Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[CH3:12].S(=O)(=O)(O)O>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To a suspension of 24.9 g (100.4 mmol) of 4-iodobenzoic acid in 46.25 g (58.9 ml, 1.0 mol) of ethanol (100%) was added 3.0 ml of conc. sulfuric acid. The resulting mixture was refluxed for 60 minutes, and then distilled until a clear, homogeneous solution was obtained. The solution was allowed to cool to room temperature, partitioned between 250 ml of water and 250 ml of pentane, and the layers were separated. The aqueous phase was washed with 3×100 ml-portions of pentane. All organic phases were combined, washed with brine solution, dried over MgSO4, filtered and concentrated in vacuo to a dark yellow oil. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) yielded the title compound as a clear, light yellow oil. PMR (CDCl3): d 1.39 (3H, t, J=7.2 Hz), 4.37 (2H, q, J=7.2 Hz), 7.73-7.82 (4H, m).
Reaction SMILES: [CH2:1]([C:7]1[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=1[O:9]C1CCCCO1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.C([O:28][B:29](OC(C)C)[O:30]C(C)C)(C)C.Cl>C1COCC1.CCOCC>[CH2:1]([C:7]1[C:8]([OH:9])=[C:16]([B:29]([OH:30])[OH:28])[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCc1ccccc1OC1CCCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCc1cccc(B(O)O)c1O
Reaction time: 0.17 h
Yield: 26.4 %

Procedure:
2-(2-Hexylphenoxy)tetrahydropyran (1.162 g, 4.43 mmol) was dissolved in dry THF (20 ml) and the solution cooled to 0° C. n-Butyl lithium (1.6M in hexanes, 4.15 ml, 6.64 mmol) was added dropwise with stirring over 10 minutes. The ice-bath was removed and the reaction stirred at room temperature overnight. Triisopropoxy borane (1.43 ml, 6.2 mmol) was added and stirring continued for 24 hours. The reaction was quenched with water, acidified to pH 1 with 2N hydrochloric acid and extracted with ether (20 ml). The combined organic extracts were washed with 2N hydrochloric acid (50 ml), dried with sodium sulphate and concentrated under vacuum. The oily solid produced was dissolved in ether (30 ml) and stirred with 2N hydrochloric acid (15 ml) for 1 hour. The organic phase was separated, dried with sodium sulphate and concentrated under vacuum. The residue was triturated with cyclohexane and the solid filtered off to give the title compound (260 mg, 26%); MS 221 (M−H)−.
Reaction SMILES: C[Al](C)C.CO[C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[C:23]([CH3:24])=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30]>C1(C)C=CC=CC=1.O>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH:30][C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[C:23]([CH3:24])=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8]
Reactant: COC(=O)c1sccc1Nc1ncnc2[nH]cc(C)c12
Reactant: NCc1cccc(Cl)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c[nH]c2ncnc(Nc3ccsc3C(=O)NCc3cccc(Cl)c3)c12
Temperature: 70 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
Trimethyl aluminum (0.35 mL, 0.69 mmol, 2M in toluene) was added to a solution of 3-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester (50 mg, 0.17 mmol) and 3-chlorobenzylamine (0.11 mL, 0.87 mmol) in toluene (2 mL), and stirred overnight at 70° C. The reaction mixture was cooled to room temperature, diluted with H2O and EtOAC, and filtered through an Extrelut column. The column was washed with EtOAC and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 100% EtOAC in hexanes to provide the desire product (34 mg, 49% yield) as an off-white solid. LC-MS (M+H=398, obsd.=398).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:19])[N:4]([CH3:18])[C:5]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[H-].[Na+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26]Br>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([OH:1])[C:3](=[O:19])[N:4]([CH3:18])[C:5]=2[C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[C:10]1=[O:12]
Reactant: CN(C)C(=O)c1c2c(c(O)c(=O)n1C)C(=O)NCC2
Reactant: Fc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
4-Hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (0.43 g, 0.0016 mol) was dissolved in 10 mL dry DMF and 100 mg NaH was added. The mixture was allowed to stir until the bubbles ceased, then 3-chloro-4-fluoro benzyl bromide (0.362 g, 0.0016 mole) was added. The reaction was quenched with 30 mL of a 10% aq KHSO4 solution and diluted with 100 mL chloroform. The reaction was further diluted with 100 mL brine and allowed to stir vigorously for 30 minutes. The layers were separated and the aqueous layer was washed with chloroform. The organic fractions were combined and dried over NaSO4, filtered and concentrated under high vacuum to remove the DMF (yield 0.5 g, 75%). HPLC analysis showed 85% purity. The solid product was crystallized first from isopropanol, then from ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:34][CH3:35])=[C:16]([CH:23]4[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)[C:17]([C:21]#[N:22])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([C:21]#[N:22])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:34][CH3:35])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CNC1
Reaction time: 1 h

