Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].COC(=O)[O-].[CH3:18][NH+:19]1[CH2:23][CH:22]([CH3:24])[N:21]([CH3:25])[CH:20]1[CH3:26]>CO>[C:1]([O-:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-:6])=[O:5].[CH3:18][NH+:19]1[CH2:23][CH:22]([CH3:24])[N:21]([CH3:25])[CH:20]1[CH3:26].[CH3:18][NH+:19]1[CH2:23][CH:22]([CH3:24])[N:21]([CH3:25])[CH:20]1[CH3:26]
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: CC1C[NH+](C)C(C)N1C
Agent: COC(=O)[O-]
Solvent: CO
Product: O=C([O-])c1ccccc1C(=O)[O-]

Procedure:
By adding 42 parts of phthalic acid (produced by Kawasaki Kasei Chemicals, Ltd.) to the methanol solution of 46 parts of 1,2,3,4-tetramethylimidazolinium methyl carbonate salt obtained in Production Example 1 and carrying out a salt exchange reaction, there was obtained a methanol solution of 1,2,3,4-tetramethylimidazolinium phthalate monoanion. The above-described solution was heated under reduced pressure of 1.0 kPa or less at 50° C. to distill methanol until no distillate of methanol was observed. Thereafter, the temperature was raised from 50° C. to 100° C. and heating was continued for 30 minutes to distill and remove monomethyl carbonate (HOCO2CH3), methanol, and carbon dioxide (slight amounts of methanol and carbon dioxide are formed by thermal decomposition of monomethyl carbonate. Hereinafter, these are abbreviated as by-products). Thus, 1,2,3,4-tetramethylimidazolinium phthalate monoanion (N-1) was obtained. The yield was 99 parts (yield based on the weight of 46 parts of 1,2,3,4-tetramethylimidazolinium methyl carbonate salt; hereinafter the same shall apply). The molecular weight of (N-1) was 280.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([CH3:10])[CH:3]=1.[C:11]([N:14]1[CH2:18][CH2:17][NH:16][C:15]1=O)(=[O:13])[CH3:12]>>[C:11]([N:14]1[CH2:18][CH2:17][N:16]=[C:15]1[NH:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([CH3:10])[CH:3]=1)(=[O:13])[CH3:12]
Reactant: Cc1cc(N)n(C(C)C)n1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1C(C)C

Procedure:
5-amino-1-isopropyl-3-methylpyrazole (J. Gen. Chem. USSR 31 234, 1961) (19.3 g.) and 1-acetyl-2-imidazolidinone (20.1 g.) were reacted as described in Example I to give 12.73 g. of product, mp 145°-147° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=3)[N:10]=2)=[CH:2]1.Cl.Cl.[NH2:20][CH:21]1[CH2:28][CH:27]2[N:29]([CH3:30])[CH:23]([CH2:24][CH2:25][CH2:26]2)[CH2:22]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:30][N:29]1[CH:23]2[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:28][CH:21]([NH:20][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)=[N:10][C:9]=13)=[O:17])[CH2:22]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3ccsc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccsc4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
A mixture of 2-thiophen-3-ylbenzoxazole-4-carboxylic acid (78 mg, 0.32 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (86 mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45 mmol) and 1-hydroxybenzotriazole (122 mg, 0.90 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then DIPEA (0.26 mL, 1.6 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and then recrystallized from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-thiophen-3-ylbenzoxazole-4-carboxamide (51 mg, 41%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.99 (d, J=7.0 Hz, 1H), 8.24 (d, J=1.5 Hz, 1H), 8.20 (d, J=7.5 Hz, 1H), 7.78 (d, J=5.0 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.52-7.51 (m, 1H), 7.44 (t, J=7.5 Hz, 1H), 4.61-4.51 (m, 1H), 3.19-3.01 (m, 2H), 2.72-2.61 (m, 2H), 2.54 (s, 3H), 2.22-1.98 (m, 2H), 1.60-1.47 (m, 4H), 1.26-1.13 (m, 2H); MS (ESI+) m/z 382 (M+H); HPLC>99% (AUC), tR=13.40 min.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2[CH:36]([CH2:42]O)[CH2:37][C:38](=[O:41])[NH:39][N:40]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:42][CH:36]2[C:35]([C:29]3[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([O:26][CH3:25])[CH:28]=3)=[N:40][NH:39][C:38](=[O:41])[CH2:37]2)=[O:9])=[CH:11][CH:12]=1
Reactant: COc1ccc(C2=NNC(=O)CC2CO)cc1OC
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C2=NNC(=O)CC2COC(=O)COc2ccc(Cl)cc2)cc1OC

