Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[CH3:24].[OH-].[Na+]>Cl.C(O)CCC>[CH3:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[NH:14][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: Clc1nccc(-c2cccnc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1

Procedure:
A 250 ml reactor, equipped with a mechanical stirrer and a reflux condenser, was charged with 2-chloro-4-(3-pyridyl)-pyrimidine (0.5 g, 2.6 mmol), 2-amino-4-nitrotoluene (0.5 g, 3.2 mmol), n-butanol (15 ml) and concentrated HCl (5 drops) and the mixture was refluxed for 38 hours. Then, the mixture was cooled, and 6 N NaOH was added to pH 8. The solvent was evaporated under reduced pressure and water (20 ml) was added to the residue, followed by extraction with dichloromethane (2×20 ml). The combined organic phase was concentrated to dryness to give the crude N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-pyrimidine-amine, which was purified by column chromatography to yield a product having 80% purity. The residue was re-slurried twice in methanol (2×2 ml) and in water (3 ml) and dried under reduced pressure.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH3:17])=[C:6]([CH2:8]P(=O)(OCC)OCC)[N:7]=1)[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.O>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([CH3:17])=[C:6](/[CH:8]=[CH:29]/[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:7]=1)[CH3:2]
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1nc(CC)sc1C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCOC)c(C)s1
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of diethyl [(2-ethyl-5-methyl-1,3-thiazol-4-yl)methyl]phosphonate (4.16 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.66 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (3.48 g) was added to the reaction mixture, and the mixture was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (5:95-25:75, v/v) to give 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazole as a yellow oil (3.56 g, yield 68%). NMR (CDCl3) δ: 1.38 (3H, t, J=7.6 Hz), 2.45 (3H, s), 2.98 (2H, q, J=7.6 Hz), 3.63 (3H, s), 5.55 (2H, s), 7.09 (1H, d, J=15.8 Hz), 7.14-7.33 (2H, m), 7.35-7.46 (2H, m), 7.55-7.65 (1H, m), 7.82 (1H, s).
Reaction SMILES: [C:1]1([C:11]2[CH:35]=[CH:34][C:14]([C:15]([N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][N:20]4[C:28]([C:31](O)=[O:32])=[CH:29][CH:30]=[C:19]4[CH2:18]3)=[O:16])=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:36]([CH2:40][CH2:41][OH:42])[CH2:37][CH2:38][OH:39]>>[OH:39][CH2:38][CH2:37][N:36]([CH2:40][CH2:41][OH:42])[C:31]([C:28]1[N:20]2[C:19]([CH2:18][N:17]([C:15](=[O:16])[C:14]3[CH:34]=[CH:35][C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)=[CH:12][CH:13]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1)=[O:32]
Reactant: OCCNCCO
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccc4ccccc34)cc1)C2
Product: O=C(c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccc4ccccc34)cc1)C2)N(CCO)CCO

Procedure:
The title compound was prepared by coupling the 10-[4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step D, with diethanolamine (1.25 equiv) in the manner of Example 1, Step G.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][O:15][C:19](=[O:20])[CH2:18][C:17]([CH3:16])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1CC(=O)O1
Reactant: OCC1CCCCN1Cc1ccccc1
Product: CC(=O)CC(=O)OCC1CCCCN1Cc1ccccc1
Yield: 70 %

