Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[C:11]([CH:13]=1)N.N([O-])=[O:18].[Na+]>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[C:11]([OH:18])[CH:13]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Br)ccc1C1CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1cc(Br)ccc1C1CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
An ice-cold solution of H2SO4 (0.23 mL, 4.31 mmol) in water (2 mL) was added to 5-bromo-2-cyclopropylaniline (300 mg, 1.42 mmol) at 0° C. The reaction was stirred for 10 min, then sodium nitrite (98 mg, 1.415 mmol) in 2 mL cold water was added dropwise. The reaction was stirred at 0° C. for 1 h and then heated at 100° C. for 1 h. Reaction was extracted with EtOAc. Combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound, which was used without further purification. LC-MS calculated for C9H9BrO: 211.98, no ionization, (Rt: 1.57/4 min.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(O)[CH2:9][CH3:10].C(O)(C)C.S(=O)(=O)(O)O>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9][CH3:10]
Reactant: CCC(O)(c1ccccc1)c1ccccc1C
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CC=C(c1ccccc1)c1ccccc1C
Temperature: 25 °C
Yield: 91 %

Procedure:
1-(2-Methylphenyl)-1-phenyl-1-propanol (10.4 g, 46 mmol) was dissolved into isopropanol (100 ml) and a 4 N sulphuric acid solution (50 ml) was added. The reaction mixture was heated at reflux temperature for 18 h and cooled to room temperature. Water (300 ml) was added and the mixture was extracted with dichloromethane (2×200 ml). The combined organic extracts was washed with a diluted sodium bicarbonate solution, dried over sodium sulphate and the solvent evaporated in vacuo to give 9.0 g (91% of 1-(2-methylphenyl)-1-phenyl-1-propene.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:8]=1[CH2:26]Br)=[O:6].[C:28]([CH2:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])#[N:29].Cl>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:8]=1[CH2:26][N:31]([CH2:30][C:28]#[N:29])[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:34])=[O:33])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)NCC#N)cc1
Reactant: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(F)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(CN(CC#N)S(=O)(=O)c2ccc(C)cc2)n(S(=O)(=O)c2ccccc2)c2ncc(F)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
Sodium hydride (1.6 g, 60% dispersion in mineral oil, 40.5 mmol) was added portionwise to a cooled (0° C.) solution of 1-benzenesulfonyl-5-fluoro-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (15.8 g, 36.9 mmol) and N-cyanomethyl-4-methyl-benzenesulfonamide (8.5 g, 40.5 mmol) in DMF (150 mL). The reaction mixture was stirred at 0° C. for 15 minutes, then allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was poured into a cooled, stirred solution of 2M hydrochloric acid (400 mL). The resultant precipitate was collected by filtration (slow) and the cake washed with water, followed by methanol and then diethyl ether. The resulting cake was dried to afford the title compound as a grey solid (16.7 g, 82%). 1H NMR (400 MHz, DMSO-d6): 8.49 (dd, J=2.8, 1.2 Hz, 1H), 8.24-8.24 (m, 2H), 8.14 (dd, J=8.8, 2.8 Hz, 1H), 7.75-7.74 (m, 1H), 7.70-7.68 (m, 2H), 7.62-7.62 (m, 2H), 7.39-7.35 (m, 2H), 5.36 (s, 2H), 4.42 (s, 2H), 3.88 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)C(Cl)=O>C(#N)C>[CH3:14][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Solvent: CC#N
Product: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
3-Hydroxy-2-nitro-benzoic acid (commercially available) (31.5 g) was suspended in acetonitrile (100 ml). Oxalyl chloride (22 ml) in acetonitrile (20 ml) was added dropwise upon which a vigorous gas stream evolved. After 15 minutes the reaction slowed down and therefore, the reaction mixture was heated with a warm water bath (40° C.) for 40 minutes. The mixture was concentrated and the residue was re-dissolved in dichloromethane (100 ml). A mixture of methanol (50 ml) and triethylamine (20 ml) in dichloromethane (30 ml) was added dropwise while cooling the mixture with an ice bath. The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: 10-55% v/v ethyl acetate in heptane) to give 3-hydroxy-2-nitro-benzoic acid methyl ester (15.9 g). 1H-NMR (400 MHz, CDCl3): 10.15 (bs, 1H), 7.60 (t, 1H), 7.27 (d, 1H), 7.08 (d, 1H), 3.93 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:10][N:11]([CH2:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17](O)=[O:18])[CH:12]=1)=[O:5])[CH3:2].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.CN(C)C=O>[C:23]1([C:9]2[C:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][N:11]([CH2:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([NH:36][CH2:35][C:34]4[CH:37]=[CH:38][C:31]([C:30]([F:39])([F:40])[F:29])=[CH:32][CH:33]=4)=[O:18])[CH:15]=3)[N:10]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)O)c2)nc1-c1ccccc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cccc(C(=O)NCc3ccc(C(F)(F)F)cc3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
A mixture of 3-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazol-1-ylmethyl]benzoic acid (700 mg), 4-trifluoromethylbenzylamine (390 mg), 1-hydroxybenzotriazole monohydrate (340 mg), WSC (430 mg), and N,N-dimethylformamide (30 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-phenyl-1-[3-(4-trifluoromethylbenzylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (900 mg, yield: 91%) was obtained as an oily substance from the fraction eluted with acetone-hexane (1:2, volume ratio).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[N:27][CH:28]=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:22][C:23]2[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: Cc1ccc(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a solution of 3-iodo-4-nitro-1H-indazole (3.0 g, 10.4 mmol) in DMF (25 mL) was added potassium carbonate (2.87 g, 20.8 mmol) at ambient temperature. After 15 minutes, 5-(chloromethyl)-2-methylpyridine hydrochloride (2.03 g, 11.4 mmol) was added. The mixture was allowed to stir at ambient temperature for 18 hours. The mixture was concentrated under reduced pressure and diluted with ice-water (300 mL). The precipitated solids were collected by filtration and washed with water to provide 3-iodo-1-((6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (3.77 g, 92% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.C(O[C:40]1(O[Si](C)(C)C)[CH2:42][CH2:41]1)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([CH:40]5[CH2:42][CH2:41]5)[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncnn2c(C3CCN(C4CC4)CC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 17 h
Yield: 50.7 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (85 mg, 0.20 mmol) in MeOH (2.25 mL) containing 3 Å molecular sieves was added AcOH (114 μL, 2.00 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (241 μL, 1.20 mmol) and sodium cyanoborohydride (57 mg, 0.90 mmol). The reaction was stirred at 60° C. for 17 h. The mixture was quenched with the addition of saturated, aqueous NaHCO3 (10 mL) and was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 47 mg (51%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 825 (s, 1 H), 7.60 (s, 1 H), 7.50 (d, 1 H), 7.28 (s, 1 H), 6.98-7.08 (m, 5 H), 6.84 (dd, 1 H), 6.27 (s, 1 H), 5.35 (s, 2 H), 3.04 (s, 2 H), 2.72 (s, 2 H), 1.99 (s, 2 H), 1.66 (s, 2 H), 1.27-1.38 (m, 2 H), 0.13 (s, 1 H), 0.11 (d, 1 H), −0.03-0.03 (m, 2 H); ES-MS m/z 464.32 [M+H]+, HPLC RT (min) 1.24.
Reaction SMILES: [OH:1][CH:2]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:1][CH:2]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)OC
Reactant: BrCc1ccccc1
Product: CCCCCCC(CCCCCCCCCCC(=O)O)OCc1ccccc1

