Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].C[O:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:31])/[C:17](/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO.ClCCl.O>[C:25]1(/[C:17](=[CH:18]\[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[C:16]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([NH:2][OH:3])=[O:7])=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NO
Reactant: COC(=O)CCCCCCNC(=O)/C(=C/c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=C(CCCCCCNC(=O)/C(=C/c1ccccc1)c1ccccc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
Hydroxylamine hydrochloride (1.4 g, 19.7 mmol) in methanol (3 mL) was mixed with KOH (1.1 g, 19.7 mmol) in methanol (2.5 mL) at 0° C. and the reaction mixture was sonicated for 5 minutes. A white precipitate was formed which was filtered. The filtrate was immediately added to the methyl-(2E)-7-(2,3-diphenylacrylamido)heptanoate (0.4 g, 1.1 mmol) in dichloromethane (1 mL) and the mixture was stirred at room temperature for 30 min. Reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate, (200 mL). The organic layer was washed successively with water (3×50 mL) and brine solution (3×50 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude compound, triturated with dichloromethane (20 mL), to afford the title compound as a pure colorless solid (0.230g, 58% yield). 1H NMR (DMSO-d6) δ (ppm): 1.23 (4H, m, —CH2), 1.42-1.49 (41-1, m, —CH2), 1.91-1.94 (2H, t, —CH2), 3.09-3.14 (2H, q, —CH2), 6.96-6.98 (2H, t, Ar—H), 7.15-7.17 (5H, m, Ar—H), 7.34 (1H, s, ═CH), 7.36-7.44 (4H, m, Ar—H & —NH), 9.00 (1H, s, —NH), 10.34 (1H, s, —NH). MS m/z: 367.0 (M++1). The following compounds were prepared according to the above procedure
Reaction SMILES: C(O)=O.C([O:6][CH:7](OCC)[C:8]1[CH:9]=[C:10]([CH:32]=[CH:33][CH:34]=1)[CH2:11][CH2:12][N:13]1[CH2:31][CH2:30][C:16]2([O:21][CH2:20][CH2:19][N:18]([C:22]([C:24]3[S:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[O:23])[CH2:17]2)[CH2:15][CH2:14]1)C>O1CCCC1.O>[CH3:29][C:26]1[S:25][C:24]([C:22]([N:18]2[CH2:17][C:16]3([CH2:30][CH2:31][N:13]([CH2:12][CH2:11][C:10]4[CH:9]=[C:8]([CH:34]=[CH:33][CH:32]=4)[CH:7]=[O:6])[CH2:14][CH2:15]3)[O:21][CH2:20][CH2:19]2)=[O:23])=[CH:28][CH:27]=1
Reactant: CCOC(OCC)c1cccc(CCN2CCC3(CC2)CN(C(=O)c2ccc(C)s2)CCO3)c1
Solvent: O=CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)N2CCOC3(CCN(CCc4cccc(C=O)c4)CC3)C2)s1
Reaction time: 0.17 h

Procedure:
Formic acid (2 mL) was added to stirred solution of (9-(3-(diethoxymethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-methylthiophen-2-yl)methanone (example 20, step e) (0.20 g) in tetrahydrofuran (3 mL) and water (1 mL) cooled in an ice bath. After 10 min, the reaction mixture was evaporated in vacuo, toluene was added and the reaction mixture was evaporated in vacuo. The residue was dissolved in acetonitrile and then evaporated in vacuo, and this process was repeated to give the subtitled compound as an oil that was used directly. Yield 0.16 g.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C@@H:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]([O:15]C(C)(C)C)=[O:14])[C:8]2=[O:24])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C@@H:12]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:13]([OH:15])=[O:14])[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccc(O)cc2)C1=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccc(O)cc2)C1=O
Yield: 100.9 %

Procedure:
A solution of Example 144B (0.04 g, 0.11 mmol) in dichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.5 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was twice azeotroped with ethyl acetate to give the crude title compound (0.034 g, 100%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4](C=C1)[CH2:3][CH:2]2[O:8]C(=O)C.C[N+]1([O-])CC[O:16]CC1.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21].C(=O)(O)[O-].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:16][CH:1]1[CH:2]([OH:8])[CH:3]2[CH2:4][CH:7]1[CH2:25][CH:24]2[O:23][C:20](=[O:22])[CH3:21]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(=O)OC1CC2C=CC1C2
