Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:9][CH2:10][O:11][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
In THF (100 ml) was dissolved N-(tert-butoxycarbonyl)-2-(methylamino)ethanol (3.03 g, 17.3 mmol). To the resulting solution was added methyl 4-hydroxybenzoate (2.77 g, 18.2 mmol) and under stirring at 0° C. in a nitrogen gas stream, triphenylphosphine (6.35 g, 24.2 mmol) and DIAD (3.5 ml, 24.5 mmol) were added. The resulting mixture was stirred further at room temperature for 18 hours. From the reaction mixture, the solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (4:1, v/v) eluate fractions, methyl 4-(2-(N-(tert-butoxycarbonyl)-N-methylamino)ethoxy)benzoate (4.09 g, 76%) was obtained as a yellow oil. The resulting compound (933 mg, 3.01 mmol) was dissolved in methylene chloride (3 ml). To the resulting solution was added trifluoroacetic acid (1 ml) under stirring at 0° C. The reaction mixture was stirred further at room temperature for 2 hours. From the reaction mixture, the solvent was distilled off under reduced pressure. The residue was neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with a chloroform-methanol mixture (5:1, v/v). The extract was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent, whereby methyl 4-(2-(N-methylamino)ethoxy)benzoate (618 mg, 98%) was obtained as a yellow oil.
Reaction SMILES: C(OC([NH:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]O)=[CH:28][CH:27]=3)[N:19]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10])=O)(C)(C)C.C(N(C(C)C)CC)C.[CH3:43][C:44]1[NH:45][CH:46]=[CH:47][N:48]=1.C([NH+](CC)CC)C>C(#N)C.O1CCCC1>[NH2:8][C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][N:45]4[CH:46]=[CH:47][N:48]=[C:44]4[CH3:43])=[CH:30][CH:31]=3)[N:19]=2)=[CH:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: Cc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(CCO)cc3)ncc2Cl)cc1
Agent: CCN(CC)C(C)C
Agent: CC[NH+](CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1nccn1CCc1ccc(Nc2ncc(Cl)c(-c3ccc(C(C)(C)N)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.4 %

Procedure:
A mixture of derivatised resin (1) (55 mg), N,N-diethylisopropylamine (38 mg, 0.30 mmol), and 2-methylimidazole (8 mg, 0.10 mmol) in anhydrous acetonitrile (2 ml) was heated at 70° for 18 h, with agitation. The mixture was allowed to cool to room temperature then diluted with anhydrous tetrahydrofuran (2 ml) and treated with polystyrene methylisocyanate (Argonaut Technologies, 120 mg, 1.65 mmol/g, 0.2 mmol equivalent) and macroporous triethylammonium methylpolystyrene carbonate (Argonaut Technologies, 38 mg, 2.64 mmol/g, 0.1 mmol equivalent). The resulting mixture was agitated at room temperature for 6 h, then filtered and washed once with dichloromethane. The combined filtrate and washings were evaporated to dryness under a stream of nitrogen, then resuspended in dichloromethane (1 mL) and treated with trifluoroacetic acid (1 mL) for 1 h at room temperature. The mixture was evaporated to give the title compound (19.4 mg).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)([CH3:9])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:42][CH2:43][C:44]1[N:49]([CH2:50][C:51](O)=[O:52])[C:48]2[N:54]=[CH:55][CH:56]=[CH:57][C:47]=2[C:46](=[O:58])[N:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:42][CH2:43][C:44]1[N:49]([CH2:50][C:51]([N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH:13]2[CH2:14][CH2:15][N:10]([C:2]([CH3:1])([CH3:9])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4])[CH2:11][CH2:12]2)=[O:52])[C:48]2[N:54]=[CH:55][CH:56]=[CH:57][C:47]=2[C:46](=[O:58])[N:45]=1
Reactant: CC(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
A mixture of 1-methylethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}-amino)-1-piperidinyl]propanoate (Int. B3) (420 mg, 1 equiv), [2-[2-(2,3-difluorophenyl)-ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (300 mg, 1 equiv), HATU (396 mg, 1.2 equiv), DIPEA (0.22 ml, 1.5 equiv) and DMF (3.0 ml) was stirred at room temperature for 30 min. The crude reaction mixture was applied directly to reverse-phase HPLC (Preparative Method A) to obtain 1-methylethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate (171 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:18][C:17]1[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NCc2ccc(Cl)cc2Cl)cc1
Yield: 89.2 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 2,4-dichlorobenzaldehyde (1.8 g) and 4-isopropylaniline (1.4 g) as starting materials, [(2,4-dichlorophenyl)methyl](4-isopropylphenyl)amine (2.7 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29]>O1CCCC1.C(OCC)(=O)C>[C:17]([C:16]([S:13]([CH2:12][CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])(=[O:15])=[O:14])([CH3:21])[CH3:20])(=[O:18])[NH2:29]
Reactant: CC(C)(C(=O)Cl)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C(N)=O)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 91.2 %

