distilled water was added thereto. Then, a solid product obtained by stirring the reaction mixture for about 30 minutes was filtered and washed with distilled water several times, followed by drying, thereby obtaining 4.89 g of 1-(9,9-di-n-butyl-7-nitrofluorene-2-yl)-ethanone oxime (7) (93.9%) as a light yellow product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][C:27](Br)=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[C:15]1=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCN2C(=NCCC2)CC1>O>[CH2:6]([O:13][N:14]1[C:15](=[O:29])[C:16]2[CH:17]=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]3[C:21]=2[C:22](=[CH:25][CH:26]=[CH:27]3)[C:23]1=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1OCc1ccccc1
Reactant: C1CCNC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2cccc3c(N4CCCC4)ccc(c23)C(=O)N1OCc1ccccc1

Procedure:
Pyrrolidine (3 mL) was added to 2-benzyloxy-6-bromo-benzo[de]isoquinoline-1,3-dione (0.8 g, 2.1 mmol, from Example M) in the presence of DBU (0.05 mL). The mixture was refluxed for 2 hours and poured into water (50 mL). The precipitate formed was filtered and dried to give 0.8 g of 2-benzyloxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione. The hydrogenation of 2-benzyloxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.4 g, 1.1 mmol) in the presence of 10% Pd/C (0.2 g) in DMA (30 mL) gave 0.27 g of the title compound, mp 268-270° C.;