Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH2:16]([O:18][C:19](=[O:49])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:18][C:19](=[O:49])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15])[CH3:17]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCCOc2ccc(C(=O)c3cccc(C(=O)OCC)c3)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Yield: 80.2 %

Procedure:
A mixture of 0.144 g (0.70 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 0.371 g (0.70 mmol) of 2-[(6-bromohexyl)oxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, 0.479 g (3.47 mmol) of anhydrous granular potassium carbonate and 13.1 mL of 2-butanone was stirred and refluxed for 18 hr. The resulting slurry was filtered with suction and the solids washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the residue was purified by flash chromatography on 75 g of silica gel, eluting with 3:1 hexane-ethyl acetate, giving 0.37 g (80.6%) of 2-[6-[(2,3-dihydro-4-oxo-8-propyl-4H-1-benzopyran-7-yl)oxy]hexyloxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester as a white solid, mp 58°-59.5° C. A mixture of 0.331 g (0.50 mmol) of this ester in 6 mL of THF and 6 mL of water was treated with 64.7 mg (1.54 mmol) of lithium hydroxide monohydrate and the resulting mixture was stirred for 25.5 hr at room temperature, before being acidified with 17 mL of 3N aqueous sulfuric acid. Work-up with ethyl acetate in the usual manner gave a crude product which was recrystallized from hexane-ethyl acetate affording 0.242 g (79.7%) of the title compound as a white solid, mp 169°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[CH2:15](C(C(OC)=O)C(OC)=O)[CH3:16]>>[Cl:8][C:6]1[C:7]([CH2:15][CH3:16])=[C:2]([Cl:1])[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]=1
Reactant: CCC(C(=O)OC)C(=O)OC
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Product: CCc1c(Cl)nc(N2CCOCC2)nc1Cl

Procedure:
4,6-Dichloro-5-ethyl-2-morpholinopyrimidine was prepared by similar procedure as 4,6-dichloro-2-morpholinopyrimidine (in Method 22) using dimethyl 2-ethylmalonate in place of diethyl malonate. LC/MS (m/z): 262.1 (MH+), Rt 3.59 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:26])[N:4]([CH3:25])[C:5]([NH:14][CH2:15][CH:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[C:27]1(=O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[O:28]1.C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl>[NH2:24][CH:16]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:15][NH:14][C:5]1[N:4]([CH3:25])[C:3](=[O:26])[C:2]([N:1]2[C:27](=[O:28])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:36])=[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:6]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cn1c(NCC(N)Cc2ccccc2)nc(-c2ccncc2)c(N)c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(NCC(N)Cc2ccccc2)nc(-c2ccncc2)c(N2C(=O)c3ccccc3C2=O)c1=O
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 5-amino-2-(2-amino-3-phenyl-propylamino)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (100 mg, 0.22 mmol), and isobenzofuran-1,3-dione (50 mg, 0.33 mmol) in DMF (0.5 mL) was heated under microwave irradiation (150° C.) for 10 min. The cooled mixture was diluted with CH2Cl2 (2 mL) followed by the addition of TFA (1 nL). After being stirred at room temperature for 6 h, the mixture was concentrated, partitioned between NaHCO3 (aq) and CH2Cl2. The organic residue was purified on silica (1–10% MeOH in CH2Cl2) to afford the desired product as a light yellow solid. M+1 481.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:10]([O:12][C:13](=[O:22])[CH:14](Br)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH3:11]>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:22])[CH:14]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:11]
Reactant: Oc1ccccn1
Reactant: CCOC(=O)C(Br)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1ccccn1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3 %

