Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C(O)(=O)C.[O-:43][C:44]#[N:45].[K+].[ClH:47]>C(Cl)Cl.O>[ClH:47].[ClH:47].[O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:44]([NH2:45])=[O:43])[CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[O-]
Reactant: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: NC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Reaction time: 18 h
Yield: 48.4 %

Procedure:
To a solution of N-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (Example 34, Step C, 0.055 g, 0.119 mmol) in CH2Cl2 (4 mL) was added pyridine (0.0940 g, 1.19 mmol), acetic acid (0.0714 g, 1.19 mmol), TEA (0.033 mL, 0.238 mmol), and potassium cyanate (0.0193 g, 0.238 mmol). The reaction was stirred for 18 hours. Water was added and the reaction was extracted with CH2Cl2. The organic layer was dried, filtered, and concentrated. The residue was purified by silica gel (1-4% MeOH in CH2Cl2) to give the title compound (0.0333 g, 48.4% yield) after HCl salt formation. 1H NMR (d6-DMSO) δ 12.33 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.67 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 3.94 (d, 2H), 2.97 (m, 1H), 2.83 (t, 2H), 1.19 (m, 2H), 1.64 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.Cl[Sn]Cl>C1COCC1.Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To 1-[3-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperidine (0.42 g, 1.3 mmol) in THF (60 mL) cooled to 0° C. was added SnCl2 (1.0 g, 5.4 mmol) dissolved in conc. HCl dropwise. The solution was stirred overnight at room temperature (TLC confirms consumption of starting material). The mixture was cooled to 0° C. and quenched with 6 N NaOH (25 mL). The solution was poured into EtOAc and H2O was washed with brine, back extracted with EtOAc, dried (MgSO4), filtered, and rotovaped down to give the title compound of step B (0.39 g, 1.3 mmol, 96%). 1H NMR (400 MHz, CDCl3) δ 1.18-1.29 (m, 2H), 1.31-1.43 (m, 1H), 1.57-1.65 (m, 2H), 1.70 (d, J=12.5 Hz, 2H), 2.37-2.43 (m, 2H), 2.92 (s, 3H), 3.07-3.14 (m, 2H), 3.34 (d, J=11.5 Hz, 2H), 3.69 (s, 3H), 4.16 (br. s., 2H), 6.25 (d, J=7.7 Hz, 1H), 6.40-6.48 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]2)[C:5]=1[N+:19]([O-:21])=[O:20])[CH3:2].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]2)[C:5]=1[N+:19]([O-:21])=[O:20])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOc1nc(SC)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
50 gm (0.15 mol) of 6-ethoxy-2-methylthio-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine together with 64.8 gm (0.15 mol) of piperazine, were dissolved in 150 ml of dimethyl sulfoxide and the solution was stirred for 6 hours at room temperature. Then, the reaction mixture was poured into ice-water, the crystals formed thereby were suction-filtered off, and the filter cake was washed with water and recrystallized from ethanol. Yield: 39.3 gm (70.7% of theory); m.p. 222°-223°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2ccc(C(=O)O)cc2)c(C(F)(F)F)c1

Procedure:
A stirred solution of 5-amino-2-bromobenzotrifluoride (2.5 g, 0.01 mol) in DME (60 ml) and water (60 ml) was treated with 4-boronobenzoic acid (1.65 g, 0.01 mol) and Na2CO3 (4.2 g, 0.04 mol). The mixture was degassed with argon for 15 mins, treated with tetrakis (triphenylphosphine) palladium (O) (230 mg, 0.2 mmol) and heated at reflux under argon for 18 hrs. The mixture was concentrated in vacuo to approx. 50% volume and the aqueous residue treated with 10% aqueous Na2CO3 solution and washed with ethyl acetate. The aqueous layer was separated, acidified with 5M HCl and concentrated in vacuo to afford an off-white solid containing the title compound. This was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:32]([N:40]1[CH2:45][CH2:44][N:43]([C:22]([C:21]2[CH:20]=[CH:19][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:29])([F:31])[F:30])[C:9]=4[CH:17]=3)=[CH:26][CH:25]=2)=[O:24])[CH2:42][CH2:41]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: O=C(c1ccccc1)N1CCNCC1
Product: O=C(c1ccccc1)N1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-benzoylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=619.98 (M+H+); retention time=0.82 minutes.
