Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:7][OH:8])=[CH:5][N:6]=1.Cl[C:10]1[CH:16]2[CH2:17][CH:13]([CH2:14][CH2:15]2)[C:12](=[O:18])[CH:11]=1.[H-].[Na+]>O1CCCC1>[Br:1][C:2]1[S:3][C:4]([CH2:7][O:8][C:10]2[CH:16]3[CH2:17][CH:13]([CH2:14][CH2:15]3)[C:12](=[O:18])[CH:11]=2)=[CH:5][N:6]=1
Reactant: OCc1cnc(Br)s1
Reactant: O=C1C=C(Cl)C2CCC1C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(OCc2cnc(Br)s2)C2CCC1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of (2-bromothiazol-5-yl)methanol (4.85 g, 25 mmol) and 4-chloro-bicyclo[3.2.1]oct-3-en-2-one (3.92 g, 25 mmol) in anhydrous tetrahydrofuran (100 ml) is added, in small portions, sodium hydride (60% dispersion in oil, 1.00 g, 25 mmol) at 0° C. The reaction mixture is stirred overnight and allowed to warm to room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 4-(2-bromothiazol-5-ylmethoxy)bicyclo[3.2.1]oct-3-en-2-one (6.43 g)
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][C:28]2([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][C:28]2([F:34])[CH2:33][CH2:32][N:31]([CH3:37])[CH2:30][CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OCC2(F)CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCc1nnc(OCC2(F)CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-fluoro-piperidin-4-ylmethoxy)-pyridazine dihydrochloride (0.058 mmol, 30 mg) in DCM (2 mL) was added formaldehyde solution in water (37%, 1 mL), and stirred for 5 min. Sodium triacetoxyborohydride (0.35 mmol, 75 mg) was added stirred at room temperature for 2 h. Reaction was diluted with DCM (5 mL), DCM layer was separated and washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 2% (NH3 in MeOH, 2M) in DCM—6% (NH3 in MeOH, 2M) in DCM gave 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-fluoro-1-methyl-piperidin-4-yl methoxy)-pyridazine, which was converted to the title compound by treating with 4 N HCl in dioxane (0.5 mL) in DCM (2 mL). The volatiles were removed under reduced pressure, salt was washed with anhydrous ether and solid was dried under high vacuum (24 mg). LCMS: m/z 457 [M+1]. 1H NMR (300 MHz, CD3OD): δ 7.86 (1H, s), 7.45 (2H, d), 7.12 (2H, d), 4.68 (2H, d), 4.44-4.50 (1H, m), 3.50-3.62 (2H, m), 3.24-3.39 (2H, m), 3.13 (2H, t), 2.94 (3H, s), 1.74-2.50 (8H, m), 1.20-1.68 (10H, m), 0.82 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.NCC(N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Agent: NCC(N)=O
Product: Cc1ccc(C(=O)NCCO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting ethanolamine for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.69 (t, 2H, J=5.6 Hz), 3.49 (t, 2H, J=5.6 Hz), 2.20 (s, 3H). ESHRMS m/z 450.1029 (M+H calculated for C21H19ClF2N3O4 requires 450.1027).
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[C:13](O)(=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]C>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:4])#[N:2]
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCCC(=O)O
Product: CCCCCCCCCC(=O)N[C@@H](C)C#N
Yield: 54.3 %