Procedure:
In a similar manner to Example 4-(1), methyl 12-hydroxyoctadecanoate was used instead of ethyl ricinoleate and benzyl bromide was used instead of methyl iodide, the title compound (8-i) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12]CCO2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][S:14]SC>>[CH3:13][S:14][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]=[O:12]
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: CSSC
Product: CSc1cccc(C=O)c1

Procedure:
2-(3-Bromophenyl)-1,3-dioxolane and dimethyl disulfide were processed as described in Example 71A to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18](/[CH:24]=[CH:25]/[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)cc1/C=C/c1ccc(F)cc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2/C=C/c2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.31 (2H, s), 5.81 (1H, d, J=2.0 Hz), 6.96-7.04 (3H, m), 7.18-7.28 (3H, m), 7.35-7.39 (3H, m), 7.59 (1H, d, J=1.6 Hz), 7.63 (1H, d, J=2.4 Hz), 7.90 (1H, s), 8.51 (1H, d, J=4.8 Hz). [M+H] Calc'd for C24H16ClFN4O, 431. Found, 431.
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][CH2:10][C:11]([CH2:13][O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH2:12])=CC=1.C(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[OH:8][CH2:9][CH2:10][C:11]([CH2:13][O:14][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH2:12]
Reactant: C=C(CCOCc1ccc(OC)cc1)COC(=O)c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: C=C(CCO)COC(=O)c1ccccc1

