Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19](Cl)=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C([O-])=O.[NH4+]>CN(C=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[CH:19]=[N:18][C:17]=3[N:16]=2)=[CH:13][CH:14]=1
Reactant: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1cnc2nc(-c3ccc(O)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 80 °C
Yield: 79.6 %

Procedure:
To a solution of 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.25 g, 0.00048 mol) in DMF:water (2.5 ml), 10% Pd/C (0.130 g) and ammonium formate (0.66 g, 0.010 mol) were added and refluxed at 80° C. for 2 hours. The mixture was cooled and filtered through celite bed, solvent was removed and the residue was diluted with water (10 ml), acidified with citric acid and extracted with ethyl acetate (3×10 ml). The organic layer was washed with brine (2×15 ml). It was dried over Na2SO4 and the solvent was removed to obtain pale yellow solid of 8-(4-hydroxy-phenyl)-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.153 g, 80%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[N:18]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[C:17]3[CH:24]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=[CH:27][C:16]=3[N:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][O:22][CH2:21][CH2:20][CH2:19][N:18]1[C:17]2[CH:24]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=[CH:27][C:16]=2[N:15]=[C:14]1[CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COCCCn1c(C2CCCN(C(=O)OC(C)(C)C)C2)nc2ccc(C(=O)OC)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCn1c(C2CCCNC2)nc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
Methyl 2-(1-(tert-bu toxycarbonyl)piperidin-3-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate (43B) (3.10 mmol, 1.25 g) in DCM (10 mL) was added TFA (2 mL). The reaction solution was stirred at rt for 1 hr and then concentrated in vacuo. The residue was purified by preparative LC/MS (15-40% CH3CN in H2O) to afford methyl 1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole-6-carboxylate (43C) (1.48 mmol, 490 mg, yield: 47.7%). ESI-MS: m/z 332.4 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1([F:17])[CH2:9][CH2:8][C:7]([CH2:15][OH:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.S(OC)(O[CH3:22])(=O)=O>C1COCC1>[F:3][C:4]1([F:17])[CH2:5][CH2:6][C:7]([CH2:15][O:16][CH3:22])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C1(CO)CCC(F)(F)CC1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(COC)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
NaH (60%, 29.4 mg, 0.736 mmol) was added to a cold (0° C.) solution of ethyl 4,4-difluoro-1-(hydroxymethyl)cyclohexanecarboxylate (109 mg, 0.490 mmol) in THF (2 mL) and the mixture was allowed to warm to rt over 30 min. Then neat dimethyl sulfate (0.070 mL, 0.736 mmol) was added and the mixture was stirred at rt overnight. Excess Me2SO4 was quenched with TEA, acidified with 1N HCl and extracted with EtOAc to afford a light brown oil which was purified by silica gel FCC (DCM) to afford ethyl 4,4-difluoro-1-(methoxymethyl)cyclohexanecarboxylate as a clear oil (47 mg). Ethyl ester was saponified as described for Cap-7 synthesis (1 N NaOH, MeOH-THF) to afford Cap-8 as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 3.47 (s, 2H), 3.39 (s, 3H), 2.25 (br. d, J=13.1 Hz, 2H), 2.10-1.95 (m, 3H), 1.69-1.55 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(-c2nc3ccccc3o2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(-c2nc3ccccc3o2)cc1

