Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4]O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:28][O:29][C:30]1[CH:49]=[CH:48][C:33]2[N:34]=[C:35]3[N:40]=[C:39]([C:41]4[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=4)[CH:38]=[CH:37][N:36]3[C:32]=2[CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[F:1][CH2:2][CH2:3][CH2:4][NH:45][C:44]1[CH:46]=[CH:47][C:41]([C:39]2[CH:38]=[CH:37][N:36]3[C:32]4[CH:31]=[C:30]([O:29][CH3:28])[CH:49]=[CH:48][C:33]=4[N:34]=[C:35]3[N:40]=2)=[CH:42][CH:43]=1
Reactant: COc1ccc2nc3nc(-c4ccc(N)cc4)ccn3c2c1
Reactant: OCCCF
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2nc3nc(-c4ccc(NCCCF)cc4)ccn3c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a stirred solution of 3-fluoropropan-1-ol (5 mg, 0.05 mmol) in 0.3 mL o DCM at rt was added Dess-Martin reagent (42 mg, 0.1 mmol). The mixture was stirred for 1 h at rt and 0.3 mL of DCE was added. It was filtered through a cotton pad into a stirred mixture of 4-(7-methoxybenzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)aniline (5 mg, 0.017 mmol, prepared following General Experiment Procedures Q and R) and NaBH(AcO)3 (42 mg, 0.2 mmol) in 0.3 mL of DCE. The reaction was vigorously stirred for 5 min and quenched by adding Na2CO3 (2 mL, saturated). The mixture was extracted with EtOAc (3×5 mL) and the combined organic phase was washed with water (2×10 mL) and dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by reversed phase HPLC (TFA buffered water/MeCN) to afford the title compound as an orange solid (5 mg, 53%, TFA salt). MS (ESI) m/z [M+H]+351.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][C:12]#[N:13].Br[CH2:15][CH2:16][CH2:17]Br>C1(C)C=CC=CC=1.O>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1([C:12]#[N:13])[CH2:17][CH2:16][CH2:15]1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(F)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(F)cc2Br)CCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
Add potassium hydroxide (8.39 g, 150 mmol) and tetrabutylamine bromide (0.3 g, catalytic) to a solution of 2-(2-bromo-4-fluorophenyl)acetonitrile (4 g, 18.69 mmol) and 1,3-dibromopropane (4.15 g, 20.5 mmol) in toluene (20 mL). Stir it at 100° C. temperature for 2 h. Dilute the mixture with water and extract with ethyl acetate. Wash the organic layer with 1 N HCl and aqueous saturated sodium chloride. Dry over magnesium sulfate. Remove the organic solvent to give the crude product. Distill to give 1-(2-bromo-4-fluorophenyl)cyclobutanecarbonitrile (boiling point 110-120° C./0.3 Torr.) (1.5 g, 31%). MS (GC) m/z 253 [M]+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:52][C:53]1[S:54][C:55]2[CH:61]=[CH:60][CH:59]=[CH:58][C:56]=2[N:57]=1.C(N(CC)CC)C>C(Cl)Cl>[S:54]1[C:55]2[CH:61]=[CH:60][CH:59]=[CH:58][C:56]=2[N:57]=[C:53]1[NH:52][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1nc2ccccc2s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 30, 182 mg, 0.50 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), and 2-aminobenzothiazole (113 mg, 0.75 mmol) in methylene chloride (10 mL) at 25° C. was treated with triethylamine (0.21 mL, 1.50 mmol). The reaction mixture was stirred at 25° C. for 48 h. The reaction mixture was then diluted with methylene chloride (25 mL) and washed with a 3N aqueous hydrochloric acid solution (1×25 mL), water (1×25 mL), and a saturated aqueous sodium chloride solution (3×25 mL). The organic layer was dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 70/30 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide (205 mg, 82.6%) as a white solid: mp 105-110° C.; EI-HRMS m/e calcd for C23H23F3N2O3S2 (M+) 496.1102, found 496.1102.
Reaction SMILES: [SH2:1].[Cl:2][C:3]1[C:8]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])=[C:7]([NH:18][C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])[N:6]=[C:5]([C:25]#[N:26])[N:4]=1.O.C(O)(=O)C>C(N(CC)CC)C.CN1CCCC1=O>[Cl:2][C:3]1[C:8]([C:9]2[C:10]([F:17])=[CH:11][C:12]([F:16])=[CH:13][C:14]=2[F:15])=[C:7]([NH:18][C@@H:19]([CH3:24])[C:20]([F:21])([F:22])[F:23])[N:6]=[C:5]([C:25](=[S:1])[NH2:26])[N:4]=1
Reactant: C[C@H](Nc1nc(C#N)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Reactant: S
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: C[C@H](Nc1nc(C(N)=S)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F