Procedure:
Combine 4-(p-methoxybenzyloxy)-2-benzoyloxymethylbut-1-ene (1.08 g, 3.30 mmol) with methylene chloride (10 mL) and water (0.5 mL) and stir rapidly. Add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.826 gm, 3.64 mmol). After 0.25 hours filter the reaction mixture and rinse the filter cake with methylene chloride (20 mL) and concentrate the filtrate in vacuo. Chromatograph on silica gel eluting with 1/9 ethyl acetate/hexane to give the title compound as an oil. Rf =0.28; silica gel, 1/9 ethyl acetate/hexane.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1c(C)c(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Yield: 76 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridylmethyloxy)benzoic acid (0.100 g, 0.221 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (0.303 g, 0.552 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform:methanol=1:2) and then recrystallized from ether to obtain the titled compound (0.071 g, 0.168 mmol, 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc2ccc(F)cc2c(O)c1C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (3.4 g, 10.0 mmol) in methanol (50 mL) was added 10% palladium on carbon (0.5 g). The resulting mixture was vigorously stirred under a hydrogen (balloon) atmosphere overnight, and then filtered. The filtrate was concentrated in vacuo to give (6-fluoro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (2.44 g, 98%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.69-7.74 (m, 2H), 7.34 (s, 1H), 7.21 (td, J=2.4, 8.4 Hz, 1H), 5.16 (s, 1H), 3.82 (s, 2H), 3.74 (s, 3H), 2.35 (s, 3H); MS cald. for C14H13FO3 248, obsd. (ESI+) [(M+H)+] 249.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:14]([OH:16])=O)[C:8]=2[CH:7]=[CH:6]1)[CH3:2].[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH:17]1([NH:20][C:14]([C:9]2[C:8]3[CH:7]=[CH:6][N:5]([CH2:4][O:3][CH2:1][CH3:2])[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:16])[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: CCOCn1ccc2c(C(=O)O)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCn1ccc2c(C(=O)NC3CC3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 1-(ethoxymethyl)-1H-indole-4-carboxylic acid (123 g, 0.56 mol) in THF (1.5 L) is added cyclopropylamine (58 mL, 0.84 mol) and triethylamine (TEA, 167 mL, 1.12 mol), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (240 g, 0.62 mol) at 0° C. The reaction mixture is stirred at ambient temperature overnight. The volatiles are removed in vacuo. The residue is stirred in EA (1.5 L) and HCl (0.5%, 1 L) for 10 minutes. The organic layer is separated, washed with aqueous saturated sodium chloride (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel to give the title compound (110 g, 77%). MS (m/z): 259 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH3:12].[H-].[Na+].I[CH3:16]>CN(C=O)C>[Br:1][C:2]1[N:6]([CH3:16])[CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH3:12]
Reactant: CCOC(=O)c1c[nH]c(Br)c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (2.0 g, 8.6 mmol) in anhyd DMF (30 mL) at 0° C. was added portionwise NaH (60% in mineral oil, 705 mg, 17.6 mmol) under nitrogen. After 1 h at ambient temperature, the reaction mixture was charged with iodomethane (1.5 mL, 24 mmol) and then stirred at ambient temperature overnight. The reaction mixture was quenched by cautious addition of water and then extracted with DCM. The combined extracts were washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography, eluting with EtOAc-Hex (0:100 to 20:80), to provide the title compound (1.64 g, 78%) as a white solid. 1H-NMR (CDCl3): δ 7.33 (1H, s), 4.25 (2H, q), 3.58 (3H, s), 2.24 (3H, s), 1.33 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:10][CH2:11][CH2:12][CH:13]([OH:51])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C@H:24]2[CH2:48][CH2:47][C@@:46]3([CH3:49])[C:26](=[CH:27][CH2:28][C@@H:29]4[C@@H:45]3[CH2:44][CH2:43][C@@:42]3([CH3:50])[C@H:30]4[CH2:31][CH2:32][C@@H:33]3[C@H:34]([CH3:41])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:25]2)=[CH:5][CH:4]=1.[C:66]1(=[O:72])[O:71][C:69](=[O:70])[CH2:68][CH2:67]1.CCOC(C)=O>C(Cl)Cl>[CH3:65][O:64][C:61]1[CH:60]=[CH:59][C:58]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[O:10][CH2:11][CH2:12][CH:13]([O:51][C:66](=[O:72])[CH2:67][CH2:68][C:69]([OH:71])=[O:70])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C@H:24]2[CH2:48][CH2:47][C@@:46]3([CH3:49])[C:26](=[CH:27][CH2:28][C@@H:29]4[C@@H:45]3[CH2:44][CH2:43][C@@:42]3([CH3:50])[C@H:30]4[CH2:31][CH2:32][C@@H:33]3[C@H:34]([CH3:41])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:25]2)=[CH:63][CH:62]=1
Reactant: COc1ccc(C(OCCC(O)CCCCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C1CCC(=O)O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(OCCC(CCCCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)OC(=O)CCC(=O)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 17 h