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OC1CC2CC1C(O)C2O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of acetic acid bicyclo[2.2.1]hept-5-en-2-yl ester (10 mmol) and N-methyl morpholine N-oxide (22 mmol) in acetone (50 mL) and water (5 mL) was added osmium tetroxide (1.2 mL 2.5% by weight solution in t-butanol). The reaction mixture is allowed to stir at room temperature for 18 h and the acetone was stripped. Ethyl acetate (50 mL) and saturated sodium bicarbonate solution (50 ml) were added. The aqueous layer was extracted with ethyl acetate (4×50 mL). The combined organic extracts were washed with 1N aqueous HCl solution (2×50 mL) and the organic layer was dried over MgSO4, filtered and concentrated to afford a yellow oil (8.3 mmol). 1H NMR (CDCl3, 400 MHz) δ 4.82 (m, 1H), 4.18 (m, 1H), 3.80–3.55 (br s, 3H), 2.40 (m, 2H), 2.00 (s, 3H), 1.80 (s, 1H), 1.19 (s, 2H), 0.80 (m, 1H); APCl MS m/z 187.3 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:19][CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>CC(N(C)C)=O.CCOCC.O>[CH2:22]([O:21][CH:20]([O:24][CH2:25][CH3:26])[CH2:19][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11])[CH3:23]
Reactant: O=C1COc2ccccc2N1
Reactant: CCOC(CBr)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCOC(CN1C(=O)COc2ccccc21)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
Dissolve 2H-1,4-benzoxazin-3(4H)-one (1.0 g, 6.64 mmol) in dimethylacetamide (5 mL); add potassium tert-butoxide (1.54 g, 13.28 mmol); and stir at ambient temperature for 5 minutes. Add 2-bromo-1,1-diethoxyethane (10.1 mL, 66.4 mmol) and tetra-N-butylammonium iodide (2.49 g, 6.64 mmol). Heat the reaction mixture to 80° C. and stir for 2 hours. Thereafter allow the reaction to cool to ambient temperature. Dilute the reaction mixture with Et2O and water; separate the layers; and extract the aqueous layer with additional Et2O. Combine the organic extracts; dry over Na2SO4; filter; and concentrate the filtrate under reduced pressure. Purify via flash column chromatography using a step gradient of 0%, 10%, 20% and 30% of EtOAc in hexanes. Concentrate the desired fractions to afford the title compound (1.65 g, 93.7%) as a waxy solid. 1H (300 MHz, CDCl3): δ 7.36-7.32 (m, 1H), 7.03-6.97 (m, 3H), 4.78 (t, J=5.5 Hz, 1H), 4.59 (s, 2H), 4.02 (d, J=5.5 Hz, 2H), 3.81-3.70 (m, 2H), 3.58-3.48 (m, 2H), 1.16 (t, J=7.0 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10]C)=[O:8])=[CH:5][C:4]=1[NH:14][S:15]([CH3:18])(=[O:17])=[O:16].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N:14]([CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)c1ccc(OC)c(NS(C)(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(N(CCN2CCOCC2)S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 104.7 %

Procedure:
To a solution of ethyl 4-methoxy-3-(methylsulfonamido)benzoate (0.600 g, 2.314 mmol) in dry DMF (23 ml), 4-(2-chloroethyl)morpholine hydrochloride (0.517 g, 2.78 mmol) and K2CO3 (0.704 g, 5.09 mmol) were sequentially added stirring at RT under nitrogen, and the reaction was heated at 70° C. overnight. Water (40 ml) was added, and the mixture was extracted Et2O (3×) and then with EtOAc (3×). The combined organic layers were dried over Na2SO4, and the solvent was removed. The crude was purified by flash chromatography on silica gel column (EtOAc:MeOH=97:3) affording methyl 4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)-benzoate (0.902 g, yield supposed to be quantitative, MS/ESI+ 373.0 [MH]+). This crude was used as such, without any further purification.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[Br:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC.CCOC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]2[C:2](=[O:3])[C:1](=[O:5])[S:14][C:10]=2[CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Sc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C1Sc2cc(Br)ccc2C1=O