Procedure:
The tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate (0.35 g, 0.73 mmol) (Step 7, peak 1) was dissolved in methylene chloride (3.0 mL) and trifluoroacetic acid (1.0 mL) at room temperature. After stirring for 1 h the reaction was complete by LC/MS. The reaction was concentrated in vacuo to give 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-methoxy-6-methylbenzonitrile (bis(trifluoroacetate) as a viscous amber oil (0.50 g, 100%). LCMS calculated for C20H24N7O (M+H)+: m/z=378.2; found: 378.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[NH:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[NH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)C(c1cccc(Cl)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)C(c1cccc(Cl)c1)CC2
Yield: 63 %

Procedure:
The title compound was synthesized from methyl 6-(3-chlorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.099 g, 0.36 mmol) and lithium hydroxide (0.151 g, 3.60 mmol in 2 mL water), according to General Procedure 7. A 1:2 mixture of methanol (MeOH) and THF (3-4 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford a light pink solid: 0.059 g (63% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.23 (ddt, J=13.18, 8.25, 5.25, 5.25 Hz, 1H), 2.62 (ddd, J=14.31, 8.70, 5.34 Hz, 1H), 2.74 (ddd, J=14.22, 8.63, 5.22 Hz, 1H), 2.89-2.99 (m, 1H), 4.25 (dd, J=8.57, 5.15 Hz, 1H), 6.68 (s, 1H), 7.02-7.05 (m, 1H), 7.10 (t, J=1.83 Hz, 1H), 7.18 (ddd, J=7.97, 2.04, 1.17 Hz, 1H), 7.25 (t, J=7.79 Hz, 1H); LCMS-MS (ESI−) 260.0 (M−H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>O.CC(OC)(C)C>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
To a flask equipped with a nitrogen inlet, addition funnel, thermowell, and mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and dimethylacetimide (9.6 L). The mixture was cooled to −5° C. in an ice/brine bath and sodium hydride (NaH, 60 wt %, 174 g, 4.35 mol, 1.1 equiv) was added in portions as a solid. The mixture went to a dark solution during 15 minutes and trimethylsilylethoxymethyl chloride (2, 763 mL, 4.31 mol, 1.1 equiv) was added slowly via an addition funnel at a rate that the temperature did not exceed 5° C. The reaction was stirred for 30 minutes, determined to be complete by TLC and HPLC, and water (1 L) was slowly added to quench the reaction. The mixture was then diluted with water (12 L) and MTBE (8 L). The layers were separated and the aqueous was re-extracted with MTBE (8 L). The combined organic layers were washed with water (2×4 L) and brine (4 L), dried over sodium sulfate (NaSO4), and solvents removed under reduced pressure. The residue was dissolved in heptane (2 L), filtered and loaded onto a silica gel (3.5 kg) column eluting with heptane (˜6 L), 95% heptane/ethyl acetate (˜12 L), 90% heptane/ethyl acetate (10 L), and finally 80% heptane/ethyl acetate (10 L). The pure fractions were combined and concentrated under reduced pressure to give 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 987 g, 1109.8 g theoretical, 88.9% yield) as a pale yellow oil that partially solidified to an oily solid on standing at room temperature. For 3a: 1H NMR (DMSO-d6, 300 MHz) δ ppm 8.67 (s, 1H), 7.87 (d, 1H, J=3.8 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.1 Hz), 1.24 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, −1.48; C12H18ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[C:9]([CH2:17][C:18](=O)[CH3:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O.[OH-].[Na+]>O.C(O)(=O)C>[NH2:8][C:4]1[N:3]=[C:2]2[C:7]([C:18]([CH3:19])=[CH:17][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:1]2)=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(-c2ccccc2)nc2nc(N)ccc12
Reaction time: 24 h

