Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:31]=[CH:30][C:13]([O:14][C:15]2[C:16]([CH:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:22]3)=[N:17][CH:18]=[CH:19][N:20]=2)=[CH:12][CH:11]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][C:15]3[C:16]([CH:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:22]4)=[N:17][CH:18]=[CH:19][N:20]=3)=[CH:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: CC(=O)N1CCC(c2nccnc2Oc2ccc(N)cc2)CC1
Reactant: Cc1ccc(Cl)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Into a sealed tube were added 2-chloro-5-methylpyridine (0.055 g, 0.431 mmol), 1-(4-(3-(4-aminophenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (0.148 g, 0.474 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.024 g, 0.026 mmol), 2-(dicyclohexylphosphino)-2′-methylbiphenyl (0.016 g, 0.043 mmol), sodium tert-butoxide (0.124 g, 1.293 mmol), and toluene (2.16 mL, 0.431 mmol). After the mixture was degassed for 5 min, the reaction was stirred at 100° C. for 18 h. The cooled reaction was diluted with CH2Cl2 and washed with water. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification (20% to 80% EtOAc (10% MeOH)/Hexanes), followed by reverse phase HPLC (Shimadzu) afforded 1-(4-(3-(4-(5-methylpyridin-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as a white amorphous solid. MS (ESI, pos. ion) m/z: 404.0 (M+1). IC50 (uM) 0.00004.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=2)=[O:32])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1cccc(N=C=O)c1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(C)c4)cc3)c2cc1OC
Yield: 56 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, 3-methylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 15 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 41 mg of the title compound (yield: 56%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:24])([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br.S([O-])([O-])=O.[Na+].[Na+].CBr>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:24])([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P(=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Br
Agent: CBr
Agent: O=S([O-])[O-]
Product: O=P(c1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 62 %

Procedure:
Bis(4-methoxyphenyl)phenyl phosphine oxide (1.77 g, 5.2 mmol) and hydrobromic acid (31.0 g, 48%, 0.18 mol) were stirred at 123° C. for 21 h. The flask was fitted with a sodium sulfite scrubber for containment of methyl bromide. The reaction mixture was worked up to give the product as a tan powder (1.0 g, 62% yield). 31P NMR: (d6-DMSO) δ 27.9 (s).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15](C)[CH2:16][OH:17].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:17][CH2:16][CH2:15][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]=2[CH:1]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CO)c1ccc2c(c1)Cc1ccccc1O2
Solvent: c1ccncc1
Product: CC(=O)OCCc1ccc2c(c1)Cc1ccccc1O2
Reaction time: 24 h

Procedure:
One gram of 2-(2-xanthenyl)-propanol is allowed to stand for 24 hours in 5 ml. of pyridine and 5 ml. of acetic anhydride. The mixture is concentrated, worked up as usual, and the product is 2-(2-xanthenyl)-propyl acetate, m.p. 62°-64°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH:10]C2C=CC=CC=2)=[CH:4][C:3]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([SiH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=1)[CH3:25]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([Si:33]([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:4]=2)([CH3:34])[CH3:35])=[CH:29][CH:28]=1)[CH3:25]
Reactant: CCOc1ccc([SiH](C)C)cc1
Reactant: Fc1ccc(CC=Cc2ccccc2)cc1Oc1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCOc1ccc([Si](C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Yield: 81.4 %

Procedure:
A few drops of a 30% solution of hexachloroplatinic acid in isopropanol are added twice at 22° C. to a mixture of 2.98 mol of 4-fluoro-3-phenoxyphenylallylbenzene (98.9% pure, 687 g) and 3.24 mol of 4-ethoxyphenyl(dimethyl)silane (595 g, 97.9% pure). After an induction phase of 11/2 hours, spontaneous heating to 130° C. takes place. After stirring is continued for a short period, 259 g of forerun are distilled off in a high vacuum of 0.4-0.15 mbar, followed by 1003 g of product (98.7% pure by GC). This corresponds to a yield of 81.4% of theory.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCCC=CCc1ccccc1
Agent: [Pd]
Product: O=C(O)CCCCCCCCCCCc1ccccc1
Yield: 97.2 %