Procedure:
Sodium hydride (520 mg; 21.8 mmol; 1.4 equiv) was stirred with 2-hydroxypyridine (1.73 g; 18.2 mmol; 1.2 equiv) in DMF (30 mL) for 15 min. This solution was added to an aliquot of bromo-pyridin-3-yl-acetic acid ethyl ester (approx. 3.6 g; 15 mmol) in DMF (20 mL). After stirring overnight, at rt., the resulting opaque black solution was concentrated in vacuo, dissolved in 20% isopropyl alcohol/chloroform, washed 5 times with saturated NaHCO3(aq), washed twice with saturated NaCl(aq), and dried over Na2SO4(s). After filtration, the solution was concentrated in vacuo and purified by SiO2 column chromatography on two consecutive columns with a 1% methanol/chloroform mobile phase and then an ethyl acetate/hexanes mobile phase (30%, 40%, 50% step gradient). A light yellow oil (134 mg; approx. 3% yield) was isolated. MS(ES) calc'd: [M+H]+=259.2 m/z. Found: 259.1 m/z.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[C:17]([C:24]([F:27])([F:26])[F:25])[C:16]=1[CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH:1]1([NH:6][C:15]2[N:20]3[N:21]=[CH:22][N:23]=[C:19]3[N:18]=[C:17]([C:24]([F:26])([F:27])[F:25])[C:16]=2[CH2:28][CH2:29][CH3:30])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCc1c(C(F)(F)F)nc2ncnn2c1Cl
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(C(F)(F)F)nc2ncnn2c1NC1CCCC1
Yield: 82.7 %

Procedure:
With stirring, a mixture of 0.13 g (1.5 mmol) of cyclopentylamine and 0.15 g (1.5 mmol) of triethylamine in 10 ml of methylene chloride was added to a mixture of 0.40 g (1.5 mmol) of 7-chloro-6-propyl-5-trifluoromethyl-[1,2,4]-triazolo-[1,5-α]-pyrimidine (cf. Ex. 5) in 20 ml of methylene chloride. The reaction mixture was stirred at room temperature for 16 h, work-up was carried out analogously to Ex. 3. This gave 0.39 g (1.24 mmol) of the title compound (melting point 179° C.).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]2[N:16]([N:30]=[C:31]([NH:33]C(OCC[Si](C)(C)C)=O)[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:33][C:31]1[CH:32]=[C:15]2[N:14]=[C:13]([CH3:43])[C:12]([C@H:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:17]([C:18]3[C:19]([CH3:29])=[C:20]4[C:25](=[C:26]([F:28])[CH:27]=3)[O:24][CH2:23][CH2:22][CH2:21]4)[N:16]2[N:30]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(NC(=O)OCC[Si](C)(C)C)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(N)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
A mixture of (2S)-ethyl 2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-((2-(trimethylsilyl)ethoxy)carbonylamino)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (2.3 g, 3.74 mmol), 1M TBAF (4.49 mL, 4.49 mmol) in THF (20 mL) was stirred at rt for 3 h. It was then concentrated, diluted with water, and extracted with EtOAc. The organic phase was washed with water, dried over MgSO4, filtered and concentrated to yield 1.5 g (85%) of (2S)-ethyl 2-(2-amino-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as a oil which solidified upon standing for one day. 1H NMR (500 MHz, CDCl3) δ 6.87 (d, J=10.56 Hz, 1H), 5.88 (s, 1H), 4.85 (s, 1H), 4.33 (t, J=5.04 Hz, 2H), 4.08-4.14 (m, 4H), 2.76 (t, J=6.38 Hz, 2H), 2.71 (s, 3H), 2.13-2.21 (m, 2H), 1.87 (s, 3H), 1.20 (t, J=7.17 Hz, 3H), 1.16 (s, 9H). LCMS (M+H)=471.36.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=1)(=O)C>Cl>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=1
Reactant: CC(=O)OCc1ccc(Br)cn1
Agent: Cl
Product: OCc1ccc(Br)cn1

