Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:50](=[O:51])[N:14]2[C:15]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3C=CC=[CH:40][CH:39]=3)=[O:35])=[C:16](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[CH2:17][S:18][C@H:13]12)=[O:10])C1C=CC=CC=1.[SH-:52].[Na+].O>CN(C)C=O.C(N(C(C)C)CC)(C)C>[O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:50](=[O:51])[N:14]2[C:15]([C:34]([O:36][CH:37]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:38]3[CH:39]=[CH:40][CH:50]=[CH:12][CH:13]=3)=[O:35])=[C:16]([SH:52])[CH2:17][S:18][C@H:13]12)=[O:10])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: [SH-]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OP(=O)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S)CS[C@H]12
Reaction time: 0.75 h
Yield: 170.7 %

Procedure:
To a solution of 16.4 g (21.9 mM) of benzhydryl 7β-phenoxyacetamido-3-diphenylphosphoryloxy-3-cephem-4-carboxylate in 128 ml of N,N-dimethylformamide were added at -10° C. a solution of 1.93 g (24.1 mM) of 70% sodium hydrosulfide in 86 ml of N,N-dimethylformamide and 4.25 g (32.9 mM) of diisopropylethylamine, and the mixture was stirred for 45 minutes. After the reaction, 200 ml of water was added and the mixture was extracted with 200 ml of diethyl ether. The aqueous layer was adjusted to pH 2 to 3 with 0.5% hydrochloric acid and extracted with ethyl acetate (300 ml), and the extract was washed with a saturated aqueous sodium chloride solution (200 ml×2) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed over silica gel column (eluent; ethyl acetate:benzene=1:2 to 2:1) to give 10.4 g of benzhydryl 7β -phenoxyacetamido-3-mercapto-3-cephem-4-carboxylate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(C(C)C)CC)(C)C.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>O1CCCC1>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Fluoro-4-trifluoromethyl-2-nitrobenzene (5.1 g) was dissolved in tetrahydrofuran (100 mL) and diisopropylethylamine (5.5 ml) and 4-amino-1-tert-butoxycarbonylpiperidine (5.37 g) were added. The mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate and the extract solution was dried and concentrated under reduced pressure to give 1-tert-butoxycarbonyl-4-(4-trifluoromethyl-2-nitrophenyl)aminopiperidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[O:12]1[CH2:17][CH2:16][CH2:15][CH:14](O)[CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:14]1[CH2:15][CH2:16][CH2:17][O:12][CH2:13]1)[N:6]=[C:5]2[I:11]
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: OC1CCCOC1
Product: Fc1ccc2c(c1)c(I)nn2C1CCCOC1
Yield: 23 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and tetrahydro-3-pyranol in 23% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 1.86-1.93 (2H, m), 2.20-2.23 (1H, m), 2.34-2.41 (1H, m), 3.48-3.55 (1H, m), 3.80 (1H, t, J=10.4 Hz), 4.00-4.07 (2H, m), 4.50-4.58 (1H, m), 7.12 (1H, dd, J=2.4, 8.0 Hz), 7.21 (1H, td, J=2.4, 8.8 Hz), 7.39 (1H, dd, J=4.0, 8.8 Hz).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:24]=[CH:25][C:26]([NH:29][C:30]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:31])=[CH:27][CH:28]=1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C=Nc1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)nc1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=431.0 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 2-chloro-5-isocyanatopyridine.
Reaction SMILES: [Mg].[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.OS(O)(=O)=O>CCOCC>[Br:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([Br:2])[CH:4]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: BrCc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: Brc1cccc(CCc2cccc(Br)c2)c1

Procedure:
1,2-Bis(m-bromophenyl)ethane was prepared by the method of Lindsay et al (JACS, 1961, 83, 943) as follows. Magnesium (0.05 g, 2.0 mmol) was added to a solution of 3-bromobenzylbromide (1.0 g, 4.0 mmol) in Et2O (10 mL) at rt. After 20 min at room temperature all the magnesium had dissolved and anhydrous ferric chloride (5 mg) was added. The reaction was heated to reflux for 1 hour, cooled, acidified to about pH 1 with 1 M aqueous H2SO4 and extracted with Et2O (3×50 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a yellow solid. Recrystallization from petroleum ether gave 1,2-bis(m-bromophenyl)ethane as a colorless solid. MS (APCI) m/z 338 (50%), 340 (100), 342 (50). 1H NMR (200 MHz, CDCl3): δ 2.85, s, 2H; 7.02-7.25, m, 2H; 7.30-7.39, m, 2H.