Procedure:
To a solution of 7.1 gm. of 2-(4-ethylphenyl) benzoxazole in 125 cc. of carbon tetrachloride is added 6.2 gm. of N-bromosuccinimide and 50 mg. of benzoyl peroxide. The mixture is refluxed for about one half hour at which time the N-bromosuccinimide was consumed. Filtration followed by concentration of the filtrate gives 2-(4-[1-bromoethyl]phenyl)benzoxazole, m.p. 128°-131°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1.[C:33](Cl)(=[O:37])[C:34](Cl)=[O:35].[N:39]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:33](=[O:37])[C:34]([NH2:39])=[O:35])=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1
Reactant: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1ccccc1-c1ccccc1
Reactant: c1ccncc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(SC)nc2n1Cc1ccccc1-c1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 187 mg (0.417 mmol) of [[2-(methylthio)-6-ethyl-7-([1,1′-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 5 mL of chloroform was added 0.11 mL of oxalyl chloride followed by 0.05 mL of pyridine. The mixture was stirred for 2 days then quenched into 4.0 mL of dilute ammonium hydroxide. The product was extracted into 5.0 mL of methylene chloride. The organic phase was dried with sodium sulfate and concentrated to 500 mg of yellow oil. The residue was purified by flash chromatography (5 g of silica, ethyl acetate) to provide 240 mg of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-([1,1′-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as an oil. nmr (300 MHz, CDCl3) δ0.82 (t, 3H), 2.52 (s, 3H), 2.59 (q, 2H), 3.77 (s, 3H), 5.00 (s, 2H), 5.40 (s, 2H), 5.68 (s, 1H), 6.54 (s, 1H), 6.85 (d, 1H), 7.1-7.6 (m, J=6.7, 8H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19]>O1CCCC1.CCCCCC>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([Sn:18]([CH3:20])([CH3:19])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: C[Sn](C)(C)Cl
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To 20.0 g (88.9 mmol) of meta-bromobenzotrifluoride stirring in 200 ml of tetrahydrofuran at 78° C., 61.2 ml of 1.6M n-butyl lithium (97.9 mmol) in hexane was added dropwise. After stirring the reaction 10 minutesat -78° C., 19.5 g (97.8 mmol) of trimethyltin chloride dissolved in30 ml of tetrahydrofuran was added dropwise and the mixture stirred for 10 minutes at -78° C. before allowing to warm to room temperature. Thereaction mixture was quenched with excess saturated sodium bicarbonate and extracted with ethyl acetate (300 ml). The extract was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo to give a crude yield of 20.2 g of the above product, isolated as a oily semi-solid. This aryl stannane was used directly as a crude material in the coupling reactions with heterocycles of Formula II.
Reaction SMILES: [NH:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[C:14]([CH2:20][C:21]#[N:22])(=O)[C:15]([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:14]1[CH:20]=[C:21]([NH2:22])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][CH:13]=2)[N:2]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Product: CCOC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
Ethyl 4-(3-t-butyl-5-amino-1H-pyrazol-1-yl)benzoate (3.67 mmol) was prepared from ethyl 4-hydrazinobenzoate and pivaloylacetonitrile by the procedure of Regan, et al., J. Med. Chem., 45, 2994 (2002).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCOC(C)=O>[Pd].CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)c2cccc(O)c2)cc1OC
Agent: [Pd]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)c2cccc(O)c2)cc1OC
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A solution of 3,4-Dimethoxy-3'-hydroxy chalcone (4) (10 g, 35.2 mmol) in a 1:1 mixture of EtOAc:Acetone (40 mL) was treated with 10% Pd on Carbon (500 mg) and the mixture hydrogenated at 40-50 psi pressure of H2 for 3 h. The reaction mixture was filtered through a pad of Celite with the aid of acetone and the filtrate concentrated to afford a crude solid. The crude solid was triturated with EtOAc and filtered to afford 7.83 g (78%) of white solids which proved to be of ~90% purity by 1H NMR analysis: 1H NMR (CDCl3, 300 MHz) 7.56 (s, 1H), 7.55, (d, J=2.2 Hz, 1H), 7.53-7.33 (m, 1H), 7.10 (dd, J=7.9, 2.4 Hz, 1H), 6.80-7.79 (m, 3H), 6.61 (s, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.28 (t, J=7.9 Hz, 2H), 3.02 (t, J=7.9 Hz, 2H); 13C NMR (CDCl3, 75 MHz) 200.6, 156.9, 149.3, 147.8, 138.6, 134.2, 130.3, 121.1, 120.6, 115.0, 112.4, 111.8, 56.3, 41.2, 30.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6](Cl)[N:5]=1)[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[N:5]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCN(CC)c1nc(Cl)cc(N2CCNCC2)n1
Solvent: O
Product: CCN(CC)c1nc(N2CCNCC2)cc(N2CCN(C)CC2)n1