Reaction SMILES: [O:1]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]1[CH2:3][NH:4]C(=O)C(F)(F)F.[OH-].[K+].[Cl-].[Na+]>>[O:1]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]1[CH2:3][NH2:4]
Reactant: O=C(NCC1OC1c1ccccc1)C(F)(F)F
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: NCC1OC1c1ccccc1
Temperature: 20 °C
Reaction time: 0.12 h

Procedure:
N-[(2RS, 3RS)-2,3-Epoxy-3-phenylpropyl]trifluoroacetamide (11 g) is added to 3.6 N aqueous potassium hydroxide solution (12.5 cc). After 7 minutes' stirring at a temperature in the region of 20° C., the solution obtained is saturated with sodium chloride and then extracted with dichloromethane (2×100 cc). The organic phases are combined, dried over magnesium sulphate and then filtered, thereby forming a methylene chloride solution of (2RS, 3RS)-2,3-epoxy-3-phenylpropanamine (solution B).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=O.[C:16](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[CH:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
To solution of Example 1C (2 g, 9.38 mmol) in methanol (20 mL) was added potassium carbonate (3.89 g, 28.1 mmol) and the mixture was stirred for 30 minutes. Dimethyl 1-diazo-2-oxopropylphosphonate (3.60 g, 18.76 mmol) was added and the mixture was stirred for 12 hours. The mixture was filtered through diatomaceous earth and concentrated to afford crude material which was purified by column chromatography (silica gel, 15% ethyl acetate in hexane) to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 1.41 (s, 9H), 1.55-1.59 (m, 1H), 1.67-1.69 (m, 2H), 1.96-1.99 (m, 1H), 2.06-2.07 (m, 1H), 2.43-2.44 (m, 1H), 2.93-3.02 (m, 2H), 3.69-3.75 (m, 1H), 3.9-4.0 (m, 1H).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[NH:23]1[CH2:26][CH2:25][C:24]1=[O:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC.[Cl-].[NH4+]>O1CCOCC1.[Cu](I)I>[O:27]=[C:24]1[CH2:25][CH2:26][N:23]1[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(I)cc12
Reactant: O=C1CCN1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CCN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
The 7-iodo-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (10.0 mg, 0.024 mmol) prepared in step D, copper iodide (I) (0.48 mg, 0.0025 mmol), 2-azetidinone (2.13 mg, 0.03 mmol), and potassium phosphate (11.1 mg, 0.0525 mmol) were suspended in 1,4-dioxane (0.25 ml). Thereafter, N,N′-dimethylethylenediamine (2.6 μl) was added to the suspension, and the obtained mixture was stirred under heating to reflux overnight. Thereafter, the reaction solution was cooled to a room temperature, and a saturated ammonium chloride aqueous solution was then added thereto, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate hexane=3:1 to 6:1), so as to obtain 7-(2-oxoazetidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (3.8 mg; yield: 44%) in the form of a colorless solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:66])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:3])=[O:2].O[N:68]1[C:72](=[O:73])[CH2:71][CH2:70][C:69]1=[O:74].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C1C=CN=CC=1)C>[O:74]=[C:69]1[CH2:70][CH2:71][C:72](=[O:73])[N:68]1[O:2][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:66])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13]
Reactant: O=C1CCC(=O)N1O
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@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
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@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
18 mg (20 μmol) of N-(5-carboxypentyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 64) were dissolved in 3.2 ml of dichloromethane and admixed with 22 mg (190 mmol) of 1-hydroxypyrrolidine-2,5-dione and then with 11 mg (60 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.24 mg (0.17 μmol) of DMAP. After stirring at RT for 2 h, another 22 mg (190 mmol) of 1-hydroxypyrrolidine-2,5-dione, 11 mg (60 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.24 mg (0.17 mol) of DMAP were added and the reaction mixture was stirred at RT for a further hour. This was followed by concentration under reduced pressure. The remaining residue was purified by means of preparative HPLC. After lyophilization, 8.2 mg (41% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][C:43]([O:50][CH3:51])=[C:44]([CH3:49])[CH:45]=2)[O:40][C:39]=1[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:47](=[O:48])[C:46]4[C:41](=[CH:42][C:43]([O:50][CH3:51])=[C:44]([CH3:49])[CH:45]=4)[O:40][C:39]=3[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2oc(-c3ccccc3)c(I)c(=O)c2cc1C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1C