Procedure:
A solution of 1.05 g (2.5 mmol) of crude (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride in 29 ml (9.3 mmol) of 0.32M ammonia in tetrahydrofuran was stirred at room temperature for 5 hours. Subsequently, the reaction solution was diluted with 40 ml of ethyl acetate and extracted with 20 ml of 1N hydrochloric acid. The ethyl acetate extract was then washed with 20 ml of saturated sodium hydrogen carbonate solution and 20 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. There was obtained 0.92 g of benzyl rac-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamate as a colourless solid, MS: 312 (M-benzyl)+.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:11]1(O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:1][C:6]2[CH:5]=[CH:4][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:7]=2)=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Oc1ccccc1
Product: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
This compound was prepared in an identical manner as described in Example 1, except p-nitrophenol was substituted for phenol, m.p. 142°-143° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20]C)[CH:15]=[O:16])([O:3]C)=[O:2].O>C(O)(=O)C.Br>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[OH:20])[CH:15]=[O:16])([OH:3])=[O:2]
Reactant: COC(=O)c1ccccc1Sc1cc(C=O)ccc1OC
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc(O)c(Sc2ccccc2C(=O)O)c1

Procedure:
Heat 126 g of the aldehyde of Step C in a mixture of 1500 ml of glacial acetic acid and 1500 ml of 48% hydrogen bromide in an oil bath at 150° C. with mechanical stirring until no trace of non-demethylated product remains (4-5 days). Cool the reaction mixture and pour into 7 l of water. Separate the precipitate, wash well with water and dry in vacuo at 70° C. to constant weight. (Yield: 108.2 g).
Reaction SMILES: [CH:1]1([CH2:7][C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:21]=[CH:20][C:19]2[C:18]([NH2:22])=[C:17]([CH3:23])[CH:16]=[CH:15][C:14]=2[N:13]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[C:18]=2[NH:22][C:8](=[O:9])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:13]=1
Reactant: Cc1ccc2nc(Cl)ccc2c1N
Reactant: O=C(Cl)CC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2nc(Cl)ccc2c1NC(=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cyclohexaneacetyl chloride (prepared according to the method of J. Am. Chem. Soc. 1986, 108,7686) (560 mg) in dichloromethane (5 mL) was added a mixture of 2-chloro-6-methyl-5-quinolinamine (prepared according to the method of Journal of the American Chemical Society 1947, 69, 179) (350 mg) and triethylamine (1 mL) in dichloromethane (5 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into saturated sodium bicarbonate solution and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried, filtered and evaporated to afford the sub-title compound (400 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]2([CH3:20])[OH:13])=[C:4]([O:21][CH3:22])[N:3]=1.C1C(=O)N([I:30])C(=O)C1>C1COCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:30])[N:8]2[C@H:11]2[C@:12]([CH3:20])([OH:13])[C@H:14]([OH:15])[C@@H:16]([CH2:18][OH:19])[O:17]2)=[C:4]([O:21][CH3:22])[N:3]=1
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: COc1nc(N)nc2c1nc(I)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Temperature: 35 °C
Reaction time: 72 h
Yield: 46.5 %

Procedure:
2-Amino-6-methoxy-9-(2-C-methyl-β-D-ribofuranosyl)purine (1.5 g, 4.82 mmol) was suspended in dry THF (40 mL) and 1 mol eq. of NIS (1.1 g, 4.82 mmol) was added. The mixture was warmed to 35° C. and stirred in the dark for 3 days. After that time, solution was concentrated and the resulting solid was purified by silica gel chromatography using 1-4% (gradient) of MeOH in chloroform to yield 980 mg (47% yield) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:17])[CH:3]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)C.[ClH:33]>CO>[ClH:33].[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:17])[CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1cc(=O)[nH]c2cc(OCC3CO3)ccc12
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1cc(=O)[nH]c2cc(OCC(O)CN3CCN(c4ccccc4)CC3)ccc12
Yield: 63 %