Reaction SMILES: [K].[CH:2]([N:4]1C=CN=C1)=[CH2:3].[CH:9]([N:11]1[CH2:15][CH2:14]C[C:12]1=[O:16])=[CH2:10]>O>[CH2:10]=[CH:9][N:11]1[C:12](=[O:16])[N:4]([CH:2]=[CH2:3])[CH2:14][CH2:15]1
Reactant: C=CN1CCCC1=O
Reactant: C=Cn1ccnc1
Agent: [K]
Solvent: O
Product: C=CN1CCN(C=C)C1=O

Procedure:
A formulation consisting of 70 kg of cellulose, 20 kg of potassium caseinate and 10 kg of polymer d2) having a content of N-vinylimidazole (Vl) of 90% by weight, a content of N-vinylpyrrolidone (VP) of 7% by weight and a content of N,N′-divinylethyleneurea (DVEU) of 3% by weight was prepared by dissolving the potassium caseinate in 400 l of water at 60° C. and suspending the cellulose therein. The suspension was atomized at 185° C. at 70 bar via a single-component nozzle and the polymer was injected into the atomization zone.
Reaction SMILES: C([Mg]Br)C.[C:5]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:10]=1[OH:21])([CH3:8])([CH3:7])[CH3:6].[CH2:22]=[O:23].C(N(CC)CC)C>C1COCC1.C1(C)C=CC=CC=1>[C:5]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[C:11]([CH:22]=[O:23])[C:10]=1[OH:21])([CH3:8])([CH3:6])[CH3:7]
Reactant: C=O
Reactant: CC(C)(C)c1cc(-c2ccccc2)ccc1O
Agent: CC[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(-c2ccccc2)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
Into a 1 liter reactor thoroughly purged with nitrogen, 66.80 ml of an ether solution containing 200.4 mmol of ethylmagnesium bromide and 100 ml of THF were introduced. To the reactor, a solution containing 43.16 g (190.7 mmol) of 2-t-butyl-4-phenylphenol diluted with 90 ml of a THF was dropwise added at 0° C. over a period of 40 minutes, then the temperature of the system was slowly raised to room temperature, and the reaction solution was stirred at room temperature for 30 minutes. Then, 700 ml of toluene was added, and the system was heated to 100° C. to distill off 52 ml of a mixed solution of ether and THF, whereby an opaque white slurry was obtained. After the slurry was cooled to −20° C., 13.84 g (460.9 mmol) of paraformaldehyde and 38.1 ml (273.4 mmol) of triethylamine were added, followed by stirring at 90° C. for 30 minutes. After ice cooling, the reaction solution was quenched with 133 ml of 18% hydrochloric acid. The organic layer was washed with 300 ml of water, 300 ml of a sodium hydrogencarbonate aqueous solution and 300 ml of a sodium chloride aqueous solution, and then concentrated. The resulting liquid was purified by silica gel column chromatography to obtain 37.73 g (yield: 78%) of 3-t-butyl-5-phenylsalicylaldehyde.