Procedure:
General procedure D was used to deprotect 0.160 g (0.94 mmols) of 4. The product was immediately carried on using general procedure F and coupled to decanoic acid (0.94 mmol, 0.162 g). The product was purified via flash chromatography to yield 0.115 g (0.51 mmols) of the title product. 1H NMR (300 MHz, CDCl3) δ 6.07 (s, 1H), 4.94 (dq, J=7.2, 14.5, 1H), 2.26-2.16 (m, 2H), 1.69-1.58 (m, 2H), 1.54 (d, J=7.2, 3H), 1.26 (d, J=6.4, 12H), 0.86 (t, J=6.7, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[C:25]([N+:26]([O-])=O)=[C:24]3[C:19]([CH:20]=[CH:21][CH:22]=[N:23]3)=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1.CCOC(C)=O.[Cl-].[Na+].O>C(Cl)Cl.C1COCC1>[NH2:26][C:25]1[C:16](/[C:14](=[N:5]/[CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])/[C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=2)=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: O=C(c1ccc(F)cc1)c1ccc2cccnc2c1[N+](=O)[O-]
Reactant: CN(C)CCN
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)CC/N=C(\c1ccc(F)cc1)c1ccc2cccnc2c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
N,N dimethylethylenediamine (2.5 ml, 3.37 mmol) and Ti(OEt)4 (1.16 ml, 5.46 mmol) were added to a solution of (4-fluoro-phenyl)-(8-nitro-quinolin-7-yl)-methanone 352 (400 mg, 1.35 mmol) in DCM/THF(10 ml:40 ml) under an argon atmosphere and the mixture was stirred at room temperature for 18 h. The mixture was poured into EtOAc/brine and the resulting solution was filtered through celite. The solid residue was washed with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (414 mg, 91%) which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24]([OH:26])=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N:33]1[CH:38]=[CH:37][C:36]([CH2:39]O)=[CH:35][CH:34]=1>>[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:25][C:24]([C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=3)[C:8](=[O:12])[C:9]3[C:4]([C:5]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)=[O:26])=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: OCc1ccncc1
Product: CS(=O)(=O)c1ccc(Cn2c(C(=O)OCc3ccncc3)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid and 4-pyridinemethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](OCCCCCC)[N:3]=1.C[Si]([C:19]#[CH:20])(C)C.[OH-].[Na+]>C(NCC)C.CO.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>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:19]#[CH:20])[N:3]=1
Reactant: CCCCCCOc1cccc(Br)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CCNCC
Solvent: CO
Product: C#Cc1cccc(Br)n1
Temperature: 20 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
A mixture of 7.7 g of 2-bromo-6-hexyloxypyridine (prepared by reacting 2,6-dibromopyridine with sodium hexoxide in DMF), 3.9 g of trimethylsilylacetylene, 0.4 g of bis(triphenylphosphine)palladium(II) chloride and 0.05 g of copper (I) iodide in 100 ml of diethylamine is stirred at 20° C. for 12 hours. After the volatile constituents have been removed in a rotary evaporator, the mixture is filtered through SiO2 using dichloromethane; the crude 1-(2-bromopyridin-6-yl)-2-trimethylsilylethtne (7.5 g of melting point 24° to 27° C.) obtained is stirred for 1 hour at 20° C. in 100 ml of methanol with 25 ml of 1N aqueous NaOH solution. The solvent is evaporated, and the residue is chromatographed over SiO2 using dichloromethane/heptane 9:1, giving 4.3 g of 2-bromo-6-ethynylpyridine (brownish oil). A solution of 2 g of 2-bromo-6-ethynylpyridine in 50 ml of benzene to which 2.6 g of 2-bromo-6-hexyloxypyridine, 0.2 g of tetrakis(triphenylphisphine)palladium(0) and 30 ml of n-propylamine have been added is stirred at 20° C. for 10 hours. The volatile constituents are removed by distillation, and the residue is chromatographed over SiO2 using dichloromethane, giving 1.9 g of 1,2-bis(2-hexyloxypyridin-6-yl)ethyne. The latter is hydrogenated quantitatively in 50 ml of THF using Lindlar catalyst [Org. Synth. 46, 89 (1966)] to 1,2-bis(2-hexyloxypyridin-6-yl)ethene. The latter is dissolved in 500 ml of cyclohexane, 4 mol % of iodine are added, and the mixture is exposed to UV light for 10 hours at 25° C. in a quartz apparatus. Chromatography on SiO2 using dichloromethane and recrystallization from acetonitrile give 0.9 g of 2,7-bis(hexyloxy)-1,8-diazaphenanthrene as colorless crystals of melting point 91° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([PH:8](=[O:12])OCC)[O:5][CH2:6][CH3:7])[CH3:2].[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[CH2:13]([PH:8](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[O:5][CH2:6][CH3:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(OCC)[PH](=O)OCC
Reactant: Cl[Mg]Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(OCC)[PH](=O)Cc1ccccc1

Procedure:
By a procedure analogous to that of Example 1, but using 1.96 g of ethyl diethoxymethylphosphinate and 20 ml of a molar solution of benzylmagnesium chloride in diethyl ether and adding 4.14 g of potassium carbonate in 5 ml of water to precipitate inorganic salts, benzyl(diethoxymethyl)phosphine oxide is obtained as a colourless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: OB(O)c1ccccc1F
Product: COc1cccc2c(-c3ccccc3F)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-Fluoro-phenyl)-5-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 349(MH+).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Br-:18].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C)(C)C1C=CC=CC=1.C[N+](C)(C)C1C=CC=CC=1>ClCCl.CO>[Br:18][C:17]1[C:2]([OH:1])=[CH:3][C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=2[CH:16]=1
Reactant: CCOC(=O)N1CCc2ccc(O)cc2CC1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N1CCc2cc(O)c(Br)cc2CC1
Reaction time: 1 h
Yield: 171 %