Procedure:
At room temperature, hydrogen sulfide was introduced for 5 minutes into a solution of 0.5 g (1.35 mmol) of (S)-4-chloro-6-(2,2,2-trifluoro-1-methylethylamino)-5-(2,4,6-trifluorophenyl)pyrimidine-2-carbonitrile, prepared according to WO 03/043993, in 0.16 g of triethylamine and 6 ml of N-methylpyrrolidone. After the reaction had ended, 20 ml of water were added, the mixture was neutralized with acetic acid and extracted with methyl tert-butyl ether and the organic phase was washed with water, dried over magnesium sulfate and concentrated.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]([C:30]1[C:31]([CH3:45])=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1)[S:26]([CH3:29])(=[O:28])=[O:27]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:34]5[CH:35]=[C:30]([N:25]([CH3:24])[S:26]([CH3:29])(=[O:27])=[O:28])[C:31]([CH3:45])=[N:32][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N(C)S(C)(=O)=O
Product: Cc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1N(C)S(C)(=O)=O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-methyl-N-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide (Stage 75.1.1) to give the title compound as a white solid. (HPLC: tR 2.19 min (Method A); M+H=492 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.55-8.51 (m, 1H), 8.16-8.10 (m, 2H), 8.03-7.97 (m, 1H), 7.95-7.91 (m, 1H), 7.60-7.56 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 3.23 (s, 3H), 3.16 (s, 3H), 2.53 (s, 3H), 1.96 (s, 3H))
Reaction SMILES: C[C:2]1[CH2:3][S:4][C@@H:5]2[CH2:9][C:8](=[O:10])[N:6]2[CH:7]=1.[O:11]=[O+][O-]>>[OH:11][C:2]1[CH2:3][S:4][C@@H:5]2[CH2:9][C:8](=[O:10])[N:6]2[CH:7]=1
Reactant: CC1=CN2C(=O)C[C@H]2SC1
Reactant: O=[O+][O-]
Product: O=C1C[C@H]2SCC(O)=CN12