Procedure:
2.4 Grams of 4-methyl-7-(2,3-epoxypropoxy)carbostyril and 1.8 g of 4-phenylpiperazine are mixed with 30 ml of ethanol and heated for 3 hours under refluxing conditions. After cooling the reaction mixture, crystals thus precipitated are collected by filtration and washed with ether. The crude crystals thus obtained are dissolved in 50 ml of methanol and 3 ml of concentrated hydrochloric acid. The mixture then is concentrated under reduced pressure to dryness. The residue thus obtained is recrystallized from ethanol-ether to obtain 2.7 g (yield: 63%) of 4-methyl-7-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]carbostyril monohydrochloride in the form of colorless crystals with a melting point of 190°-191° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2F)[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[CH:9]=[CH:8][C:7]([C:6]([NH:5][CH:3]5[CH2:4][N:1]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:2]5)=[O:37])=[CH:12][C:11]=4[O:13][CH3:14])=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CN(S(C)(=O)=O)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
To a solution of N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide (100 mg, 0.19 mmol) in DCM (2.5 mL, 1:2:2) was added DIEA (50 μL, 0.285 mmol), followed by methanesulfonyl chloride (23 μL, 0.21 mmol). After stirring overnight the solvent was removed and the product purified by reverse phase HPLC, free based, and lyophilized to yield a white solid (9.3 mg, 9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.79 (m, 6 H) 1.96 (br. s., 2 H) 3.05 (s, 3 H) 3.92 (s, 3 H) 3.94 (d, J=1.77 Hz, 2 H) 4.03-4.15 (m, 4 H) 4.61-4.72 (m, 1 H) 4.76-4.87 (m, 1 H) 7.24 (d, J=6.57 Hz, 1 H) 8.08 (s, 1 H) 8.27 (d, 1 H) 8.31 (s, 1 H) 8.73 (d, J=3.79 Hz, 1 H). [M+H] calc'd for C25H30F3N7O5S, 598; found 598.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.[H-].[Na+].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][S:22]([CH3:21])(=[O:24])=[O:23])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(Cl)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OS(C)(=O)=O)cc(Cl)c21
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-(4-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (60 mg, 0.22 mmol) in DMF (3 mL) was slowly added NaH (27 mg, 0.66 mmol) at 0° C. The reaction mixture was stirred for 20 min and MsCl (29 mg, 0.27 mmol) was added. The reaction mixture was stirred overnight at room temperature and quenched with ice water. The resulting mixture was extracted with EtOAc (2×15 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step reaction without further purification. MS (ESI) m/z=349 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[C:16]([NH2:29])[N:15]=2)[CH2:12][CH2:11][CH2:10]1.O>C(Cl)(Cl)Cl>[Br:1][C:19]1[N:20]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:21]2[C:17]([N:18]=1)=[C:16]([NH2:29])[N:15]=[C:14]([O:13][CH:9]1[CH2:12][CH2:11][CH2:10]1)[N:22]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(OC2CCC2)nc2c1ncn2C1CCCCO1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc(OC2CCC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 25 °C
Yield: 112.8 %

Procedure:
N-Bromosuccinimide (1.152 g, 6.47 mmol) was added to a stirred solution of 2-(cyclobutyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.248 g, 4.31 mmol) in chloroform (15 ml) at 0° C. The mixture was warmed to room temperature and left overnight when water (15 ml) was added and the phases separated. The aqueous layer was extracted with dichloromethane and the organic extracts were combined, washed with brine, dried over anhydrous magnesium sulphate and evaporated to give the title compound as an orange foam (1.79 g).
Reaction SMILES: I[C:2]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][C:21]1[C:20]([CH3:24])=[CH:19][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[CH:22]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3I)c2cc1OC
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3-c3cccnc3)c2cc1OC
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
4-(2-Iodo-4,5-dimethyl-phenoxy)-6,7-dimethoxyquinoline (compound 164) (59 mg), pyridine-3-boronic acid (33 mg), and tetrakistriphenylphosphine palladium (10 mg) were dissolved in N,N-dimethylformamide (4 ml), a 2 M aqueous potassium carbonate solution (0.5 ml) was added to the reaction system, and the mixture was stirred at 100° C. for 30 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (13 mg, yield 25%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[C:12](Cl)(=O)[CH2:13][CH2:14]CC>C(Cl)Cl.C(C(C)=O)C>[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH2:5][CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCC(=O)Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCCCC(=O)CC(=O)OC
Yield: 95.5 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 138.7 g (1.15 mol) of valeryl chloride. The pH in this gave 151 g (GC purity 82.5%) of methyl valerylacetate (yield 79.0%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[N:13][C:12]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]2=3)[CH2:4][CH2:3]1.[N:23]1[C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=[C:25]([CH:33]=O)[N:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(Cl)[Cl:55]>CO>[ClH:55].[ClH:55].[N:23]1[C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=[C:25]([CH2:33][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:15](=[O:16])[CH:14]=[N:13][C:12]4[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]3=4)[CH2:6][CH2:7]2)[N:24]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Reactant: ClCCl
Reactant: O=Cc1cc2c(nn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(nn4)OCCO5)CC3)c2n1
Product: Cl
Reaction time: 24 h
Yield: 35 %