Procedure:
2-Diethylamino-4,6-dichloropyrimidine (10 g) is reacted with piperazine (14.45 g) in ethanol (200 ml) at reflux for 2 hr. The mixture is concentrated and the product isolated by silica gel chromatography giving 2-diethylamino-4-piperazino-6-chloropyrimidine. The 2-diethylamino-4-piperazino-6-chloropyrimidine (8 g) and N-methylpiperazine (8 g) is heated neat at 70° for 16 hr. Then water (2.5 ml) is added and the mixture is heated at 100° for 50 hr. The mixture is chromatographed on silica gel, the appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.15, 2.80, 2.85, 2.90, 3.30, 3.70 and 4.95 δ.
Reaction SMILES: Br[C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C([Li])C(C)C.[B:19](OCCCC)([O:25]CCCC)[O:20]CCCC>CCOCC>[CH:11]([C:10]1[CH:9]=[CH:8][C:7]2[NH:6][N:5]=[CH:4][C:3]=2[C:2]=1[B:19]([OH:25])[OH:20])([CH3:13])[CH3:12]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: CC(C)c1ccc2[nH]ncc2c1Br
Agent: [Li]CC(C)C
Solvent: CCOCC
Product: CC(C)c1ccc2[nH]ncc2c1B(O)O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-bromo-5-isopropyl-1H-indazole (1.6 g, 6.9 mmol) in Et2O (4 mL) is added slowly to a suspension of KH (1.0 g of 30% dispersion in mineral oil, 7.7 mmol) in Et2O (20 mL) at 0° C. and the mixture is stirred for 20 min. After cooling to −78° C., i-BuLi (8.9 mL of 1.7 M in Hex, 15 mmol) is added and the resulting mixture is stirred for 40 min at −78° C. To this is added B(On-Bu)3 (5.6 mL, 21 mmol) and the mixture is stirred for 24 h at room temperature. The reaction mixture is quenched with 1N H3PO4 and extracted with Et2O. The combined Et2O layers are back-extracted with 1N NaOH (3×10 mL). The combined NaOH extracts are acidified with 1N H3PO4 and extracted with EtOAc. The EtOAc extracts are washed with saturated brine, dried (MgSO4), and concentrated to yield 5-isopropyl-1H-indazole-4-boronic acid. 1H NMR (CDCl3) 7.85 (s, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 3.6 (br s, 2H), 2.88 (m, 1H), 1.32 (d, 6H).
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[Na+].[CH3:9][NH:10][C@H:11]([C:15]([NH:17][C@H:18]([C:22]([N:24]([C@@H:26]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:27]([O:66][CH3:67])[CH2:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C@H:36]([O:64][CH3:65])[C@@H:37]([CH3:63])[C:38]([NH:40][C@@H:41]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:42]([O:44][CH2:45][C:46]12[CH2:55][CH:50]3[CH2:51][CH:52]([CH2:54][CH:48]([CH2:49]3)[CH2:47]1)[CH2:53]2)=[O:43])=[O:39])=[O:30])[CH3:25])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[CH:12]([CH3:14])[CH3:13].C([BH3-])#N.[Na+].Cl.C([O:81][C:82](=[O:111])[CH2:83][C@@H:84](OC)[C@@H](N(C(=O)[C@H](C(C)C)NC(OCC1C=CC=CC=1)=O)C)[C@@H](C)CC)(C)(C)C>>[C:82]([CH2:83][CH2:84][CH2:9][N:10]([CH3:2])[C@H:11]([C:15]([NH:17][C@H:18]([C:22]([N:24]([C@@H:26]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:27]([O:66][CH3:67])[CH2:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C@H:36]([O:64][CH3:65])[C@@H:37]([CH3:63])[C:38]([NH:40][C@@H:41]([CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[C:42]([O:44][CH2:45][C:46]12[CH2:47][CH:48]3[CH2:54][CH:52]([CH2:51][CH:50]([CH2:49]3)[CH2:55]1)[CH2:53]2)=[O:43])=[O:39])=[O:30])[CH3:25])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16])[CH:12]([CH3:14])[CH3:13])([OH:111])=[O:81]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: O=C([O-])C(F)(F)F
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCC12CC3CC(CC(C3)C1)C2)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCC12CC3CC(CC(C3)C1)C2)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
26 mg (26 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(adamantane-1-ylmethoxy)-1-oxo-3-phenylpropane-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide sodium trifluoroacetate (intermediate 29) and 33.9 μl of 15% aqueous amber aldehyde acid solution (53 μmol) were dissolved in 957 μl of a 1:1-dioxane/water composition and heated for 1 hour at a temperature of 100° C. After a short cooling period 1.81 mg (29 μmol) of sodium cyanoborohydride were added. The reaction composition was formulated with 0.1 of N hydrochloric acid to pH 3 and heated for 2 hours at a temperature of 100° C. It was reheated again for 2 hours at 100° C. after the same amounts of amber aldehyde acid solution, sodium cyanoborohydride, and hydrochloric acid had been added once again. Afterwards, the reaction composition had been separated directly by means of preparative HPLC. The yield was 18.5 mg (73% o. th.) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH2:22][CH2:23][CH2:24][P:25]([O:30][CH2:31][CH3:32])(=[O:29])[O:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][P:25](=[O:29])([O:30][CH2:31][CH3:32])[O:26][CH2:27][CH3:28])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CCOP(=O)(CCCCCl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O)OCC
Temperature: 70 °C