Temperature: 25 °C
Yield: 50.2 %

Procedure:
Oxalyl chloride (3.7 mL, 42 mmol) was added dropwise to a solution of 3-bromothiophenol (5.00 g, 26.4 mmol) in ether (20 mL). The mixture was heated at reflux for 1.5 hours, cooled to room temperature, and concentrated in vacuo. The resulting residue was taken up in DCM (50 mL) and cooled to 0° C. Aluminum chloride (4.23 g, 31.7 mmol) was added in portions. The resultant mixture was stirred at reflux for 30 minutes, cooled to room temperature and poured into ice water with stirring. The organic layer was separated and successively washed with saturated aqueous NaHCO3, water and brine. The organic layer was dried and concentrated in vacuo to give a solid, which was suspended in 20% EtOAc in hexanes (50 mL) and heated at reflux for 10 minutes. After cooling, the precipitated solid was collected by filtration to afford crude 6-bromobenzo[b]thiophene-2,3-dione (3.22 g, 50%). The 6-bromobenzo[b]thiophene-2,3-dione was added to ammonium hydroxide (35% aqueous solution, 40 mL) at 5-10° C., followed by dropwise addition of hydrogen peroxide (35% aqueous solution, 5.5 mL, 66 mmol). The resulting mixture was stirred at room temperature for 30 minutes, and then filtered to give 6-bromobenzo[b]thiophene-3-carboxamide (1.30 g, 38%) as a solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.66 (d, J=8.8 Hz, 1H), 8.62 (s, 1H), 8.23 (s, 1H), 7.81 (s, 1H), 7.73 (d, J=8.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:19]=[N+:20]([O-])[CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:26][N:27](C)C(Cl)=O.C[Si](C#N)(C)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:26]#[N:27])=[N:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(c1ccc[n+]([O-])c1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: CC(c1ccc(C#N)nc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
A mixture of the product of part (i) (0.93 g) and N,N-dimethylcarbamoyl chloride (0.40 g) in dichloromethane (10 ml) was stirred at room temperature overnight. Trimethylsilyl cyanide (0.40 g) was added and stirring was continued for a further 60 hours. The solution was washed with 10% sodium carbonate solution and the aqueous layer was separated and washed with dichloromethane. The organic layers were combined, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using hexane/isopropanol (4:1) as eluant to give 2-(2,4-difluorophenyl)-3-(2-cyanopyridin-5-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, (0.18 g), m.p. 136°-141°.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[CH3:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=1)[CH2:16][CH:13]1[CH2:15][CH2:14]1)=[O:6]
Reactant: NCC(CC1CC1)c1cnc(C(F)(F)F)nc1
Reactant: COc1cccc(C(=O)O)c1C
Product: COc1cccc(C(=O)NCC(CC2CC2)c2cnc(C(F)(F)F)nc2)c1C

Procedure:
From 2-methyl-3-methoxybenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=394.0, tR (minutes, Method F)=2.59
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(OCC)(=O)C.O>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][N:24]([CH2:40][CH2:41][O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:23][CH2:22]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCOc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 0.10 g of ethyl 4-(3-(7-methoxy-2-oxo-1,2-dihydroquinolin-1-yl)propyl)piperidine-4-carboxylate, 74 mg of potassium carbonate and 1 mL of an N,N-dimethylformamide solution containing 60 mg of (2-bromoethoxy)benzene were added at room temperature. After stirred at 50° C. for 30 min, it was allowed to stand overnight. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=30:1], to give 0.12 g of ethyl 4-(3-(7-methoxy-2-oxo-1,2-dihydroquinolin-1-yl)propyl)-1-(2-phenoxyethyl)piperidine-4-carboxylate as a yellow oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16].Cl[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1)=[O:17]