Procedure:
Under an argon atmosphere, to a mixed solution of 5.0 g of ethyl 7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 100 ml of dichloromethane and 20 ml of methanol was added portionwise 8.05 g of N,N,N-trimethylanilinium tribromide under ice-cooling, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was extracted by the addition of ethyl acetate and water, and the organic layer was washed with 1 M aqueous hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to obtain 6.67 g of ethyl 7-bromo-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a beige solid.
Reaction SMILES: C(N(CC)CCCl)C.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[C:47]2[CH:48]=[C:49]([N+:52]([O-:54])=[O:53])[CH:50]=[CH:51][C:46]=2[N:45](CCN(CC)CC)[C:44](=[O:62])[C:43]([CH3:64])([CH3:63])[N:42]=1>CCOCC.CCCCCC>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[C:47]2[CH:48]=[C:49]([N+:52]([O-:54])=[O:53])[CH:50]=[CH:51][C:46]=2[NH:45][C:44](=[O:62])[C:43]([CH3:64])([CH3:63])[N:42]=1
Reactant: CCN(CC)CCN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Agent: CCN(CC)CCCl
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
From 25 g (0.073 mol) of 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and 2-diethylaminoethyl chloride there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 60 hours, 5-(o-chlorophenyl)-1,3-dihyro-1-(2-diethylaminoethyl)-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 109° (ether/n-hexane).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:5]=2[S:4](=[O:19])[CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([OH:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:5]=2[S:4](=[O:19])[CH2:3]1
Reactant: CN1CS(=O)c2cc(C(=O)c3ccccc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CS(=O)c2cc(C(O)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
0.02 mol of 3-methyl-6-benzoylbenzothiazolinone prepared in Example 2 are dissolved, with magnetic stirring, in 200 cm3 of methanol in a 250 cm3 flask 0.04 mol of sodium borohydride is added very slowly, with agitation. The agitation is maintained for 4 hours at ambient temperature. The reaction medium is evaporated under vacuum on a water bath. The residue is taken up in water, and the precipitate formed is drained and dried.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](O)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[NH2:26]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:26][C:12](=[O:13])[C:11](=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: O=C(O)C(=C1C(=O)Nc2ccccc21)c1ccccc1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(NC(=O)C(=C2C(=O)Nc3ccccc32)c2ccccc2)cc1OC
Yield: 7.8 %

Procedure:
(2-Oxo-1,2-dihydro-indol-3-ylidene)-phenyl-acetic acid (85 mg) was reacted with 3,4-dimethoxyaniline (110 mg) using method B to give 10 mg (8%) of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[N:13][CH:14]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cn2)noc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cn2)c1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
To a solution of 3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (2.5 g, 10 mmol) in dry THF (34 mL), cooled to 0° C., was added lithiumaluminiumhydride (209 mg, 2.3 mmol) portionwise. After allowing to warm up to room temperature over 1 h, the mixture was cooled to 0° C. and water (0.2 mL) was added carefully followed by aqueous sodium hydroxide (15%, 0.2 mL) and water (0.6 mL). The resulting suspension was stirred for 4 h at ambient temperature and filtered over Hyflo®. The filtrate was then concentrated and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (1.47 g, 71%) as a light yellow solid. MS: m/e=209.1 [M+H]+.
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([Si:25]([CH2:37][CH:38]=[CH2:39])([CH2:34][CH:35]=[CH2:36])[CH2:26][CH2:27][CH2:28][Si:29](OC)([CH3:31])[CH3:30])[CH:23]=[CH2:24]>ClCCl>[CH2:22]([Si:25]([CH2:37][CH:38]=[CH2:39])([CH2:34][CH:35]=[CH2:36])[CH2:26][CH2:27][CH2:28][Si:29]([Br:1])([CH3:31])[CH3:30])[CH:23]=[CH2:24]
Reactant: [Br-]
Reactant: C=CC[Si](CC=C)(CC=C)CCC[Si](C)(C)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CC[Si](CC=C)(CC=C)CCC[Si](C)(C)Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To triphenylphosphine dibromide (2.3 g, 5.5 mmol), distilled dichloromethane (15 ml) was added under a nitrogen atmosphere, to dissolve. Then, a solution, in which {3-(triallylsilyl)propyl}(methoxy)dimethylsilane (32) (1.5 g, 5.0 mmol) is dissolved in distilled dichloromethane (5 ml), was added and stirred at room temperature for 5 hours to obtain {3-(triallylsilyl)propyl}(bromo)dimethylsilane (33). After stirring, glass beads which was treated with Piranha solution was added and stirred further at room temperature for 4 hours. Water was added to the reaction mixture to stop the reaction, then 10% hydrochloric acid was added until the salt was dissolved. After that, glass beads were filtered out and washed each three times with toluene, ethanol and diethyl ether, dried, obtaining a functional material (34) represented by the following chemical reaction equation.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:36]=[CH:35][S:34][CH:33]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C>CO.Cl>[S:34]1[CH:35]=[CH:36][C:32]([CH2:31][NH:30][C:26]2[N:25]=[C:24]([C:23]3[C:18]4[C:19](=[N:20][C:15]([NH:14][CH:11]5[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]5)=[N:16][CH:17]=4)[NH:21][N:22]=3)[CH:29]=[CH:28][N:27]=2)=[CH:33]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5ccsc5)n4)n[nH]c3n2)CC1
Agent: Cl
Solvent: CO
Product: NC1CCC(Nc2ncc3c(-c4ccnc(NCc5ccsc5)n4)n[nH]c3n2)CC1