Procedure:
20.4 g (0.08 mol) of 7-benzyl-3-methylxanthine were suspended in 200 ml of dimethylformamide (DMF), treated with 22 g (0.96 mol) of diethyl 4-chlorobutanephosphonate and 13.8 g (0.1 mol) of activated potassium carbonate and heated at 70° C. for 4 hours and filtered, the filtrate was concentrated under reduced pressure and the oily residue which remained was taken up in ethyl acetate, filtered again and crystallized from diisopropyl ether.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:25]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:26][C:27]1[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([CH2:20][C:21]([F:22])([F:23])[F:24])[N:18]=[CH:17][N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:25]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: OB(O)c1cccnc1F
Reactant: FC(F)(F)Cn1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Product: Fc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2
Yield: 55 %

Procedure:
Following the procedure for 203, 10-bromo-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was reacted with 2-fluoropyridin-3-ylboronic acid to give 10-(2-fluoropyridin-3-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.108 g, 55%), 1H NMR (400 MHz, DMSO) δ 8.71 (t, J=2.0, 1H), 8.57-7.83 (m, 4H), 7.80-7.39 (m, 2H), 7.22 (d, J=8.5, 1H), 5.88 (q, J=8.8, 2H), 4.79-4.38 (m, 4H). MS (ESI(+)): m/z 431.1 (M+H), which was hydrolyzed with HCl to give 218 (0.072 g, 72%). 1H NMR (400 MHz, DMSO) δ 11.85 (s, 1H), 8.78 (d, J=2.3, 1H), 8.09 (d, J=2.8, 2H), 7.69 (ddd, J=8.9, 7.7, 2.2, 2H), 7.36 (t, J=23.8, 1H), 7.08 (d, J=8.6, 1H), 6.30 (t, J=6.7, 1H), 5.91 (q, J=8.8, 2H), 4.56 (dd, J=13.5, 5.5, 4H). MS(ESI(+)): m/z 429.1 (M+H)
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=O)[NH:9]2)=[N:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([I:1])=[CH:3][N:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2ncc(I)cc2[nH]1
Product: Clc1ccc2ncc(I)cc2n1
Yield: 90.5 %

Procedure:
7-iodo-1,5-naphthyridin-2(1H)-one (D-16) (740 mg, 2.72 mmol, 1.0 eq) was dissolved in POCl3 (10 mL), and then heated at reflux for 1 h. The reaction was complete based on TLC analysis. The reaction mixture was concentrated in vacuo, poured into ice-water (30 mL), and neutralized with saturated sodium carbonate solution (about 30 mL) to adjust pH value to 8-9. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (5-10% ethyl acetate/petroether) to afford the desired product, 2-chloro-7-iodo-1,5-naphthyridine (D-17) (715 mg, 90.5%) as a solid. 1H NMR (400 MHz, CDCl3-d6) δ: 9.13 (d, J=2.0 Hz, 1H), 8.74 (d, J=1.6 Hz, 1H), 8.33 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H); ESI-MS m/z: 290.93 [M+H]+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]([CH:20]=[CH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][C:17](=[O:28])[C:12]([C:13]([O:15]C)=[O:14])=[CH:11]2)=[CH:6][CH:5]=1.C(O)(=O)C>C(O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:19]([CH:20]=[CH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][C:17](=[O:28])[C:12]([C:13]([OH:15])=[O:14])=[CH:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cn(-c2ccc(F)cc2)c(C=Cc2cccnc2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c(C=Cc2cccnc2)cc1=O
Yield: 82.6 %