Procedure:
A solution of 4-[2-(4-amino-1-piperidinyl)ethyl]-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one (50 mg, 0.1648 mmoles) and 6,7-dihydro[1,4]dioxino[2,3-c]pyridazine-3-carbaldehyde (30.1 mg, 0.181 mmoles) in anhydrous DCM (5 ml) and anhydrous MeOH (0.5 ml) was stirred at rt for 5 minutes. Sodium triacetoxyborohydride (115 mg, 0.543 mmoles) was added and the mixture was stirred, under argon, for 24 hours. A further 6,7-dihydro[1,4]dioxino[2,3-c]pyridazine-3-carbaldehyde (15 mg, 0.09 mmoles) and sodium triacetoxyborohydride (50 mg, 0.236 mmoles) were added and reaction was stirred for 5 hours, treated with sat. aq. NaHCO3 solution (2 ml) and 9:1 DCM:MeOH (5 ml). The layers were separated and the aqueous layer was washed with 9:1 DCM:MeOH (10 ml) and 5:1 DCM:MeOH (2×20 ml). The organic extracts were combined, passed through a hydrophobic frit and evaporated to an orange gum. Purification on a 20 g silica column eluted with a 20:1 to 10:1 DCM:MeOH gradient elution gave the free base of the title compound as a pale yellow gum (26.1 mg, 35%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([Cl:12])=[C:6]2[S:5][CH:4]=1.[OH:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1>C1(OC)C=CC=CC=1>[ClH:12].[CH3:1][O:2][C:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([OH:18])=[CH:20][C:21]=3[CH3:26])=[C:6]2[S:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2c(OC)csc2c1Cl
Reactant: Cc1cc(O)ccc1N
Solvent: COc1ccccc1
Product: CCOC(=O)c1cnc2c(OC)csc2c1Nc1ccc(O)cc1C
Product: Cl

Procedure:
Ethyl 3-methoxy-7-chlorothieno[3,2-b]pyridine-6-carboxylate (1.5 g, 0.0055 mol) and 4-hydroxy-2-methylaniline (1.36 g, 0.011 mol) in anisole (30 ml) were heated under reflux in an inert atmosphere for thirty hours. The solid obtained on cooling was collected by filtration and recrystallised from ethanol to give a brown crystalline solid, 1.09 g. Recrystallisation from ethanol after filtration through charcoal gave the title compound, 0.63 g, m.p. 286°-288°.
Reaction SMILES: C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([CH:24]1[CH2:28][CH2:27][C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[C:32]([F:39])[C:31]=2[F:40])(O)[CH2:25]1)[CH2:21][CH2:22][CH3:23]>O>[CH2:20]([CH:24]1[CH2:28][CH2:27][C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[C:32]([F:39])[C:31]=2[F:40])=[CH:25]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCC1CCC(O)(c2ccc(OCC)c(F)c2F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC1C=C(c2ccc(OCC)c(F)c2F)CC1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
Toluene (50 ml) and p-toluenesulfonic acid monohydrate (0.14 g) were added to 3-butyl-1-(4-ethoxy-2,3-difluorophenyl)cyclopentanol (2.8 g) obtained in the second step, in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen. The mixture was refluxed for 30 minutes, while forming water was removed with a Dean-Stark apparatus. The reaction solution was cooled to room temperature and was washed with water. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane= 1/9 by volume) to give a mixture (2.4 g) of 1-(3-butylcyclopent-1-enyl)-4-ethoxy-2,3-difluorobenzene and 1-(4-butylcyclopent-1-enyl)-4-ethoxy-2,3-difluorobenzene.