Procedure:
A solution of 40 g (170 mmol) 2-(acetoxymethyl)-5-bromopyridine in conc. HCl (200 ml) was heated to reflux for 1 hour. The solution was concentrated in vacuo and the residue was neutralized with aq. KHCO3 and extracted with CH2Cl2. Concentration of the extract afforded 2-hydroxymethyl-5-bromopyridine. 1H-NMR (400 MHz, DMSO) δ 8.57 (d, J=2.4 Hz, 1H), 8.00 (m, 1H), 7.42 (q, J1=8.4 Hz, J2=0.6 Hz, 1H), 5.49 (t, J=5.4 Hz, 1H), 4.50 (d, J=4.8 Hz, 2H) m/z: 189.12 (M+1)
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:2].Br[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH:1]=[O:2])=[CH:4]1)[CH3:19]
Reactant: CCOC(=O)CCBr
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCn1cc(C=O)c2ccccc21
Reaction time: 48 h
Yield: 103.4 %

Procedure:
A mixture of 3-formylindol (10 g, 69 mmol), ethyl 3-bromopropionate (10.5 mL, 83 mmol) and potassium carbonate (28.5 g, 207 mmol) and acetonitrile (100 mL) was stirred vigorously at refux temperature for 2 days. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo to afford 17.5 g (quant.) of 3-(3-formylindol-1-yl)propionic acid ethyl ester as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[CH2:14][C:15](=O)[N:16]([CH3:18])[CH2:17][C:12]3=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]([CH3:18])[CH2:17][C:12]3=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ncc3n2CC(=O)N(C)C3)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(-c2ncc3n2C=CN(C)C3)c1
Reaction time: 0.75 h

Procedure:
A mixture of 3-(3-Methoxyphenyl)-7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-6-one (65 mg) and 1N lithium aluminum hydride in tetrahydrofuran (2 mL) in tetrahydrofuran (4 mL) was kept at room temperature for 45 min. After quenching the reaction with 2N sodium hydroxide the reaction was filtered through celite and the solvent was removed in vacuo. The residue was subjected to flash chromatography on silica gel with 5% methanol in chloroform as the eluent to afford 3-(3-Methoxyphenyl)-7-methyl-7,8-dihydro-imidazo[1,5-a]pyrazine followed by 3-(3-Methoxyphenyl)-7-methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine whose mono fumarate salt (Compound 32) was crystallized from ethanol/ether and melted at 211°-214°.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[NH:20]2)=[CH:9]1)(C)(C)C.[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)#[N:32]>>[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:20]2[CH:19]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[CH:9]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:29])=[O:28])=[CH:35][CH:34]=1)#[N:32]
Reactant: COc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)cc1
Product: COc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1Cc1ccc(C#N)cc1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 4, step c) and 4-cyanobenzyl bromide. MS: ESI (negative): 486 (M−H).
Reaction SMILES: [CH:1]1([N:7]([CH3:30])[CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])[CH:16]=[CH:17][C:18]=2[N+:19]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:31]#[C:32]Br>C(O)C>[NH2:31][C:32]1[N:11]([CH2:10][CH2:9][CH2:8][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:30])[CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])[CH:14]=2)[N:19]=1
Reactant: N#CBr
Reactant: CN(CCCNCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-])C1CCCCC1
Solvent: CCO
Product: CN(CCCN1Cc2cc(C(=O)c3ccccc3)ccc2N=C1N)C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of (3-{[3-(Cyclohexyl-methyl-amino)-propylamino]-methyl}-4-nitro-phenyl)-phenyl-methanone (0.0037 mol) in ethanol (40 mL) was stirred at room temperature. Cyanogen bromide (0.0055 mol) was added, and the reaction mixture was stirred and refluxed for 4 hours, then cooled and the resulting precipitate was filtered off and dried. This fraction was recrystallized from CH3CN, then filtered off and recrystallized from methanol, filtered off, washed with diisopropyl ether, then dried to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]#[C:20][CH2:21][CH2:22][NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>N.CO.O.C1COCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]#[C:20][CH2:21][CH2:22][NH:23][C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28]
Reactant: CC(C)(C)C(=O)NCCC#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: N
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCCC#Cc1c(Cl)ccc2c1CCNCC2
Yield: 94.4 %