Yield: 47 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-7-methoxy-6-methyl-2-phenyl-chromen-4-one (78 mg, 0.20 mmol) was reacted to give the title compound (46 mg, 47%). 1H NMR (400 MHz, CDCl3): δ 8.20-7.98 (m, 1H), 7.44-7.15 (m, 9H), 6.86 (s, 1H), 5.05 (s, 1H), 3.94 (s, 3H), 2.61-2.44 (m, 4H), 2.33-2.28 (m, 3H), 2.14-1.98 (m, 1H), 1.91-1.75 (m, 1H), 1.49-1.12 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([O:14]C(=O)C2C=CC=CC=2)[CH3:13])[CH2:11][O:10]1.C[O-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](OC(=O)c1ccccc1)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
[(1S)-1-[(2R)-2-(2,4-Difluorophenyl)-2-oxiranyl]ethyl]benzoate (15.9 g) was dissolved in 800 ml of methanol. 28% Methanolic solution (12.9 ml) of sodium methylate was added with ice cooling and the reaction solution was stirred at room temperature for 6 hours. To the reaction solution was added 63.2 ml of 1N hydrochloric acid and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluate; hexane:ethyl acetate=6:1 to 2:1) to give 9.7 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)- 2-oxiranyl]ethanol as a colorless oil.
Reaction SMILES: C(=[N:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:19])=[C:13]([CH:16]=[CH2:17])[CH2:14][S:15][C@H:10]12)C1C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1(OC)C=CC=CC=1.C(OCC)(=O)C>[NH2:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([OH:20])=[O:19])=[C:13]([CH:16]=[CH2:17])[CH2:14][S:15][C@H:10]12
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N=Cc3ccccc3)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
To a suspension of benzhydryl 7-benzylideneamino-3-vinyl-3-cephem-4-carboxylate (8.6 g) in anisole (10 ml) was added dropwise trifluoroacetic acid (10 ml) at -20° C., and the reaction temperature was gradually raised to ambient temperature with stirring, followed by stirring at ambient temperature for half an hour. The reaction mixture was poured into a mixture of ethyl acetate (100 ml) and a saturated aqueous sodium bicarbonate (100 ml), and then the mixture was adjusted to pH 7.5 with 20% aqueous sodium carbonate. The separated aqueous solution was washed with ethyl acetate (100 ml) and adjusted to pH 7.2 with conc. hydrochloric acid, followed by subjecting to column chromatography on alumina (10 ml). Elution was carried out with 15% aqueous sodium chloride, and fractions containing a desired compound were collected and then adjusted to pH 3.3 with conc. hydrochloric acid. The precipitated crystals were collected by filtration, washed with acetone and dried to obtain 7-amino-3-vinyl-3-cephem-4-carboxylic acid (2.0 g), mp 200°-230° C. (dec.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:14][C:15]1[C:24]2[C:23](=[O:25])[N:22]([CH3:26])[CH:21]=[N:20][C:19]=2[CH:18]=[C:17]([C:27]2[CH:28]=[N:29][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:31][CH:32]=2)[N:16]=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:36][C:33]([C:30]1[N:29]=[CH:28][C:27]([C:17]2[N:16]=[C:15]([NH:14][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[C:24]3[C:23](=[O:25])[N:22]([CH3:26])[CH:21]=[N:20][C:19]=3[CH:18]=2)=[CH:32][CH:31]=1)([CH3:34])[CH3:35]
Reactant: Cn1cnc2cc(-c3ccc(C(C)(C)O)nc3)nc(N)c2c1=O
Reactant: Ic1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cn1cnc2cc(-c3ccc(C(C)(C)O)nc3)nc(Nc3ccccn3)c2c1=O
Temperature: 85 °C

Procedure:
2-iodopyridine (7.51 μL, 0.071 mmol), Cs2CO3 (41.9 mg, 0.129 mmol), and a catalytic amount of Pd(OAc)2 and xant phos ligand were added to a solution of 5-amino-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (20.0 mg, 0.064 mmol) in anhydrous THF (0.5 mL). The reaction mixture was purged with N2 and heated at 85° C. overnight. The mixture was then cooled, quenched with H2O (5 mL) and extracted with ethyl acetate (3×2.5 mL). The combined organic layers were evaporated under vacuo and the residue was purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C21H20N6O2 (M+H+) 389.2, found 389.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[C:21]3[C:20](=[O:31])[N:19]([CH2:32][C:33]([OH:35])=[O:34])[C:18](=[O:36])[N:17]([CH3:37])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:22]1[C:21]2[C:20](=[O:31])[N:19]([CH2:32][C:33]([OH:35])=[O:34])[C:18](=[O:36])[N:17]([CH3:37])[C:16]=2[N:15]=[C:14]1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CC(=O)O)c(=O)n2C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-n1c(N2CCNCC2)nc2c1c(=O)n(CC(=O)O)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[7-(2-Methoxyphenyl)-1-(carboxymethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (3 mg) was dissolved in trifluoroacetic acid (0.5 ml), and the reaction mixture was stirred at room temperature for 30 minutes. After the solvent was removed, the residue was purified by reversed phase high performance liquid chromatography to give 4.14 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[I:15]I.Cl>O>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:15])[N:3]=1
Reactant: Oc1cccnc1Br
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Oc1ccc(I)nc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-bromo-3-hydroxy pyridine (8-1, 28 g, 161 mmol) in water (360 mL) was added K2CO3 (22.24 g, 161 mmol) and I2 (20.42 g, 80 mmol). The system was stirred for 1.5 h at ambient temperature, cooled to 0° C. and then treated with concentrated HCl until solids precipitated from solution (pH˜6.0). The solids were isolated by filtration and dried to give the title compound (8-2) as a brown solid. ESI+MS[M+H]+C5H3BrINO=299.8
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:19]#[N:20])([O:14][Si](C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:19][NH2:20])([OH:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(O[Si](C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Cyano-4-trimethylsilanyloxy-piperidine-1-carboxylic acid tert-butyl ester (7.5 g) was dissolved in 100 ml of tetrahydro-furan under an argon atmosphere. A solution of lithium aluminium hydride in tetrahydro-furan (30 ml, 1 molar) was dropwise added at 0° C. After stirring for 15 hours at room temperature, a sodium hydroxide solution (20%) was slowly added under cooling. The solid was filtered after dilution with ethyl acetate and the organic layer evaporated. The crude material contains a mixture of the desired product (MS: 231.2 (M+H)+) and the corresponding trimethylsiliyl ether (MS: 303.1 (M+H)+) and was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][C:39]([F:43])=[CH:38]5)[CH:35]=[C:34]([F:44])[CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:45])[NH:19][C@:18]2([C:47]([O:49]CC)=[O:48])[CH2:46][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@@H]1C(=O)N2C[C@H](OC3N=C4C(=C5C=3C=CC=C5)C=CC=C4)C[C@H]2C(=O)N[C@]2(C(OCC)=O)C[C@H]2C=CCCCCC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][C:39]([F:43])=[CH:38]5)[CH:35]=[C:34]([F:44])[CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:45])[NH:19][C@:18]2([C:47]([OH:49])=[O:48])[CH2:46][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccc(F)cc4c4cc(F)ccc34)C[C@H]1C(=O)N2
Agent: CC(C)(C)OC(=O)N[C@H]1CCCCC/C=C\[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccc(F)cc4c4cc(F)ccc34)CN2C1=O
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccc(F)cc4c4cc(F)ccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccc(F)cc4c4cc(F)ccc34)CN2C1=O

Procedure:
Example 38e was prepared according to the procedure used for the preparation of Example 24c, substituting the product of Example 38d for the product of Example 24b.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:15](OCC)(OCC)[O:16][CH2:17][CH3:18].C(OC(=O)C)(=O)C>>[CH2:17]([O:16][CH:15]=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[CH3:18]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)CC(=O)OCc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC=CC(=O)CC(=O)OCc1ccccc1

Procedure:
From benzyl acetoacetate (38.4 g, 0.20 mol), triethyl orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol): 10.7 g, 21.5%; bp=170°-183° C. at 0.5 mm Hg; NMR (CDCl3) δ 1.0-1.4 (t, 3H), 2.2-2.3 (d, 3H), 4.0-4.4 (q, 2H), 5.2 (d, 2H), 7.4 (s, 5H), 7.8-8.0 (d, 1H).