Procedure:
This compound was synthesized from 12-phenyl-10-dodecenoic acid (1.92 g, 7 mmol) by a hydrogenation reaction using Pd/C (190 mg). Crystallization (petroleum ether) afforded the product (1.88 g, 97%) as white crystals (mp 47°-48° C.). IR: 3400-2500, 1700 cm-1 ; 1H-NMR: 1.30 (m, 14H), 1.60 (m, 4H), 2.32 (t, 2H), 2.57 (t, 2H), 7.20 (m, 5H), 10.20 (bs, 1H). Anal. Calcd. for C18H28O2 : C, 78.21, H, 10.21%; Found: C, 78.29, H, 10.25%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[CH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]#[C:16][C:20]2[CH:21]=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(OCc2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1nccc(C#Cc2ccc(OCc3ccccc3)cc2)n1
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
Into a 250 mL round-bottomed flask was charged 1-(benzyloxy)-4-ethynylbenzene (2.0540 g, 9.86 mmol) and tetrahydrofuran (49.3 ml). 2,4-Dichloropyrimidine (1.469 g, 9.86 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.346 g, 0.493 mmol), copper(I) iodide (0.033 ml, 0.986 mmol), and triethylamine (4.12 ml, 29.6 mmol) were added. The reaction was heated to 45° C. overnight. Silica gel (approx. 15 g) was added, and the reaction concentrated. The reaction was purified by flash chromatography (10% ethyl acetate:hexanes for 10 minutes, then to 30% ethyl acetate:hexanes over 30 minutes, then to 50% ethyl acetate in hexanes over 5 minutes, then to 100% ethyl acetate over 5 minutes.) to provide the title compound. MS (ESI) m/e 321 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:17][C:18](=[O:20])[CH3:19].[BH4-].[Na+].CO.O>C(O)C>[CH3:19][CH:18]([OH:20])[CH2:17][C:5]1[N:4]([CH2:3][CH:2]([CH3:21])[CH3:1])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CC(=O)Cc1nc2cnc3ccccc3c2n1CC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(C)Cn1c(CC(C)O)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[1-(2-Methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-2-one (8 g, 28.4 mmol, Example 73) was suspended in ethanol (400 mL). Sodium borohydride (1.64 g, 43.3 mmol) was added and the reaction mixture was stirred at room temperature for about 2 hours. Methanol (about 20 mL) was added and stirring was continued over night. Water was added then the solvents were removed under vacuum. The residue was partitioned between methylene chloride and water. The methylene chloride layer was separated, dried over magnesium sulfate then concentrated under vacuum to give the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[C:22](=O)[C:23]2[C:31](=[CH:32][CH:33]=1)[C:30]1[C:25](=[CH:26][C:27]([Br:34])=[CH:28][CH:29]=1)[CH:24]=2.[C:36](Br)(Br)([Br:38])[Br:37]>O1CCCC1>[Br:20][C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][C:27]([Br:34])=[CH:28][CH:29]=3)[C:24](=[C:36]([Br:38])[Br:37])[C:23]=2[CH:22]=1
Reactant: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrC(Br)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 25 °C
Yield: 58.4 %

Procedure:
Triphenylphosphine (34.89 g, 133.0 mmol) was added to a solution of 2,7-dibromofluorenone (17.94 g, 53.08 mmol) in anhydrous tetrahydrofuran (550 mL) under nitrogen and the reaction mixture was heated at just below reflux with stirring. A solution of carbon tetrabromide (35.16 g, 106.0 mmol) in anhydrous tetrahydrofuran (150 mL) was added dropwise over 1.5 h, and the reaction mixture was heated at reflux for 17 h with stirring. After cooling to room temperature, the solvent was removed under reduced pressure and dichloromethane was added forming a slurry. The solid was filtered off and washed with dichloromethane. Recrystallisation of the solid from dichloromethane afforded 2,7-dibromo-9-dibromomethylene-fluorene (2) (15.30 g, 58%) as a bright orange powder, purity 100% (GC): υmax (KBr, cm−1) 3115, 3066, 1605, 1566, 1547, 1450, 1399, 1264, 1073; 1H and 13C NMR spectra as expected; M+=494 (pent).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[Cl-].[C:19](O)(=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH3:24]>O1CCCC1.O>[C:19]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH2:1])(=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH3:24]
Reactant: CC=CC=CC(=O)O
Reactant: Nc1nc2ccccc2[nH]1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC=CC=CC(=O)n1c(N)nc2ccccc21
Yield: 60 %

Procedure:
A solution of 2-amino benzimidazole (4 g, or 0.030 mole) and triethylamine (4.2 ml, or 0,029 mole) in 70 ml of anhydrous tetrahydrofuran, is chilled to a temperature of between -5° and 0° C. To this solution is slowly added 4 g (0.030 mole) chloride of 2,4 hexadienoic acid in solution in 50 ml of anhydrous tetrahydrofuran. After being agitated, the mixture is left to return to ambiant temperature, after which it is poured into water. The precipitate is drained and washed with water. After recrystallization in toluene, 4.12 g (60% yield) is obtained of a crystallized compound having a melting point of 215° C. and the following structure (90% purity): ##STR4##
Reaction SMILES: S([CH2:11][CH:12]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13](=[CH2:19])[CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[CH2:43][NH:42][CH2:41][CH2:40]2>O>[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[CH2:43][N:42]([CH2:11][CH:12]([C:13]([CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[CH2:19])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:41][CH2:40]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: C=C(C[Si](C)(C)C)C(CC(C)C)CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C[Si](C)(C)C)C(CC(C)C)CN1CCc2cc(OC)c(OC)cc2C1
Temperature: 80 °C
Reaction time: 30 h
Yield: 70.1 %