Procedure:
2,6-Diaminopyridine (16.4 g., 0.15 mole), 24 g. of benzoylacetone, 75 ml. of acetic acid and 1.5 ml of 96% sulfuric acid was refluxed with stirring for 24 hours. The solution was poured slowly with stirring into 50 g. of sodium hydroxide in 250 ml. of water; the temperature was held 20°-30° by cooling. The tan solid was filtered, washed well with water and dried, 21.8 g. One recrystallization from 100 ml. of 95% ethanol gave 6.9 g. of coarse needles, m.p. 65°-190°; a second recrystallization from 50 ml. of ethanol furnished 2.1 g. (6) of the title compound, m.p. 253°-255°; 1H nmr (deuteriochloroform+DMSO-d6, 60 MHz): δ2.67 (s,3H, CH3), 6.20 (broad exchangeable s, 2H, NH2), 6.92 (d, 1H, H5, J=9 Hz), 7.58 (d,1H, H6), 7.50 (m,3H,meta and para protons on C6H5), 8.30 (m,2H, ortho protons on C6H5).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C@@H:9]1[O:11][CH2:10]1)Cl.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)#[N:13]>CC#N>[O:11]1[CH2:10][C@H:9]1[CH2:7][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OC[C@@H]2CO2)cc1
Yield: 90 %

Procedure:
Potassium carbonate (414 g) and (R)-(−)-epiclorohydrin (800 mL) were added to a stirred solution of p-cyanophenol (238 g) in 2.0 L MeCN and the reaction mixture was refluxed under an inert atmosphere for 2 h. The hot solution was filtered and the filtrate concentrated, giving a clear oil which was crystallised from di-iso-propyl ether giving the product in 90% yield.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Product: O=C(O[C@H]1CCNC1)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)acetic acid and t-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:16][C:17]1[C:18]([CH3:23])=[N:19][O:20][C:21]=1[CH3:22]>CN(C=O)C.O>[CH3:23][C:18]1[C:17]([CH2:16][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[C:21]([CH3:22])[O:20][N:19]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc([N+](=O)[O-])cn1
Yield: 67.5 %

Procedure:
1H-pyrazole (10 g, 147 mmol) was added in small portions to concentrated H2SO4 (100 mL), cooled to 0° C. via an ice/water bath, maintaining the internal reaction temperature below 40° C. Concentrated HNO3 (10 mL) was carefully added, dropwise, to the reaction mixture maintaining the internal reaction temperature below 55° C. The reaction was then heated to 55° C. and stirred for 5 hours. The mixture was cooled to 0° C. and carefully made basic (pH˜8) with aqueous NaOH solution (110 g NaOH in 150 mL H2O) until a white precipitate formed, carefully ensuring the internal temperature of the solution remain below 40° C. The white solid was collected by filtration and washed with ethyl acetate/hexanes (1/3) then dried en vacuo to afford 4-nitro-1H-pyrazole (7 g, 42%, isolated yield). 13C NMR (DMSO-d6, 137.0, 126.4. To 4-nitro-1H-pyrazole (9 g, 80 mmol) in DMF (100 mL) 100 MHz) δ was added cesium carbonate (26 g, 80 mmol) followed by the addition of 4-(chloromethyl)-3,5-dimethylisoxazole (12.3 g, 85 mmol). The reaction mixture was stirred in DMF (100 mL) at 80° C. for 30 minutes, then cooled, diluted with H2O (150 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was taken up in ethyl acetate (200 mL) and washed with H2O (2×, 100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The solid product was triturated with ethyl acetate/hexanes(1/9) and collected by filtration. The product was dried under high vacuum to afford 3,5-dimethyl-4-((4-nitro-1H-pyrazol-1-yl)methyl)isoxazole (12 g, 67%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz): δ 2.23 (s, 3H), 2.46 (s, 3H), 5.08 (s, 2H), 8.02 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: C[C:2]1[C:3]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:21][CH:20]=2)[CH2:17][CH2:16][NH:15][CH2:14]1)[C:5]([OH:7])=[O:6].[OH-].[Na+].Cl>CO>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][CH2:28][CH2:27][CH2:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH:18]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[O:12][CH2:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:2]=2)=[CH:24][CH:23]=1
Reactant: COCCCOc1c(C(=O)O)ccc(COC2CNCCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCOc1cc(COC2CNCCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
The solution of 0.025 g of methyl 4-(4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidin-3-yloxymethyl)-2-(3-methoxypropoxy)benzoic acid (Example 29) in 0.200 ml of methanol is admixed with 0.200 ml of 1M NaOH and stirred at 65° C. over 1 hour. The reaction mixture is cooled, admixed with 0.100 ml of 2M HCl and extracted with ethyl acetate (3×2 ml). The organic phases are concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.19 (750:270:50:5 dichloromethane-methanol-water-AcOH); Rt=4.08.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[CH2:11][C:12]([NH2:14])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][C:12]([NH2:14])=[O:13])#[CH:2]
Reactant: C#Cc1cccc(O)c1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#Cc1cccc(OCC(N)=O)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 90.1 %