Procedure:
Then, 10.0 g of the 1-benzyl-2-piperidine methanol and 4.30 g of diketene were reacted similarly as in Reference Example 1, and the reaction product was purified by silica gel column chromatography (eluent:chloroform:methanol=9:1 v/v), to obtain 9.86 g of acetoacetic acid-N-benzyl-2-piperidinylmethyl ester (yield: 69.9%). This was used in the reaction of Example 5 without distillation.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:32])[CH:12](P(OCC)(OCC)=O)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:9])([CH3:8])[CH3:7].[C:33]([O:37][C:38](=[O:48])[NH:39][C@H:40]1[CH2:45][CH2:44][C@H:43]([CH:46]=O)[CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34].O>C1COCC1>[C:6]([O:10][C:11](=[O:32])[C:12](=[CH:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([NH:39][C:38]([O:37][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:48])[CH2:45][CH2:44]1)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([CH3:7])([CH3:8])[CH3:9]
Reactant: CCOP(=O)(OCC)C(CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=C(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Butyllithium (1.6 M in hexane, 5.0 ml, 8.00 mmol) was added dropwise to a solution of 2-(diethoxy-phosphoryl)-succinic acid 4-benzyl ester 1-tert-butyl ester (3.21 g, 8.00 mmol) in THF (25 mL) at 0° C. under nitrogen. After stirring at 0° C. for 1 h, the solution was transferred to a solution of trans-(4-Formyl-cyclohexyl)-carbamic acid tert-butyl ester (1.30 g, 5.72 mmol) in THF (10 mL). The resulting mixture was stirred at 0° C. for 1 h and at room temperature overnight. Water was added and the product extracted with CH2Cl2. The organic phase was dried and concentrated under reduced pressure. Flash chromatography (hexane/EtOAc, 80:20) gave trans-2-(4-tert-Butoxycarbonylamino-cyclohexylmethylene)-succinic acid 4-benzyl ester 1-tert-butyl ester (1.10 g)
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][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:28]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[N:27]=1)([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[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][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[N:28]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: COc1ccc(-n2nc(C(C)C)cc2NC(=O)Oc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(C)C)cc2NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)cc1
Yield: 59 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3.3 ml) was added DMAP (23 mg, 0.18 mmol) and phenyl 3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate (105 mg, 0.3 mmol), described in Example 348A, to afford 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)urea (101 mg, 59%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (d, J=7 Hz, 6H), 2.86 (s, 1H), 3.81 (s, 3H), 3.99 (s, 6H), 6.28 (s, 1H), 7.07 (d, J=8.7 Hz, 2H), 7.23 (d, J=7.5 Hz, 1H), 7.34 (d, J=5 Hz, 2H), 7.39-7.44 (m, 4H), 7.79 (s, 1H), 8.35 (s, 1H), 8.68 (s, 1H), 9.18 (s, 1H); LC-MS (ESI) m/z 571 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)Cl.[C:15]([S:19]([NH:21][CH:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:20])([CH3:18])([CH3:17])[CH3:16]>C(OCC)(=O)C>[C:15]([S:19]([NH:21][CH:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)(=[O:9])=[O:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1CCC(NS(=O)C(C)(C)C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1CCC(NS(=O)(=O)C(C)(C)C)CC1
Reaction time: 3 h

Procedure:
Metachloroperbenzoic acid (1.25 g) was added, under cooling with ice, to a methylene chloride solution (10 mL) containing ethyl 4-tert-butylsulfinylaminocyclohexane-carboxylate (1.0 g) as prepared by the above-described preparation method, and stirring was effected at room temperature for 3 hrs. The reaction mixture, after being diluted with ethyl acetate, was washed with an aqueous saturated sodium-hydrogencarbonate and sodium-chloride solutions successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was separated and purified by silica-gel chromatography (C-300, hexane:ethyl acetate=1:1) to give ethyl 4-tert-butylsulfonylamino-cyclohexanecarboxylate composed mainly of the trans isomer (673 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[NH:9][C@@H:10]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:9][C@@H:10]([C:12]2[CH:13]=[C:14]([F:20])[C:15]([F:19])=[C:16]([F:18])[CH:17]=2)[CH3:11])[C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1cc(F)c(F)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc(N)c1)c1cc(F)c(F)c(F)c1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 2.38 g of N-[(4-clorophenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-(3,4,5-trifluorophenyl)ethyl]amine [prepared as described in step (a) above], 2.69 g of nickel chloride hexahydrate and 866 mg of sodium borohydride were reacted, to obtain 942 mg of isomer A and 663 mg of isomer B of the title compound, each as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH2:16][NH:17]/[C:18](/SC)=[CH:19]/[N+:20]([O-:22])=[O:21])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[NH4+:35].[ClH:36].O1CCOCC1>C(O)C.CO>[ClH:36].[NH2:35]/[C:18](/[NH:17][CH2:16][C:13]1([OH:15])[CH2:14][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[O:10])[CH2:12]1)=[CH:19]\[N+:20]([O-:22])=[O:21]
Reactant: [NH4+]
Reactant: CS/C(=C\[N+](=O)[O-])NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: C1COCCO1
Product: N/C(=C\[N+](=O)[O-])NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a solution of (0.05 g 0.08 mmol) 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(Z)-1-(methylthio)-2-nitroethenyl]amino}methyl)azetidin-3-ol in ethanol (2 mL) was added ammonium hydroxide (0.1 mL, 0.8 mmol) and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC. The fractions were collected and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an amorphous residue, which was dissolved in methanol, and 4 N HCl in dioxane (40 μL, 0.16 mmol) was added to the solution. A white precipitate formed and was collected by vacuum filtration. The solid was washed with hexane, and dried to afford 42 mg (87%) 3-({[(E)-1-amino-2-nitroethenyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol hydrochloride. 1H NMR (400 MHz, d4-MeOH): 7.58 (t, 0.5H), 7.44 (t, 0.5H), 7.36 (m, 1H), 7.31 (m, 1H), 7.04 (m, 1H), 6.63 (m, 1H), 3.90-4.30 (m, 4H) 3.72 (s, 2H); MS (EI) for C19H17F3IN5O4: 564 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]2[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][C:5]=2[C:4]=1[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35]>ClCCl>[CH2:27]([N:24]1[CH2:23][CH2:22][CH:21]([N:20]2[C:4]3[C:5]4[CH:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[C:6]=4[N:7]=[CH:8][C:3]=3[CH2:2][NH:1][C:34]2=[O:35])[CH2:26][CH2:25]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(CN)cnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c3c(cnc21)CNC(=O)N3C1CCN(Cc2ccccc2)CC1
Yield: 77.6 %