Procedure:
4.7 g (0.025 mol) of 4-chlorophenoxyacetic acid and 4.3 g (0.027 mol) of carbonyldiimidazole are heated under reflux in 100 of tetrahydrofuran for 15 minutes. After the mixture has been cooled, 6.7 g (0.025 mol) of 6-(3,4-dimethoxyphenyl)-5-hydroxymethyl-2,3,4,5-tetrahydropyridazin-3-one are added with stirring. After a reaction time of 5 hours, the mixture is concentrated at room temperature and the residue is worked up as in Example 5.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][N:20]=[C:21]3[Cl:24])=[CH:16][CH:15]=2)[C:9]1=[O:25])(C)(C)C.Cl>CCOC(C)=O>[ClH:24].[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][N:20]=[C:21]3[Cl:24])=[CH:16][CH:15]=2)[C:9]1=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 200 %

Procedure:
To a solution of [1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3(S)-yl]-carbamic acid tert-butyl ester (2.1 g, 5.6 mmol) in EtOAc (170 mL) at 0° C. is bubbled HCl gas for 5 minutes. The solution is stirred at 0° C. for 15 minutes, then the ice bath is removed and the solution allowed to warn to room temperature. After 4 hours at room temperature, the solution is concentrated and the remaining solid is washed with ether to give the title compound (1.74 g, 5.6 mmol) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:8]#[N:9].O.O.[Sn](Cl)Cl>CO>[NH2:13][C:12]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:4][C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Br:1]
Reactant: N#Cc1ccc([N+](=O)[O-])c(Oc2ccccc2Br)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: N#Cc1ccc(N)c(Oc2ccccc2Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a mixture of 3-(2-bromophenoxy)-4-nitrobenzonitrile, 1 (5 g; 15.67 mmol) in methanol (100 mL) was added tin(II) chloride dihydrate (17.68 g; 78.36 mmol). The mixture was stirred at rt overnight, and the solvent was removed via evaporation. Ethyl acetate (100 mL) and 1N NaOH (100 mL) were added, and the solvents were removed via evaporation. Ethyl acetate (200 mL) was added, and white solid formed. The solid was removed via filtration, washed with ethyl acetate, and the combined filtrates were evaporated. The residue was purified via column chromatography (eluent gradient: 10% to 30% ethyl acetate in heptane) to yield 3.0 g (66%) of 4-amino-3-(2-bromophenoxy)-benzonitrile, 2a. MS m/z (MH+) 288.7/289.7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:4]([CH:25]=[O:26])[CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:27])=[O:14])=[C:4]([CH:25]=[O:26])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN(CCCCC(=O)O)c2ccc(Br)cc2C=O)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCCCN(Cc1ccc(OC)cc1)c1ccc(Br)cc1C=O
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of 5-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)pentanoic acid (77.2 g) and potassium carbonate (30.5 g) in DMF (500 ml) was added dropwise a solution of iodomethane (36.5 g) in DMF (100 ml) at 0° C. under nitrogen atmosphere. After stirring for 2 hours, water was added and the mixture was extracted with ethyl acetate. After washing the organic layer with water three times and with saturated brine once, the resultant was dried with magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→hexane:ethyl acetate=4:1) to give methyl 5-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)-pentanoate (45.7 g) as a brown oily material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH3:15][O:16][C:17](=[O:22])[CH2:18][CH2:19][C:20]#[CH:21]>>[CH3:15][O:16][C:17](=[O:22])[CH2:18][CH2:19][C:20]#[C:21][C:8]1[N:7]=[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:14])[C:11]([OH:12])=[CH:10][CH:9]=1
Reactant: COC(=O)CCc1nc(I)ccc1O
Reactant: C#CCCC(=O)OC
Product: COC(=O)CCC#Cc1ccc(O)c(CCC(=O)OC)n1
Yield: 84.3 %