Procedure:
(3-(tosylmethyl)-5-methyl-2-methylenehexyl)trimethylsilane (Formula 4; 72.0 mg, 0.195 mmol) and Na2CO3 (41.4 mg, 0.391 mmol) were added to DMF (2 mL). Then, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Formula 3; 75.4 mg, 0.391 mmol) was added thereto, and the mixture was heated up to 80° C. and stirred for 30 hr. Distilled water was put into the reaction solution to complete the reaction, and then the temperature was increased to normal temperature. An organic layer was extracted, the organic layer collected was washed with distilled water and a brine solution, and the remaining solvent was distilled under reduced pressure. Anhydrous magnesium sulfate was used to dry the organic layer, filtration under reduced pressure and evaporation under reduced pressure were performed, and then column chromatography was used to obtain 53.3 mg (yield 75%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14]O)=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:3][CH2:2]1.CS([Cl:25])(=O)=O.C(N(CC)CC)C.O>ClCCl>[Cl:25][CH2:14][C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:6]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)Cc1nc2cc(CO)ccc2n1CC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Cc1nc2cc(CCl)ccc2n1CC1CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of [1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]methanol (Step D, 200 mg, 0.73 mmol) in dichloromethane (3 mL) were added methanesulfonyl chloride (114 μL, 1.5 mmol) and triethylamine (226 μL, 1.6 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. Water (2 mL) was added and the mixture was extracted with ethyl acetate (10 mM×2). The organic extracts were dried over sodium sulfate and concentrated to afford the title compound as pale red oil.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12](O)=O)([CH2:5]3)[CH2:3]1)[CH2:9]2.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH2:36][C:37]1[C:38](=[O:51])[N:39]([CH2:48][CH2:49][CH3:50])[C:40](=[O:47])[N:41]([CH2:44][CH2:45][CH3:46])[C:42]=1[NH2:43].C(=O)(O)[O-].[Na+].[OH-].[Ca+2].[OH-].Cl>C(Cl)Cl.O.CN(C)C=O>[OH:1][C:2]12[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][C:4]([C:12]4[NH:36][C:37]5[C:38](=[O:51])[N:39]([CH2:48][CH2:49][CH3:50])[C:40](=[O:47])[N:41]([CH2:44][CH2:45][CH3:46])[C:42]=5[N:43]=4)([CH2:10]3)[CH2:3]1)[CH2:11]2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2[nH]c(C34CC5CC(CC(O)(C5)C3)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a solution of 1.10 g (5.61 mmol) of 3-hydroxy-1-adamantane carboxylic acid (3-hydroxy-1-tricyclo [3.3.1.13,7 ]decane carboxylic acid) [Syn. Commun. 18, 1967 (1988)] in a mixture of 10 ml-methylene chloride and 25 ml-dimethyl formamide, 1.03 g (6.73 mmol) of 1-hydroxy benzotriazole and 1.61 g (8.42 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide were added and stirred at room temperature for 30 minutes. To the reaction mixture was added dropwise 15 ml of a solution of 5,6-diamino-1,3-dipropyluracil in methylene chloride under ice-cooling and with stirring, and the resulting mixture was stirred at room temperature for 1 hour. 50 ml of a saturated aqueous sodium bicarbonate was added to the resulting mixture and extracted three times with chloroform. The combined organic layer was washed with a saturated aqueous sodium chloride twice and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. A suspension of the obtained residue and calcium hydroxide (2.77 g, 37 mmol) in 35 ml of water was heated under reflux for 3 hours. The mixture was then cooled, adjusted to pH 2 with concentrated hydrochloric acid, and extracted three times with chloroform. The extracts were washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 4% methanol/chloroform), and recrystallized from hexane/toluene to give 680 mg (yield 33%) of Compound 8 as a white plate crystal.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH2:17].[H-].[Na+]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH3:13])[CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH2:17])(=[O:11])=[O:10])=[CH:7][CH:8]=1)#[N:2]
Reactant: CNS(=O)(=O)c1ccc(C#N)cc1
Reactant: C=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(CN(C)S(=O)(=O)c1ccc(C#N)cc1)c1ccccc1
Yield: 46.4 %