Procedure:
5-(Aminomethyl)-N-(1-benzylpiperidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine (38 mg, 0.081 mmol) in dichloromethane was stirred with 1,1′-carbonyldiimidazole (20.0 mg, 0.123 mmol) at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1 (v/v)) to give the title compound (30.9 mg, yield 77%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23](O)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][C:29]2([C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:32]2)[CH2:28][CH2:27]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([N:26]1[CH2:27][CH2:28][C:29]2([C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:32]2)[CH2:30][CH2:31]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)O)cnc12
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)c2ccccc21
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)CN(C(=O)OC(C)(C)C)c3ccccc34)cnc12
Yield: 79.3 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.363 g, 1.07 mmol) obtained in Example 21, step 4 and tert-butyl spiro[indoline-3,4′-piperidine]-1-carboxylate (0.370 g, 1.28 mmmol) obtained in Reference Example 8, the title compound (0.518 g, 79%) was obtained.
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:13](Br)[CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CC(=O)CC.CCO>[CH2:13]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])[CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCC(C)=O
Product: CCCCOc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Under N2, the mixture of ethyl salicylate (4.16 g, 25 mmol), butyl bromide (4.80 g, 3.77 ml, 35 mmol) and potassium carbonate (4.15 g, 30 mmol) in dry 2-Butanone (100 ml) was heated to reflux for 48 h. After the reaction mixture cooled down to 25° C., the suspended inorganic salt was removed by filtration. The concentration of the resulting solution by rotary evaporation yielded pale yellowish syrup, which was then mixed with 2N NaOH (18 ml, 36 mmol) and EtOH (30 ml). After this mixture was stirred for 2 h at 50° C., ethanol was removed at reduced pressure. After the aqueous solution was acidified by 6N HCl to pH 2 at 5° C., the mixture was extracted with Et2O (50 ml×3). The organic phase was combined and washed with water (10 ml×2) respectively. The ether extract was dried with anhydrous sodium sulfate and then concentrated to give 2-Butoxy-benzoic acid as oil (3.40 g, 17.5 mmol), which was then treated with of 1M sodium trimethylsilanolate (17.0 ml, 17.0 mmol) to give Sodium 2-allyloxy-6-methyl-benzoate (3.53 g, 65.3%) as white powder. 1H-NMR (400 MHz, D2O): 7.22 (m, 2 arom. H); 6.93 (m, 2 arom. H); 3.94 (t, CH3CH2CH2CH2O); 1.59 (m, CH3CH2CH2CH2O); 1.32 (m, CH3CH2CH2CH2O); 0.78 (t, CH3CH2CH2CH2O). 13C-NMR (100 MHz, D2O): 176.54 (—C═O); 154.93; 130.10; 129.81; 127.85; 120.82; 114.13; 69.26; 30.64; 18.68; 13.21.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[CH3:17]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(COc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 170 °C
Reaction time: 2.5 h
Yield: 75.2 %