Procedure:
A mixture of 3-ethynylphenol (3.31 g, 28.0 mmol), 2-bromoacetamide (2.36 g, 17.1 mmol) and K2CO3 (5.53 g, 40.0 mmol) in acetone (50 mL) was stirred at 70° C. for 7 h. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (2.70 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[CH2:27]([O:34][CH2:35][CH2:36][CH2:37][C:38](Cl)=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C1COCC1>[CH2:27]([O:34][CH2:35][CH2:36][CH2:37][C:38]1[N:6]=[C:4]([OH:5])[C:3]2[C:2](=[CH:10][C:9]([C:11]3[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:8][CH:7]=2)[N:1]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)CCCOCc1ccccc1
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Oc1nc(CCCOCc2ccccc2)nc2cc(-c3ncccc3C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (3.56 mmol) and pyridine (3.91 mmol) in THF (20 ml) add 4-benzyloxy-butyryl chloride (3.91 mmol). Stir the mixture 20 minutes at room temperature, add 20 ml of 20% NaOH, stir for 60 minutes at 50° C. Concentrate, add water, filter, acidify to pH=6, collect the precipitate to obtain 2-(3-benzyloxy-propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[C:13]([NH:15][N:16]=[CH:17][C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[CH3:22][O:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:25]=1.N12CCCN=C1CCCCC2.Cl>CN(C)C(=O)C>[CH3:31][O:30][C:28]1[N:29]=[C:24]([O:23][CH3:22])[N:25]=[C:26]([NH:32][C:33]([NH:1][S:2]([C:5]2[CH:14]=[C:13]([NH:15][N:16]=[CH:17][C:18]([F:19])([F:20])[F:21])[CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:3])=[O:4])=[O:34])[N:27]=1
Reactant: COC(=O)c1ccc(NN=CC(F)(F)F)cc1S(N)(=O)=O
Reactant: COc1nc(NC(=O)Oc2ccccc2)nc(OC)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(NN=CC(F)(F)F)cc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
At room temperature, 166 mg (0.5 mmol) of methyl 2-(aminosulfonyl)-4-[(2,2,2-trifluoroethlidene)hydrazino]benzoate and 138 mg (0.5 mmol) of phenyl (4,6-dimethoxy1,3,5-triazin-2-yl)carbamate were dissolved in 1.5 ml of N,N-dimethylacetamide. Then, 86.1 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene were added, followed by stirring for 5 minutes. The resultant mixture was allowed to stand for 6 hours. Thereafter, 0.2 ml of 35% hydrochloric acid was added to 30 ml of ice water, followed by the addition of the reaction mixture in 0.2 ml portions under stirring. After the reaction mixture was stirred for 20 minutes, the resulting precipitate was collected by filtration and dried in air. Using as an eluent a 1:9 mixed solvent of methyl acetate and benzene, the crude product was purified by chromatography on a column of silica gel ("WAKO GEL C-300", trade name; product of Wako Pure Chemical Industries, Ltd.). The title compound was obtained as a white solid. Yield: 103 mg (41%). Melting point: 117°-119° C. (foamed). Its physicochemical properties are shown in Table 4.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(OC(F)(F)F)cc4)cc3CC[C@@H]12
Reaction time: 24 h
Yield: 54.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 4-trifluoromethoxyphenylboronic acid (161 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was healed at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 137 mg (56%) of the title compound as a waxy solid. FDMS: m/e=389. α[D]589 =+48.95 (c=0.96, chloroform).
Reaction SMILES: C(O[C:4](OCC)([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])C.[Br:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:24]=1[NH2:25].C(O)(=O)C>>[Br:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:24]=1[N:25]=[C:4]([CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1c(F)cccc1Br
Reactant: CCOC(=O)CCC(CCC(=O)OCC)(OCC)OCC
Solvent: CC(=O)O
Product: CCOC(=O)CCC(CCC(=O)OCC)=Nc1c(F)cccc1Br
Temperature: 145 °C

Procedure:
To the ketal of Step 1 (8.46 kg, 24.31 mol), were charged 2-bromo-6-fluoroaniline (2.509 L, 22.10 mol) and acetic acid (0.253 L, 4.42 mol) under nitrogen. The mixture was heated to 145° C. and ethanol was removed by distillation. The product was used in the next reaction.