Procedure:
To a mixture of 2.30 g of 4-cyano-N-methylbenzenesulfonamide, 2.40 g of α-(bromomethyl)styrene and 20 ml of N,N-dimethylformamide, 0.63 g of 50% sodium hydride (oil dispersed) was slowly added with stirring under ice cooling, then the mixture was stirred at room temperature for 6 hours. After evaporating the solvent under a reduced pressure, ethyl acetate was added to the residue. The organic layer was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate n-hexane) to obtain 1.70 g of the titled compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH2:24]Br)[C:18]([CH2:22]Br)=[C:19]([F:21])[CH:20]=1.O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[C:19]([F:21])[CH:20]=1)[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:24]2
Reactant: Fc1cc(Br)cc(CBr)c1CBr
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2Cc3cc(Br)cc(F)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
In 30 ml of N,N-dimethylformamide was suspended 1.30 g of sodium hydride (purity: 60%), and 15 ml of a N,N-dimethylformamide solution containing 2.80 g of p-toluenesulfonamide was added thereto at room temperature, after which the resulting mixture was stirred at the same temperature for 30 minutes and then at 60° C. for 1 hour. A solution of 5.70 g of 5-bromo-2,3-di(bromomethyl)fluorobenzene in 15 ml of N,N-dimethylformamide was added to the reaction mixture at 60° C. and the resulting mixture was stirred at the same temperature for 10 minutes. The reaction mixture was added to 200 ml of water and the precipitate was collected by filtration to obtain 2.40 g of 5-bromo-7-fluoro-2-(p-toluenesulfonyl)isoindoline as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C@H:27]1[O:31][C:30](=[O:32])[C@H:29]([CH3:33])[CH2:28]1)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH2:35]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[C@@H:27]([OH:31])[CH2:28][C@@H:29]([CH3:33])[C:30]([NH:35][CH3:34])=[O:32])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)[C@H](Cc2cscn2)NC(=O)OC(C)(C)C)OC1=O
Reactant: CN
Product: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A solution of 500 mg (1.04 mmole) of (3R, 5S)-5-{(1S)-1-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-2-cyclohexylethyl}-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 25) in 2.5 ml of a 40% by volume methanolic solution of methylamine was allowed to stand at room temperature for 1 hour. At the end of this time, any excess of the methylamine and the methanol were removed by distillation under reduced pressure. The resulting residue was recrystallized from ethyl acetate to afford 405 mg of the title compound as white crystals, melting at 158°-160° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[N:8]1([C:6]2[CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:3]=[C:2]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:24][CH:25]=3)[N:7]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1nc(-c2ccccc2)cc(N2CCOCC2)n1
Product: FC(F)(F)Oc1ccc(Nc2nc(-c3ccccc3)cc(N3CCOCC3)n2)cc1

Procedure:
A sample of (4-morpholin-4-yl-6-phenyl-pyrimidin-2-yl)-(4-trifluoromethoxy-phenyl)-amine was prepared from 4-(2-chloro-6-phenyl-pyrimidin-4-yl)-morpholine (0.3 g, 1.04 mmol) and 4-trifluoromethoxy phenylamine (0.14 mL, 1.04 mmol) according to a procedure analogous to that described above in Example 48.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH2:13][OH:14]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCOc1ccc(Br)cc1
Yield: 78.2 %

Procedure:
To a sol. of 4-bromophenol (40 g, 231 mmol) in EtOH (140 mL) was added NaOH (10.2 g, 254 mmol). The resulting mixture was stirred at 70° C. for 30 min until the whole amount of NaOH had dissolved. A sol. of 2-bromoethanol (17.3 mL, 231 mmol) in EtOH (40 mL) was added dropwise at 70° C. The sol. rapidly turned milky. The mixture was heated to reflux overnight. The solvents were removed under reduced pressure, and the residue was dissolved in EtOAc. The mixture was washed with water and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:5→1:4→1:3→1:2→EtOAc) yielded the title compound (39.2 g, 78%) as a pale brown oil that crystallized when placed at −18° C. Rf=0.3 in (EtOAc/heptane 1:1).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][N:5]=1)([CH3:3])[CH3:2].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=1>>[CH:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: OCc1ccc(CCl)cc1
Reactant: CC(C)c1cc(-c2ccccc2)[nH]n1
Product: CC(C)c1cc(-c2ccccc2)n(Cc2ccc(CO)cc2)n1
Yield: 9 %

Procedure:
In the same manner as in Reference Example 41, the title compound (285 mg, yield 9%) was obtained as a colorless oil from 3-isopropyl-5-phenyl-1H-pyrazole and [4-(chloromethyl)phenyl]methanol. 1H NMR (CDCl3) δ: 1.32 (6H, d, J=7.0 Hz), 1.64 (1H, t, J=5.8 Hz), 2.99-3.09 (1H, m), 4.66 (2H, d, J=5.8 Hz), 5.30 (2H, s), 6.18 (1H, s), 6.97-7.06 (2H, m), 7.24-7.39 (7H, m).