Procedure:
Under the conditions of example 5A, 2 g of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester is reacted with 0.8 g of 4-pentynoic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-30% ethyl acetate. 1.6 g of 5-[3-hydroxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-4-pentynoic acid methyl ester of melting point 119°-121° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[N:45][CH:46]=[N:47][CH:48]=2)=[CH:38][C:37]=1[CH3:49].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:49][C:37]1[CH:38]=[C:39]([C:43]2[CH:48]=[N:47][CH:46]=[N:45][CH:44]=2)[CH:40]=[C:41]([CH3:42])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2cncnc2)cc(C)c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cncnc6)cc5C)ccc(F)c43)ccc21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In a microwave vial methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (100 mg), 5-(4-bromo-3,5-dimethylphenyl)pyrimidine (85 mg), K3PO4 (90 mg) are suspended in toluene (1 mL) and water (100 μL) and purged for 10 minutes with argon. Palladium-(II)-acetate (2.4 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (8.8 mg) are added, the vial is sealed and the mixture is stirred at 100° C. for 12 hours. The mixture is diluted with tetrahydrofuran and purified by HPLC on reversed phase to give the title compound. Yield: 40 mg; Mass spectrum (ESI+): m/z=525 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.[CH3:33][C@@H:34]1[O:38][C:37](=[O:39])[NH:36][CH2:35]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:36]5[CH2:35][C@H:34]([CH3:33])[O:38][C:37]5=[O:39])=[CH:3][C:4]=4[N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Reactant: C[C@H]1CNC(=O)O1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@H](C)OC3=O)cc2N2CCCS2(=O)=O)CC1
Yield: 84.8 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (519 mg) described in Preparation Example 179 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (457 mg) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:6]#[N:7].[CH3:26][CH:27]1[C:36]2[C:31](=[CH:32][C:33]([OH:38])=[C:34]([OH:37])[CH:35]=2)[CH2:30][CH2:29][NH:28]1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)([CH2:4][CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][C:31]3[C:36](=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=3)[CH:27]2[CH3:26])[C:6]#[N:7])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: CC1NCCc2cc(O)c(O)cc21
Reactant: COc1ccc(C(C#N)(CCCCl)Sc2ccc(C)cc2)cc1OC
Product: COc1ccc(C(C#N)(CCCN2CCc3cc(O)c(O)cc3C2C)Sc2ccc(C)cc2)cc1OC
Yield: 18.3 %

Procedure:
The procedure of Example 3 is repeated using 1.0 g of α-(3-chloropropyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 0.76 g of 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline. This affords 0.253 g of the desired product as a beige gum.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][NH:21][CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl.[CH3:31][N:32]([CH3:38])[CH2:33][CH2:34][C:35](O)=[O:36]>>[CH3:31][N:32]([CH3:38])[CH2:33][CH2:34][C:35]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]=2[CH2:22]1)=[O:36]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Reactant: CN(C)CCC(=O)O
Agent: Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)CCN(C)C)CC3)cc1

Procedure:
Method as described for example 17 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea (example 12) and 3-dimethylamino propionic acid hydrochloride as starting materials. Purified by prep HPLC (low pH).
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[CH:14][CH:13]=2)[C:9](=[O:30])[C:8]([CH:31]([OH:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:7]([CH3:39])[N:6]=1)[CH2:2][CH2:3][CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O>[C:31]([C:8]1[C:9](=[O:30])[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[CH:14][CH:13]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][C:7]=1[CH3:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCc1nc(C)c(C(O)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc(C)c(C(=O)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of 2-butyl-5-[hydroxy(phenyl)methyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.1 g) in dichloromethane (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.12 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.07 g, 70%).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]([CH:17]=[CH:18][C:19](=[O:22])[CH2:20][CH3:21])=[C:11]([CH3:23])[CH2:10]1)(C(C)(C)C)(C)C.[OH:24]C1(C)CC(O)CC(C)(C)C1C=CC(O)C>>[OH:24][C:11]1([CH3:23])[CH2:10][CH:9]([OH:8])[CH2:14][C:13]([CH3:16])([CH3:15])[CH:12]1[CH:17]=[CH:18][CH:19]([OH:22])[CH2:20][CH3:21]
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Reactant: CCC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Product: CCC(O)C=CC1C(C)(C)CC(O)CC1(C)O

Procedure:
The entitled compound was prepared from 1-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1-enyl]pent-1-en-3-one in the same manner as described in Example 1-(4), (5), and (6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:5][CH2:6][CH2:7][C:8]([OH:10])=O.F>>[Cl:14][C:13]1[CH:12]=[C:11]2[C:4](=[CH:3][C:2]=1[Cl:1])[O:5][CH2:6][CH2:7][C:8]2=[O:10]
Reactant: O=C(O)CCOc1ccc(Cl)c(Cl)c1
Agent: F
Product: O=C1CCOc2cc(Cl)c(Cl)cc21
Reaction time: 8 h