Procedure:
To a solution of 4-(benzyloxy)phenol (10.01 g, 50 mmol) and bromoacetaldehyde diethyl acetal (7.52 ml, 50 mmol) in dimethylformamide (100 ml) was added potassium carbonate (10.37 g, 75 mmol) and the mixture was heated at 170° C. After 2.5 hr, the reaction mixture was cooled to room temperature. The mixture was diluted with water and ethyl acetate, and aqueous layer was removed. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2-[4-(benzyloxy)phenoxy]acetaldehyde diethyl acetal (11.902 g, 75%, pale-brown oil).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:5]([CH:7]=[CH:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH:15]=[CH:14]2)=[O:6]>CO.[C].[Pd]>[OH:1][CH2:2][CH2:3][N:4]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:5]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH:15]=[CH:14]2)=[O:6]
Reactant: O=C(C=CCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1
Reaction time: 5 h

Procedure:
1.0 Gram of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]-2-propenyloxy}carbostyril was dissolved in 50 ml of methanol and 0.1 g of 5% palladiumcarbon was added. The mixture was catalytically hydrogenated at a room temperature under an atmospheric pressure for 5 hours. After the reaction was completed, the catalyst was removed by filtration and the filtrate was concentrated by distillation under a reduced pressure to dryness. The residue thus obtained was recrystallized from chloroform-petroleum ether. 0.8 Gram of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyril was obtained as in the form of colorless needle-like crystals. Melting point: 165°-166° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][CH:12]=[O:13])[CH3:10].C[Si](C)(C)[C:23]([F:26])([F:25])[F:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][C@H:12]([OH:13])[C:23]([F:26])([F:25])[F:24])[CH3:10]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)[S@@](=O)N[C@@](C)(CC=O)c1cccc(F)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](C)(C[C@H](O)C(F)(F)F)c1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 24.7 %

Procedure:
To a cooled solution of (R)-N-((S)-2-(2-chloro-3-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (5.8 g, 18.14 mmol) in tetrahydrofuran (80 mL) at −78° C. was added trimethyl(trifluoromethyl)silane (26.8 mL, 181 mmol). After stirred for 20 min, tetrabutylammonium fluoride, 1.0M solution in THF (27.2 mL, 27.2 mmol) was added dropwise. After 3 h, the reaction was quenched with 1N HCl (30 ml), and then the cooling bath was removed. The reaction mixture was diluted with water (60 mL) and EtOAc (60 mL), and warmed to ambient temperature. The solution was extracted with EtOAc twice. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with MTBE (15 mL). The resulted solid was filtered and washed with DCM. The filtrate was concentrated in vacuo and purified by silica gel column (240 g, 0-100% EtOA/hexane in 25 min) to afford additional product. The solids were combined to give (R)-N-((2S,4S)-2-(2-chloro-3-fluorophenyl)-5,5,5-trifluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (1.75 g, 25% yield). MS m/z=390 [M+H]+. Calculated for C15H20ClF4NO2S: 389.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][CH2:29][N:30]=[N+]=[N-])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][CH2:29][NH2:30])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CCN=[N+]=[N-])c(=O)n2C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CCN)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
4-[1-(2-Azidoethyl)-7-(2-butynyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (0.17 g) was dissolved in tetrahydrofuran (3.5 ml), and water (0.23 ml) and triphenylphosphine (0.13 g) were added to the solution. After the mixture was stirred at room temperature overnight, the solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to give 0.12 g of the title compound from the elution fraction of ethyl acetate-methanol (10:1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]4)[CH2:11]2)[CH2:17]3)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]#[C:29][CH3:30].CN(C=O)C>C1C=CC=CC=1>[CH2:27]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]23[CH2:11][CH:12]4[CH2:18][CH:16]([CH2:15][CH:14]([CH2:13]4)[CH2:19]2)[CH2:17]3)=[CH:7][CH:8]=1)[C:28]#[C:29][CH3:30]
Reactant: CC#CCBr
Reactant: CNc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC#CCN(C)c1ccc(OC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A mixture of 2.0 g. (0.0079 mole) of N-methyl-p-(1-adamantyloxyl)aniline, 1.07 g. K2CO3 and 1.03 g. of 1-bromo-2-butyne in 10 ml. DMF and 40 ml. C6H6 was heated at reflux for 17 hours. The mixture was allowed to cool and washed well with H2O and brine. The gum which remained when the organic layer was taken to dryness was dissolved in Et2O. The solid which precipitated on addition of HCl in Et2O was recrystallized from CH2Cl2 :EtOAc. There was obtained 2.09 g. (77%) of N-(2-butynyl)-N-methyl-p-(1-adamontyloxy)aniline, m.p. 180°-181°.