Procedure:
Use a method similar to the General Procedure 1-1, using 7N ammonia in methanol/water/THF (10:1:1 ratio) as solvent, to deprotect 7-chloro-6-[4-(2,2-dimethyl-propionylamino)-but-1-ynyl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (62 mg, 0.14 mmol) and afford the title compound as an oil (44 mg, 91%). MS (ES+) m/z: 333.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=1)[OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: O=Cc1ccccc1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2-benzyloxybenzaldehyde (3.0 g, 14.1 mmol) in THF (50 mL), a solution of 4-methoxyphenyl-magnesium bromide in THF (1.0 M, 17.0 mL) was added dropwise in a nitrogen stream under cooling with ice. The mixture was stirred at room temperature for one hour, and then a saturated ammonium chloride aqueous solution was added thereto under cooling with ice and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (4.92 g, 100%).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]([F:28])([F:27])[C:23](OC)=[O:24].Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:23](=[O:24])[C:22]([F:28])([F:27])[F:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: -40 °C

Procedure:
A solution of 91.2 ml (0.23 mol) of 2.5M n-butyllithium solution was added dropwise at -40° C. to a solution of 50.0 g (0.19 mol) of 4-bromophenol benzyl ether in 250 ml of tetrahydrofuran. The mixture was subsequently stirred for a short time at -40° C., then cooled to -78° C., and 34 g (0.27 mol) of methyl trifluoroacetate were added dropwise. The mixture was allowed to come to room temperature and then stirred at 0° C. for 3 hours. For working up, 120 ml of dilute hydrochloric acid were added dropwise, the mixture was diluted with toluene, and the organic phase was separated off, washed with water, dried and concentrated. A brown solid was obtained which was recrystallized from petroleum ether/ethyl acetate 10:1.
Reaction SMILES: C([O:5]C(C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)C(O)=O)(C)(C)C.[C:29]([O:33][C@@H:34]([C:37]1[C:38]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([CH2:48][CH3:49])[CH:41]=[CH:40]2)[CH2:35][OH:36])([CH3:32])([CH3:31])[CH3:30].C(OC(C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)CO)(C)(C)C>>[C:29]([O:33][C@@H:34]([C:37]1[C:38]([C:50]2[CH:51]=[CH:52][C:53]([Cl:56])=[CH:54][CH:55]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([CH2:48][CH3:49])[CH:41]=[CH:40]2)[C:35]([OH:5])=[O:36])([CH3:30])([CH3:31])[CH3:32]
Reactant: CCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(C(OC(C)(C)C)C(=O)O)c(Cl)cc2n1
Agent: Cc1ccc2c(-c3ccc(Cl)cc3)c(C(CO)OC(C)(C)C)c(Cl)cc2n1
Product: CCc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)acetic acid was prepared following the procedure used to prepare compound tert-butoxy-[7-chloro-5-(4-chloro-phenyl)-2-methyl-quinolin-6-yl]-acetic acid of Example 1, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)ethanol was used instead 2-tert-butoxy-2-[7-chloro-5-(4-chloro-phenyl)-2-methyl-quinolin-6-yl]ethanol. 1H-NMR 300 MHz, (CD3OD) δ 8.31 (d, 1H), 7.98 (s, 1H), 7.76 (d, 1H), 7.70-7.60 (m, 3H), 7.42-7.35 (m, 1H), 5.25 (s, 1H), 3.21 (q, 2H), 2.78 (s, 3H), 1.48 (t, 3H), 0.98 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C24H27ClNO3: 412.9. Found: 412.2, 414.2.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:3]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28]>C(OCC)(=O)C>[CH2:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[N:3][C:4]=2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH3:12]
Reactant: NCCCO
Reactant: CCn1cnc2c(Nc3cccc(C(F)(F)F)c3)nc(Cl)nc21
Solvent: CCOC(C)=O
Product: CCn1cnc2c(Nc3cccc(C(F)(F)F)c3)nc(NCCCO)nc21