Procedure:
500 mg of 3-(3,4-dichlorophenoxy)propionic acid, is stirred in 50 ml. of liquid hydrogen fluoride surrounded by a solid carbon dioxide/acetone bath. This slurry is allowed to stir overnight without replenishing the cooling bath. The hydrogen fluoride is removed by a stream of air. The residual solid was then dissolved in ether and washed with 10% aqueous sodium carbonate solution. The organic layer is dried over anhydrous magnesium sulphate and the solvent is evaporated to give the required chromanone with sufficient purity.
Reaction SMILES: Cl.[N:2]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:24]([OH:26])=O)=[CH:18]3)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][C:50]1([F:56])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:49][C:50]1([F:56])[CH2:55][CH2:54][N:53]([C:24]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[CH2:7][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:14])=[CH:23][CH:22]=3)=[O:26])[CH2:52][CH2:51]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1
Reactant: FC1(F)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow solid (74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=O)[CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Temperature: 0 °C

Procedure:
Compound A (1.0 g) in 25 ml dry methylene chloride and 10 ml of 2.5 N NaOH was cooled to 0° C. and treated with 0.25 ml of acetyl chloride dropwise. After 2 hours the solution was allowed to warm up to room temperature and stirring was continued overnight. The solution was treated with distilled water and extracted with methylene chloride. The methylene chloride layer was separated, dried over anhydrous sodium sulfate, filtered and evapotated to give 1.33 g of crude amide reaction product, which was purified by flash column (silica, methylene chloride:methanol: 25 %NH4OH 90:9:1) to yield 0.7 g of 2-(4-fluorophenyl)-5-(N-acetylpiperidin-4-yl)-3-(4-pyridyl)pyrrole. This amide was dissolved in 15 ml of tetrahydrofuran and treated with 3 ml of 1M lithium aluminum hydride (LAH) in THF under an atmosphere of nitrogen at room temperature. After completion of addition of LAH, the solution was refluxed for two hours, cooled to 0° C., quenched with water (0.19 ml) and 2.5 N NaOH (0.19 ml) and filtered. The filtrate was dried over sodium sulfate, filtered, evaporated and purified by flash column as shown above to give compound B (0.65 g).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31].C(N(C(C)C)C(C)C)C>C(O)CC>[OH:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1
Reactant: NCc1cccc(O)c1
Reactant: Clc1ncnc2c1ncn2C1CCCO1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: Oc1cccc(CNc2ncnc3c2ncn3C2CCCO2)c1
Yield: 85 %

Procedure:
A mixture of 10 mmol (2240 mg) of 6-chloro-9-(tetrahydrofuran-2-yl)-purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) of 3-hydroxybenzylamine, and 5 ml of N-ethyldiisopropylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 85%, white solid. TLC (EtOAc:hexane (1:1 (v:v)): single spot; HPLC: purity >98%. 1H NMR (400 MHZ, DMSO): 2.20sep (1H, J=6.8 Hz); 2.22sep (1H, J=6.8 Hz); 2.44m (2H); 3.91q (1H, J=7.3 Hz); 4.14q (1H, J=7.3 Hz); 4.63bs (2H); 6.26m (1H); 6.59dd (1H, Ja=7.8 Hz, Jb=2.2 Hz); 6.73s (1H); 6.75d (1H, J=7.8 Hz); 7.07t (1H, J=7.8 Hz); 8.20s (1H); 8.26bs (1H); 8.27s (1H); 9.23bs (1H). MS (ES): [M+H]+=312 (100).
Reaction SMILES: [CH2:1]([C:3]([CH2:8][CH3:9])([CH2:6][NH2:7])[CH2:4][NH2:5])[CH3:2].OO.[O-]Cl.[Na+]>O.CO>[CH2:1]([C:3]1([CH2:8][CH3:9])[CH2:6][N:7]=[N:5][CH2:4]1)[CH3:2]
Reactant: CCC(CC)(CN)CN
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CO
Product: CCC1(CC)CN=NC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2,2-Diethyl-propane-1,3-diamine (5.0 g) was taken up in a mixture of H2O (40 mL) and MeOH (10 mL), and cooled in an ice bath. Simultaneously, H2O2 (24.2 mL of a 30% solution, 6 equiv.) and NaClO (54.9 mL of a 10% solution, 2.4 equiv.) were added dropwise, the ice bath was removed, and the mixture was stirred for 2 h. at room temperature. Extraction with DCM, drying over Na2SO4 and evaporation under reduced pressure yielded 3.51 g of a clear, yellow liquid containing 77% of the anticipated product and 23% of the diamine starting material. This material was used in subsequent steps without further purification. 1H NMR (400 MHz, CDCl3) δ 0.78 (t, J=7.5 Hz, 6H), 1.36 (q, J=7.5 Hz, 4H), 4.14 (s, 4H).