Procedure:
In yet a further method for preparing compounds of the invention wherein R2 is methyl, methoxy, or chloro, a 7-aminocephalosporanic acid ester is acylated with the desired benzothienylglycine or dihydrobenzothienyl glycine and the product is reacted with a thiol such as a C1 -C4 alkyl mercaptan or with thiourea to form, the 3-alkylthio or isothiouronium derivative, respectively, by nucleophilic displacement of the 3-acetoxy group. The thio derivative is then subjected to reductive displacement with Raney nickel and hydrogen or with zinc and formic acid in DMF to provide the 3-exomethylenecepham compound. The latter is then isomerized to the 3-methyl-3-cephem as described hereinabove. The 3-exomethylenecepham can be reacted with ozone in the cold to provide the 3-hydroxy-3-cephem and the latter converted to the 3-halo or 3-methoxy compound as described hereinabove. The above-described conversion of the 3-acetoxymethyl compound to the 3-exomethylenecepham is carried out according to the methods described by Chauvette in U.S. Pat. No. 3,932,393.
Reaction SMILES: Cl.[O:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[CH:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:5]2[CH2:6][CH2:7][CH2:8][O:2][CH2:3][CH2:4]2)=[CH:13][CH:12]=1)#[CH:10]
Reactant: C#Cc1ccc(C=O)cc1
Reactant: C1CNCCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: C#Cc1ccc(CN2CCCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
1,4-Oxazepane hydrochloride (1.0 g) and TEA (1.1 mL) were added to a chloroform (20 mL) solution of 4-ethynylbenzaldehyde (1.0 g) obtained by the same method as the synthesis method described in the literature (Tetrahedron Letters, 2007, Vol. 48(33), pp. 5817-5820). The mixture was stirred for 30 minutes at room temperature, and acetic acid (0.45 mL) was added, followed by stirring the mixture for 1 hour at room temperature. Then, sodium triacetoxyborohydride (2.4 g) was added, and the mixture was stirred for 15 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and then the mixture was extracted with chloroform. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH type silica gel chromatography (gradient elution with hexane/ethyl acetate=90/10→60/40) to obtain 4-(4-ethynylbenzyl)-1,4-oxazepane (yellow solid) (1.4 g, 87%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].O>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: Oc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of 3-iodophenol (2.20 g, 10.0 mmol) in dimethylformamide (20 ml) were added potassium carbonate (2.07 g, 15.0 mmol) and t-butyl bromoacetate (1.62 ml, 11.0 mmol), and the mixture was stirred for 1 hour at room temperature. Thereto was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, water, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in the order, and dried over magnesium sulfate. The solvent was removed to give the subject compound as a colorless oil (3.28 g, 98%).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[C:13]3[C:12]([C:24]#[N:25])=[CH:11]2)(=O)=O)C=CC=CC=1.CCO.[OH-].[Na+]>ClCCl.CO>[S:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]1[CH:18]=[C:13]2[C:12]([C:24]#[N:25])=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: N#Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3cccs3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1c[nH]c2ncc(-c3cccs3)cc12
Temperature: 105 °C
Yield: 67.3 %

Procedure:
A mixture of 11 (18.3 mg, 50.1 μmol), EtOH (2.0 mL) and 10% aqueous NaOH (1.0 mL) was refluxed (oil bath temp. 105° C.) for 40 min. The mixture was poured onto water (3 mL), extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated. The product was isolated by PTLC using dichloromethane:methanol (19:1) as eluent to give 12 as a white solid (7.6 mg, 68%); 1H NMR (400 MHz, CDCl3) δ 10.30-10.10 (bs, NH), 10.74 (d, J=1.9 Hz, 1H), 8.31 (d, J=1.9 Hz, 1H), 7.90 (s, 1H), 7.39 (m, 2H), 7.16 (dd, J=5.0, 3.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: BrC1CCCC1
Reactant: N#CCc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: N#CC(c1ccc(F)cc1)C1CCCC1
Temperature: 100 °C

Procedure:
4-Fluorophenylacetonitrile (10 g, 74 mmol) was combined with tetrabutylammonium bromide (2.76 g), 50% sodium hydroxide (38 g), and sodium hydroxide pellets (8.5 g, 213 mmol). The flask was warmed to 50° C. (internal) and bromocyclopentane (8.57 mL, 80 mmol) was added over a 5 minute period. The temperature was raised to 100° C. and maintained for 30 minutes. Workup consisted of pouring the reaction mixture onto ice (100 mL) and extracting with ether (100 mL, then 2×50 mL). The combined ethereal extracts were washed with saturated with sodium chloride solution (20 mL), dried using MgSO4, filtered through silica, and concentrated. The residue was subjected to vacuum distillation, affording the a product compound as an oil, which was characterized as follows: 13CNMR(CDCl3, 100 MHz, partial): 45.3, 41.7, 30.9, 30.2, 24.9, 24.8. NMR(CDCl3, 400 MHz, partial): 3.72 (d, 1H, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:20]3[CH2:23][CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14](F)=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][N:7]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:20]3[CH2:23][CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([O:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][N:7]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Oc1ccccc1
Temperature: 120 °C
Yield: 29.9 %