Procedure:
200 mg (0.58 mmol) of 2-chloro-9-ethyl-6-(3-trifluoromethyl-phenyl-amino)-9H-purine and 2 ml of 3-amino-1-propanol are stirred at 140° C. for 2 h and the mixture is allowed to cool and is diluted with 60 ml of ethyl acetate. The organic phase is washed with water and dried over sodium sulfate. After removal of the solvent, the residue is recrystallized from ethyl acetate and diethyl ether. 9-Ethyl-2-(3-hydroxy-propyl-amino)-6-(3-trifluoromethyl-phenyl-amino)-9H-purine is obtained; m.p. 136–137° C.; FAB-MS: (M+H)+=381; Rf=0.7 (ethyl acetate:methanol=9:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH2:15][C:16](=O)[CH2:17]C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:15]([CH2:16][CH3:17])[CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(=O)CC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.9 %

Procedure:
A mixture of piperazine-1-carboxylic acid tert-butyl ester (7.00 g), 3-pentanone (3.89 g), glacial acetic acid (2.22 mL) and sodium triacetoxyborohydride (11.95 g) in dichloromethane (DCM, 200 mL) was stirred for 18 h at room temperature. The reaction mixture was quenched with 1 N aqueous NaOH (80 mL) and stirred for 2.5 h at room temperature. Additional water (100 mL) was added, and the resulting mixture was extracted with DCM (3×100 mL). Extracts were combined and washed with water (2×100 mL), dried (Na2SO4), and concentrated under reduced pressure, yielding the title compound (6.28 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[C:9]([F:17])=[C:10]([C:13]([Cl:16])=[CH:14][CH:15]=1)[CH:11]=[O:12].O.Cl>C1COCC1>[Br:7][C:8]1[C:9]([F:17])=[C:10]([CH2:11][OH:12])[C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: O=Cc1c(Cl)ccc(Br)c1F
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1c(Cl)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Add 1M LAH in THF (20 mL, 20 mmol) to 3-bromo-6-chloro-2-fluoro-benzaldehyde (Preparation 7) (4.9 g, 20 mmol) in THF (20 mL) at −78° C. Stir for 15 minutes and warm up to room temperature. Add reaction mixture into ice and water. Add 1M HCl (5 mL, 5 mmol) to dissolve the solid. Extract the mixture with ethyl acetate (50 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure to obtain 4.6 g (94%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[CH3:42][N:43]([CH3:48])[CH2:44][CH2:45][CH2:46]O>>[CH3:42][N:43]([CH3:48])[CH2:44][CH2:45][CH2:46][O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(O)cc21
Reactant: CN(C)CCCO
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CN(C)CCCOc1ccc2c(c1)C(=O)C(c1cccnc1)=C2c1ccccc1
Reaction time: 96 h
Yield: 30 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 6-hydroxy-3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 55 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 3-(dimethylamino)propanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 4 d, and being recrystallized with EtOAc to obtain the title compound (30%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][N:11]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:9])[CH:15]=2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(-c2ncc(Br)cn2)ccn1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a sealed tube were added 5-bromo-2-iodopyrimidine 183-1 (114 mg, 0.4 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 183-2 (88 mg, 0.4 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), Na2CO3 (170 mg, 1.6 mmol), toluene (0.4 mL), H2O (0.4 mL) and ethanol (0.1 mL). The reaction mixture was stirred at 100° C. for 10 hours. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (3 ml) and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by silica gel flash chromatography and eluted with 20% ethyl acetate in hexane to give 5-bromo-2-(2-methylpyridin-4-yl)pyrimidine 183-3. MS m/z 250.0 (M+1).