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1Cl
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1Cl
Temperature: 150 °C

Procedure:
A solution of N-[(1S,2S)-2-aminocyclopentyl]-2-chlorobenzamide hydrochloride (Intermediate 19; 100 mg, 0.36 mmol), 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 79 mg, 0.44 mmol) and DIPEA (190 μl, 1.09 mmol) in dry DMSO (1.2 ml) was sealed and heated at 150° C. for 17 hours. The reaction mixture was filtered through cotton wool and purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].P([O-])([O-])([O-])=O.C([O-])(=O)C>>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: CCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
Ethyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (0.5 ml of a solution containing 2 mg/ml in a phosphate, pH 7; 0.1M, or acetate buffer, pH 5; 0.1 M) was added to the reaction vessel followed by an enzyme (0.5 ml enzyme solution). The reaction mixture was shaken at room temperature and analysed at different times (maximum 36 h). The reaction mixture was analysed without work up by the gradient HPLC method 1 and by chiral HPLC methods 2 and 5.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].C(#N)C.[C:13]1(=[O:36])[N:17]([CH:18]2[C:29](=[O:30])[N:20]3[CH:21](C(O)=O)[C:22]([CH3:25])([CH3:24])[S:23][C@H:19]23)[C:16](=[O:31])[C:15]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:14]12.N1C=CC=CC=1>CN(C)C=O>[C:16]1(=[O:31])[N:17]([CH:18]2[C:29](=[O:30])[N:20]3[CH:21]([C:5]([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])=[O:6])[C:22]([CH3:25])([CH3:24])[S:23][C@H:19]23)[C:13](=[O:36])[C:14]2=[CH:35][CH:34]=[CH:33][CH:32]=[C:15]12
Reactant: CC1(C)S[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC1(C)S[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl

Procedure:
2,2,2-Trichloroethyl 6-phthalimido-2,2-dimethyl-penam-3-carboxylate is prepared by adding a solution of 11.6 g.(0.06 mole) of 2,2,2-trichloroethylchloroformate in 50 ml. of acetonitrile dropwise over a 15-minute period of a reaction mixture of 17.2 g.(0.05 mole) of 6-phthalimido-2,2-dimethyl-penam-3-carboxylic acid in 100 ml. of dimethyl formamide and 4.8 g.(0.06 mole) of pyridine at room temperature.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH:18]([CH3:20])[CH3:19])([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH:18]([CH3:20])[CH3:19])([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@]1(C(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@]1(C(=O)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of methyl (1S,4S)-4-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopent-2-ene-1-carboxylate (18.42 g, 65 mmol) in THF (500 mL), methanol (500 mL) and water (100 mL) was added lithium hydroxide monohydrate (5.00 g, 119 mmol). The mixture was heated to reflux overnight. After 18 hours, TLC indicated a very trace amount of starting material. The organic solvents were removed in vacuo and the aqueous layer was extracted with ether (200 mL) to remove the unreacted starting material. The aqueous layer was acidified with concentrated HCl to pH=4 while being cooled in an ice bath. The resulting solution was extracted with methylene chloride three times. The extracts were dried over MgSO4 and concentrated to give a solid (17 g). The solid was dissolved in hot ethyl acetate (22 mL) and hexanes (550 mL) were added to the solution. The solution was slowly cooled down to room temperature before putting into a freezer reading at −22 to −24° C. After two days, the crystals were removed off and the liquid was evaporated in vacuo to give the desired product as a white foamy solid (9.78 g, 56%). MS calculated for C14H23NO4: (M+H)+270; found 170.1 (M-Boc+H)+.