Procedure:
In a mixture of 9 ml of ethanol and 9 ml of a 10% by weight aqueous sodium hydroxide solution was suspended 0.45 g of methyl 1-(4-fluorophenyl)-6-[2-(pyridin-3-yl)ethenyl]-4-oxo-1,4-dihydronicotinate and the suspension was subjected to reaction at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was adjusted to a pH of 6.0 with acetic acid, and the precipitated crystals were collected by filtration and dried to obtain 0.357 g of 1-(4-fluorophenyl)-6-[2-(pyridin-3-yl)ethenyl]-4-oxo-1,4-dihydronicotinic acid having a melting point of 250° C. or more.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH:10]1[CH:14]([OH:15])[CH:13]=[CH:12][C:11]1=O)([OH:3])=[O:2].[OH-:17].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[C:14](=[O:15])[CH2:13][CH:12]([OH:17])[CH:11]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCCC/C=C\C1C(=O)C=CC1O
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)CCCC/C=C\C1=CC(O)CC1=O

Procedure:
A solution of 1.0 mmole of all-cis-2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanone (Example 1106) and 3.0 mmoles of sodium carbonate in 15 ml. of water is allowed to stand at room temperature for 3 hours. The solution is acidified with HCl, saturated with sodium chloride, and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give a mixture of the title compound and the isomeric compound, 2-(6-carboxy-2-cis-hexenyl)-3-hydroxycyclopent-4-en-1-one. Further treatment of this mixture with N/10 sodium hydroxide at room temperature for 30 minutes causes the rearrangment of the latter isomer to the title compound, which is isolated from basic solution as above.
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][CH:17]2[C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23]O>>[CH3:23][O:21][C:20]([CH:17]1[C:18]2[C:14](=[CH:13][CH:12]=[C:11]([C:3](=[O:10])[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=2)[CH2:15][CH2:16]1)=[O:22]
Reactant: O=C(c1ccccc1)c1ccc2c(c1)C(C(=O)O)CC2
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1CCc2ccc(C(=O)c3ccccc3)cc21

Procedure:
Analogously to the description in Example 2, 13 g of 6-benzoyl-indane-1-carboxylic acid methyl ester and 75 ml of 2 N sodium hydroxide solution in 500 ml of methanol give 6-benzoyl-indane-1-carboxylic acid of boiling point 200° C/0.04 mm Hg as a yellowish, viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+].O>C1(C)C=CC=CC=1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cnc(Oc2ccccc2)nc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (5.00 g, 0.0259 mol), phenol (3.16 g, 0.0336 mol), dibenzo-18-Crown-6 (0.47 g, 0.0013 mol) and ground potassium hydroxide (3.51 g, 0.0626 mol) in toluene (75 ml) was heated at reflux for 5 hours with azeotropic removal of water. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between water and chloroform. The layers were separated and the aqueous phase was extracted with chloroform three times. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica using n-heptane/ethyl acetate (98:2) as an eluent to give 5-bromo-2-phenoxy-pyrimidine as a white solid (3.55 g, 0.0141 mol): 1H NMR (DMSO-d6, 400 MHz) 8.80 (s, 2H), 7.45 (t, 2H), 7.27 (t, 1H), 7.22 (d 2H); TLC (n-heptane/ethyl acetate=95:5) Rf 0.20.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Br:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Br:18][C:19]1[CH:24]=[C:23]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(Br)c2)cn1
Yield: 35 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-bromophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (66 mg, 35%) which was obtained as a white solid. MS (ESI): m/e=379.9 [M+H]+.