Procedure:
To a solution of [4-(3-{2-[(thiophen-3-ylmethyl)-amino]-pyrimidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (24 mg, 0.046 mmol) in methanol (30 mL) was bubbled in HCl (gas) for 3 hours at room temperature. The mixture was then concentrated by evaporation to afford N-(3-{2-[(thiophen-3-ylmethyl)-amino]-pyrimidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-cyclohexane-1,4-diamine; hydrochloride. (Yield 25 mg, 96%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[N:3]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:4](=[NH:8])[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(N)sc1C
Reactant: BrCC1CCOCC1
Product: Cc1sc(=N)n(CC2CCOCC2)c1C
Temperature: 85 °C
Yield: 12.6 %

Procedure:
A mixture of 4,5-dimethyl-thiazol-2-ylamine (0.36 g, 2.8 mmol) and 4-bromomethyltetrahydropyran (0.75 g, 4.2 mmol) was heated at 85° C. for 16 hours. The residue purified by preparative HPLC to afford 80 mg (13%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:25][C:26](=[O:33])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:18]([O:25][C:26](=[O:33])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[CH:10][CH:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(CNCCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 64.3 %

Procedure:
The compound (951.6 mg) obtained in Example 103-3 was dissolved in anhydrous methanol (38 ml) and added with (4-amino-butyl)-carbamic acid benzyl ester (898.0 mg) and trimethyl orthoformate (1.33 ml), followed by stirring at room temperature for 15.5 hours. After that, the solution was cooled with ice and added with sodium borohydride (458.5 mg), followed by stirring at room temperature for 1.5 hours. After the reaction, the solvent was distilled off and the residue was then added with water, followed by extraction with chloroform. The extract was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.1479 g) as a colorless oily substance.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:19](=[O:47])[CH2:20][CH2:21][N:22]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:46])[CH:35]=2)[CH:29]=1)[C:23](=[O:27])[CH:24]([Cl:26])[Cl:25])[CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[NH2:8][C@@H:9]([C:19](=[O:47])[CH2:20][CH2:21][N:22]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([C:39]3[C:40]([Cl:46])=[CH:41][CH:42]=[CH:43][C:44]=3[Cl:45])[CH:35]=2)[CH:29]=1)[C:23](=[O:27])[CH:24]([Cl:26])[Cl:25])[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CCC(=O)O)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1

Procedure:
(R)-tert-Butyl 4-(tert-butoxycarbonylamino)-7-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)-5-oxoheptanoate (165 mg) was dissolved in anhydrous dichloromethane (2 mL) and cooled in an ice-bath under nitrogen. Then trifluoroacetic acid (2 mL) was added. After 4.5 h at 4° C. the mixture was concentrated under reduced pressure. The residue was dissolved and concentrated under reduced pressure again to give (R)-4-amino-7-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)-5-oxoheptanoic acid trifluoroacetate salt as a tan solid. 1H NMR (CD3CN): 8.73 (m, 1H), 7.99 (m, 2H), 7.48 (m, 3H), 7.11 (s, 1H), 6.48 (s, 1H), 4.05 (m, 2H), 3.05-2.85 (m, 2H), 2.30 (m, 2H), 2.15 (m, 1H), 1.97 (m, 2H), 1.80 ppm (m, 1H). MW=594 confirmed by LC-MS, tr=10.07 min (Method Y) MH+=592-596.