Procedure:
Into a round bottom flask was added 5-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-fluorobenzonitrile (30 mg, 0.0001 mol), phenol (0.023 g, 0.00024 mol), potassium carbonate (0.040 g, 0.00029 mol), DMF (0.8 mL, 0.01 mol) and the reaction mixture was heated at 120° C. for 4 h. Purification by Gilson HPLC afforded 11.4 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ=1.98-2.11 (m, 1H), 2.12-2.26 (m, 1H), 2.44-2.55 (m, 2H), 2.55-2.67 (m, 2H), 3.82 (dq, J=8.72, 8.55 Hz, 1H), 5.04 (br. s., 2H), 6.98 (d, J=8.84 Hz, 1H), 7.09 (d, J=5.05 Hz, 1H), 7.12-7.17 (m, 3H), 7.26-7.29 (m, 1H), 7.40-7.48 (m, 2H), 7.79 (dd, J=8.59, 2.27 Hz, 1H), 8.02 (d, J=2.02 Hz, 1H). MS (ES+): m/z 381.94 (100)[MH+]. HPLC: tR=2.53 min (Open Lynx, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9](OCC)=[O:10])[N:5]=[N:4][N:3]=1.CN(C)C=O.[O-]CC.[K+]>C(O)(=O)C>[N:5]1[N:6]2[C:7]3[C:8]([C:9]([OH:10])=[CH:1][C:2]2=[N:3][N:4]=1)=[CH:14][CH:15]=[CH:16][N:17]=3
Reactant: CCOC(=O)c1cccnc1-n1nnnc1C
Agent: CC[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1cc2nnnn2c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Ethyl 2-(5-methyl-1H-tetrazol-1-yl)nicotinate (6.3 g, 27 mmole) was covered with N,N-dimethylformamide (50 mL), potassium ethoxide (4.5 g, 54 mmole) was added and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into ice water containing about 17 mL of acetic acid. The resulting precipitate was isolated by filtration, washed with water then dried to provide 4.5 g of tetrazolo[1,5-a][1,8]naphthyridin-5-ol as an off white solid, m.p. 236° (decomposition). Analysis: Calculated for C8H5N5O: %C, 51.34; %H, 2.69; %N, 37.42; Found: %C, 51.23; %H, 2.77; %N, 37.25.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[F:9].[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:6]3[CH:5]=[CH:4][C:3]([F:9])=[C:2]([Cl:1])[CH:7]=3)/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: Fc1ccc(I)cc1Cl
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(F)c(Cl)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 2-chloro-1-fluoro-4-iodo-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.00 (s, 1H), 7.93 (d, 1H), 7.50 (d, 1H), 7.22-7.42 (m, 9H), 7.09 (dt, 1H), 6.73 (dt, 1H), 6.66 (d, 1H), 6.51 (d, 1H), 4.95 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2(O)[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=[O:16])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH:1]1([CH:4]2[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:7](=[O:16])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: O=C1CCC(O)(C2CC2)N1Cc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCC(C2CC2)N1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
To 5-cyclopropyl-5-hydroxy-1-(phenylmethyl)-2-pyrrolidinone (400 mg, 1.73 mmol) in CH2Cl2 (10 mL) at −78° C. was added a mixture of triethylsilane (2.76 mL, 17.3 mmol) and BF3.OEt2 (0.88 mL, 6.92 mmol) dropwise. The resulting reaction mixture was stirred for 2 hours at −78° C., then allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding a saturated aqueous NaHCO3 solution, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% hexanes to 100% EtOAc) afforded the title compound (240 mg, 65%) as a colorless oil. LC-MS (ES) m/z=216 [M+H]+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]1([CH2:22][C:23]2[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[OH:1][CH:2]([CH2:3][O:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:24]=1)[CH2:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: Oc1cccc(CN2CCCCC2)c1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CC(O)COc1cccc(CN2CCCCC2)c1
Temperature: 130 °C
Yield: 100.1 %