Reaction SMILES: O[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]2[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:13]([CH3:14])[C:3]=12.P(Cl)(Cl)([Cl:23])=O.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>O1CCCC1>[Cl:23][C:2]1[C:7]([C:8]([N:27]([CH3:26])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:10])=[CH:6][N:5]=[C:4]2[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:13]([CH3:14])[C:3]=12
Reactant: CNc1ccccc1
Reactant: Cc1nn(-c2ccccn2)c2ncc(C(=O)O)c(O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccn2)c2ncc(C(=O)N(C)c3ccccc3)c(Cl)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A solution of 4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (2.0 g, 7.4 mmol) in phosphorous oxychloride (15 mL, 63 mmol) was heated and stirred at 100° C. for 3 hours. After the solution was cooled to room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL). To the solution, a solution of N-methylaniline (1.0 mL, 9.2 mmol) and triethylamine (5.2 mL, 37 mmol) in tetrahydrofuran (10 mL) was added at 0° C. After the mixture was stirred at room temperature for 1.5 hours, the reaction solvent was evaporated under reduced pressure. Purification of the residue thus obtained by silica gel chromatography (chloroform:methanol=50:1 to 20:1) gave the title compound (2.14 g, 76% yield).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([NH:18]C=O)[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=C(OC)C=2)[N:3]=1.[CH3:25][NH2:26].[Cl-].[Na+].[C:29]([O:32][CH2:33][CH3:34])(=O)C>O1CCCC1.CO>[NH2:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:33]([O:32][CH3:29])[CH:34]=3)[N:3]=[C:2]([CH2:25][NH2:26])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CN
Reactant: COc1cc2nc(Cl)nc(-c3cccc(NC=O)c3)c2cc1OC
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2nc(CN)nc(-c3cccc(N)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
To 354 mg (1.00 mmol) of N-[3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenyl]formamide, tetrahydrofuran (2.06 mL), and methanol (1.03 mL) was added a methanol solution (2.06 mL) of 40% methylamine, and the mixture was reacted at 90° C. for 12 hours. The reaction mixture was allowed to cool and then poured into a mixed solution of ethyl acetate (30 mL), tetrahydrofuran (30 mL), and 5% w/w sodium chloride solution (30 mL) to extract the organic layer. The organic layer was washed with 5% w/w sodium chloride solution (30 mL) and then concentrated under reduced pressure. To the concentration residue was added ethyl acetate (1.5 mL), and the mixture was crystallized with a spatula followed by stirring at 50° C. for 1.5 hours. To this suspension was dropwise added t-butyl methyl ether (1.5 mL), and the mixture was further stirred for 1 hour and allowed to cool gradually. The precipitated crystals were collected by filtration and dried to give 288 mg of a target product (yield: 90.5%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([F:17])[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.N(CCO)CCO>C1(C)C=CC=CC=1>[Br:1][CH2:2][C@@H:3]([C:5]1[C:14]2[C:9](=[C:10]([F:17])[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: COc1cc(F)c2nccc(C(=O)CBr)c2c1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: OCCNCCO
Solvent: Cc1ccccc1
Product: COc1cc(F)c2nccc([C@@H](O)CBr)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
8.0 g (26.8 mmol) of 2-Bromo-1-(8-fluoro-6-methoxy-quinolin-4-yl)-ethanone was dissolved in 200 mL of toluene. 17.2 g (53.6 mmol) of (+)-DIP-chloride was added and the contents were allowed to stir at rt overnight (16 hrs). 8 mL (80.4 mmol) of diethanolamine was added and the contents were allowed to stir at rt for 3 hrs. The contents were filtered and the solids washed; first with hot toluene, then with ethyl acetate until the washings no longer had UV activity. The crude material was preadsorbed onto silica gel and purified by flash chromatography using 2:1 hexanes/ethyl acetate and going to 100% ethyl acetate afforded 7.95 g (98%) of the product. 1H NMR (DMSO, 400 MHz) 8.81 (d, 1H), 7.71 (d, 1H), 7.39 (d, 1H), 7.30 (s, 1H), 6.28 (d, 1H), 5.75 (m, H), 4.00 (s, 3H), 3.97 (dd, 1H), 3.91 (dd, 1H). LCMS (M+H)+ 300. Enantiomeric excess was determined by chiral HPLC to be ≧94%.