Procedure:
In a 20 mL scintillation vial was 1-((bis(4-methoxyphenyl)(phenyl)methoxy))-12-(Cholest-5-en-3β-oxy)dodecan-3-ol (0.5 g, 0.562 mmol) and succinic anhydride (0.113 g, 1.124 mmol) in DCM (10 ml) to give a colorless solution. TEA (0.313 ml, 2.249 mmol) was added and the mixture set to stir for 17 hours. The reaction was judged complete by TLC (25% EtOAc/Hex, PMA visualization). The reaction mixture was washed with 5% NaHPO4 solution (3×15 mL) and brine (1×15 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness for use without further purification. 1H NMR (300 MHz, CDCl3) δ0.70 (3H, s); 0.83-1.74 (49H, m); 1.77-2.12 (5H, m); 2.14-2.29 (1H, m); 2.33-2.44 (1H, m); 2.53-2.72 (4H, m); 3.00-3.09 (2H, m); 3.16 (1H, tt, J=11.2, 4.4 Hz); 3.48 (2H, t, J=6.8 Hz); 3.80 (6H, s); 4.85-5.00 (1H, m); 5.36 (1H, d, J=5.1 Hz); 6.78-6.90 (4H, m), 7.15-7.38 (7H, m); 7.40-7.49 (2H, m); 9.29 (1H, bs).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1([CH2:18][C:19]#[C:20][C:21]([OH:23])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.[NH2:24][C:25]1[CH2:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[C:28]2[CH:39]=[C:40]([CH2:46][CH3:47])[C:41]([S:43][CH2:44][CH3:45])=[CH:42][C:27]=2[N:26]=1>O1CCCC1.CN(C)C=O>[CH2:44]([S:43][C:41]1[C:40]([CH2:46][CH3:47])=[CH:39][C:28]2[C:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[N:30][CH2:31][C:25]3[N:26]([C:19]([CH2:18][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)=[CH:20][C:21](=[O:23])[N:24]=3)[C:27]=2[CH:42]=1)[CH3:45]
Reactant: O=C(O)C#CCN1CCCC1
Reactant: CCSc1cc2c(cc1CC)C(c1ccc(C)cc1)=NCC(N)=N2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCSc1cc2c(cc1CC)C(c1ccc(C)cc1)=NCc1nc(=O)cc(CN3CCCC3)n1-2

Procedure:
In the manner given in Example 21, carbonyldiimidazole, 4-(1-pyrrolidinyl)tetrolic acid, and 2-amino-8-ethylthio-7-ethyl-5-(p-methylphenyl)-3H-1,4-benzodiazepine was stirred in tetrahydrofuran-dimethylformamide to give 10-ethylthio-9-ethyl-1-(1-pyrrolidinylmethyl)-7-(p-methylphenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]3[O:40][C:41]4[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:42]=4[N:43]=3)=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:33]=[CH:34][C:35]([NH:38][C:39]4[O:40][C:41]5[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:42]=5[N:43]=4)=[CH:36][CH:37]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Yield: 198.7 %

Procedure:
To a solution of rac-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinecarboxylate (0.412 g, 0.958 mmol) in ethylene glycol dimethyl ether (6 mL) and water (3 mL) was added N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.436 g, 1.20 mmol), tetrakis(triphenylphosphine)palladium (0) (0.055 g, 0.048 mmol), and sodium carbonate (0.254 g, 2.39 mmol). The solution was heated at 80° C. for 18 h, and then cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford rac-tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinecarboxylate as an orange solid (1.029 g), which was used in the next step without further purification.