Procedure:
A mixture of 2-(oxiranylmethyl)-1H-isoindole-1,3-(2H)-dione (9.10 g) and 3-(1-piperidinylmethyl)phenol (8.55 g) was heated at 130° C. under nitrogen for 10 minutes. The resulting mixture was dissolved in chloroform (100 ml), washed with 1N sodium hydroxide (2×25 ml), dried (MgSO4) and evaporated to give the title compound as a gum (17.65 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][P:11](Cl)([CH3:13])=[O:12]>C1COCC1>[CH3:10][P:11]([CH3:13])([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: CP(C)(=O)Cl
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CP(C)(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
To a cooled (0° C.) flask containing 34.0 mL (2.0 M in Et2O, 68.4 mmol) of 4-fluorophenylmagnesium bromide, under an atmosphere of N2, was added a solution of dimethylphosphinic chloride (3.50 g, 31.1 mmol) in 84 mL of THF, dropwise via cannulation, over 20 min. The green reaction mixture was stirred at 0° C. for 1 h, then quenched at 0° C. with 30 mL of saturated NH4Cl resulting in the formation of a white precipitate. The mixture was concentrated on a rotary evaporator and partitioned between EtOAc (200 mL) and H2O (200 mL), upon which the layers were separated. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organics washed with brine, then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 5% MeOH/DCM) to provide 2.08 g of an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.83 (m, 2H), 7.35 (td, J=8.9, 1.7 Hz, 2H), 1.66 (s, 3H), 1.61 (s, 3H). 31P NMR (121 MHz, DMSO-d6) δ 37.186. 9F NMR (282 MHz, DMSO-d6) 3-105.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH2:12][C:13](O)=[O:14])([CH3:11])[CH2:8][CH2:7][C:6]=2[CH:16]=1.S(Cl)([Cl:19])=O>CN(C)C=O.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH2:12][C:13]([Cl:19])=[O:14])([CH3:11])[CH2:8][CH2:7][C:6]=2[CH:16]=1
Reactant: CC1(CC(=O)O)CCc2cc(Cl)ccc2O1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC1(CC(=O)Cl)CCc2cc(Cl)ccc2O1

Procedure:
To a solution composed of 2.89 g of (6-chloro-3,4-dihydro-2-methyl-2H-benzopyran-2-yl)acetic acid, 2 drops of N,N-dimethylformamide and 50 ml of benzene was added 0.9 ml of thionyl chloride and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was evaporated under reduced pressure to remove the low-boiling substances. The above procedure gave (6-chloro-3,4-dihydro-2-methyl-2H-benzopyran-2-yl)acetyl chloride in a quantitative yield of 3.1 g.
Reaction SMILES: Cl.[CH3:2][C:3]([NH2:9])([CH:6]([CH3:8])[CH3:7])[C:4]#[N:5].[OH-].[Na+].O.[Br:13][CH:14]([CH2:18][Br:19])[C:15](Cl)=[O:16]>ClCCl>[C:4]([C:3]([NH:9][C:15](=[O:16])[CH:14]([Br:13])[CH2:18][Br:19])([CH3:2])[CH:6]([CH3:8])[CH3:7])#[N:5]
Reactant: CC(C)C(C)(N)C#N
Reactant: O=C(Cl)C(Br)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)C(C)(C#N)NC(=O)C(Br)CBr

Procedure:
A mixture of 4.5 g (0.03 mole) of the 2,3-dimethyl-2-aminobutyronitrile hydrochloride, 4.8 g (0.06 mole) of 50% aqueous sodium hydroxide, 15 ml of dichloromethane and 15 ml of water was prepared. A second solution of 7.5 g (0.03 mole) of 2,3-dibromopropionyl chloride in 15 ml dichloromethane was added with rapid stirring to the first mixture at 10°-15° C. The mixture was then allowed to reach room temperature.
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[C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)CCC>CN(C=O)C.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>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(Cl)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccccn3)ncnc21
Temperature: 160 °C
Yield: 87.8 %

Procedure:
A mixture of 3-(6-chloro-purin-9-yl)-N-cyclopropyl-4-methyl-benzamide (16 mg, 0.049 mmol), Pd(PPh3)4 (5.7 mg, 0.0049 mmol) and the 2-tributylstannanyl-pyridine (36 mg, 0.098 mmol) was suspended in DMF (0.25 ml). The mixture was heated with microwave at 160° C. for 10 minutes. The mixture was purified by HPLC to give the desired product as a white solid (16 mg, 0.043 mmol, 88%). HPLC tR=1.59 min; MS m/z 371 [M+H]+.