Reaction SMILES: [N:1](/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>C1(C)C(C)=CC=CC=1>[Br:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:1]2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)/C(=C/c1ccc(Br)cc1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A solution of ethyl (Z)-2-azido-3-(4-bromophenyl)acrylate (6.24 g) in xylene (200 ml) was heated at reflux for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with xylene and hexane to obtain ethyl 6-bromo-1H-indole-2-carboxylate (3.21 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=O.P(Cl)(Cl)(Cl)=O.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:28]=[C:31]4[CH2:32][CH2:33][CH2:34][N:30]4[CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CN1CCCC1=O
Reactant: Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN1CCCC1=Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8 %

Procedure:
N4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-N6-(1-methyl-pyrrolidin-2-ylidene)-quinazoline-4,6-diamine is prepared by reacting N4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine and 1-methyl-pyrrolidin-2-one. Phosphorous oxychloride (0.047 g, 0.30 mmol) is added to a stirred solution of 1-methyl-pyrrolidin-2-one (0.63 g, 0.63 mmol) in methylene chloride (3 ml) at −78° C. under N2 (Bullock et al WO0220526). After 10 minutes, the reaction mixture is warmed to room temperature and stirred for 1 hour. N4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine (0.100 g, 0.253 mmol) is added followed by Et3N (0.031 g, 0.30 mmol). After 16 hours, the reaction mixture is quenched with saturated aqueous Na2CO3, the layers separated and the aqueous layer extracted with methylene chloride. The combined organic extracts are dried (Na2SO4), concentrated and purified on a silica gel column (10:2:1 EtOAc:hexanes:MeOH with 0.3% NH4OH solution) to yield 0.010 g (8%) N4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-N6-(1-methyl-pyrrolidin-2-ylidene)-quinazoline-4,6-diamine. MS APCI (+) m/z 476, 478 (M+1, Cl pattern) detected; 1H NMR (400 MHz, MeOH4) δ 8.42 (s, 1 H), 7.89 (s, 2 H), 7.77 (d, 1 H), 7.58 (m, 2 H), 7.33 (m, 3 H), 7.18 (d, 1 H), 7.04 (t, 1 H), 5.20 (s, 2 H), 3.60 (t, 2 H), 2.61 (t, 2 H), 2.03 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:14][CH3:15])=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1.[N:16]([CH:19]1[CH2:21][CH2:20]1)=[C:17]=[S:18]>O1CCOCC1>[CH:19]1([NH:16][C:17](=[S:18])[N:14]([C:10]2[S:9][C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:12][C:11]=2[CH3:13])[CH3:15])[CH2:21][CH2:20]1
Reactant: S=C=NC1CC1
Reactant: CNc1sc(-c2cncc(F)c2)nc1C
Solvent: C1COCCO1
Product: Cc1nc(-c2cncc(F)c2)sc1N(C)C(=S)NC1CC1
Yield: 73 %

Procedure:
A solution of 2-(5-fluoropyridin-3-yl)-N,4-dimethylthiazol-5-amine (200 mg, 0.896 mmol) and isothiocyanatocyclopropane (266 mg, 2.69 mmol) in dioxane (10 mL) was heated at 100° C. for 24 h before the solvent was removed under reduced pressure. The residue was purified via silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford the title compound as a yellow solid (211 mg, 73%): mp 117-119° C.; 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.56 (d, J=2.8 Hz, 1H), 7.96 (dt, J=9.2 Hz, 2.4 Hz, 1H), 5.91 (br s, 1H), 3.62 (s, 3H), 3.04-2.99 (m, 1H), 2.31 (s, 3H), 0.89-0.81 (m, 2H), 0.57-0.48 (m, 2H); ESIMS m/z 323 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[S:7]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8]1.Br[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[S:7]1[CH:11]=[CH:10][C:9]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=2)=[CH:8]1
Reactant: OB(O)c1ccsc1
Reactant: CC(=O)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(-c2ccsc2)cc1
Yield: 52.9 %

Procedure:
A mixture of toluene (7.5 mL) and water (3 mL) was degassed with argon for 10 min, to which sodium carbonate (297 mg, 2.8 mmol) was added and the mixture was further degassed with argon for 5 min. Thiophene-3-boronic acid (215 mg, 1.68 mmol) and N-(4-bromo-phenyl)-acetamide (300 mg, 2.27 mmol) were added and the mixture was degassed with argon for another 10 min. To the above resulting mixture was added tetrakispalladium triphenylphosphine (161 mg, 0.14 mmol) and the mixture was degassed with argon for another 10 min. The resulting reaction mixture was heated to reflux for 3 hrs. After completion, the reaction mixture was diluted with ethyl acetate and washed with water followed by brine solution. The ethyl acetate layer collected was dried over sodium sulphate and concentrated under reduced pressure. Purification by column chromatography, (using silica gel 60-120 and 35% ethyl acetate in hexane as eluent) afforded 193 mg (63.44% Yield) of N-(4-thiophen-3-yl-phenyl)-acetamide.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].C(N(CC)CC)C.[CH2:25](Cl)[CH:26]=[CH2:27]>O>[F:7][C:8]([F:16])([F:17])[C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[CH2:27]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:8]([F:16])([F:17])[F:7])[CH:10]=1)[CH:26]=[CH2:25]
Reactant: C=CCCl
Agent: Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCNc1cccc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
Sodium carbonate (318 g; 3 moles), water (0.5 liter), meta-trifluoromethylaniline (966 g; 6 moles) and triethylamine (20 g; 0.2 mole) were introduced, in an inert atmosphere, into a 2 liter round flask. The reaction medium was heated to a temperature of 50° C. with good stirring. Allyl chloride (230 g; 3 moles) was then introduced over approximately a 4 hour period. The temperature increased from 50° C. to 70° C. during the addition of allyl chloride. The reaction mass was then heated to a temperature of 100° C. for 1 hour before being cooled to about 50° C. After washing with water and phase separation, the organic phase was distilled under vacuum (5,000 Pa). This resulted in the separation of unconverted m-trifluoromethylaniline (540 g; 3.35 moles) from N-allyl-meta-trifluoromethylaniline (367 g; 1.83 moles), which corresponds to a 61% yield based on allyl chloride and a 70% yield based on meta-trifluoromethylaniline. The mass/volume output was 245 gel of reaction medium.
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]1[CH2:33][CH2:32][C:15]2[C:16]3[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=4)=[N:20][CH:19]=[N:18][C:17]=3[S:31][C:14]=2[CH2:13]1)=[O:11])(=O)OCC)C.[H-].[Na+].[CH:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=O.CO>C1COCC1>[Cl:30][C:25]1[CH:24]=[C:23]([NH:22][C:21]2[C:16]3[C:15]4[CH2:32][CH2:33][N:12]([C:10](=[O:11])/[CH:9]=[CH:36]/[C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:13][C:14]=4[S:31][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: CCOP(=O)(CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of diethyl(2-{4-[(3-chloro-4-fluorophenyl)amino]-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-7(6H)-yl}-2-oxoethyl)phosphonate from Example 13A (644 mg, 1.26 mmol) in THF (2.5 mL) was cooled to −78° C. Sodium hydride (60% in mineral oil, 50 mg, 1.26 mmol) was added, and the mixture was stirred for 15 min. Subsequently, a solution of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (250 mg, 1.26 mmol) in THF (2.5 mL) was added dropwise. The mixture was slowly warmed to rt and stirred overnight. Methanol was added, and the solvent was removed in vacuo. The crude product was purified by preparative HPLC, and the title compound crystallized from PE/MTBE to yield 397 mg (56%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=2[CH2:21][OH:22])[CH:5]=[CH:6][C:7]=1[F:8]>C(Cl)(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=2[CH:21]=[O:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cn1c(CO)c(-c2ccc(F)c(F)c2)c2ccccc2c1=O
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: Cn1c(C=O)c(-c2ccc(F)c(F)c2)c2ccccc2c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of 4-(3,4-Difluoro-phenyl)-3-hydroxymethyl-2-methyl-2H-isoquinolin-1-one (500 mg, 1.66 mmol) in CHCl3 (10 ml) was added MnO2 (1.87 g, 21.6 mmol). The reaction mixture was stirred at 70° C. overnight under N2. TLC showed SM was consumed, cooled to RT, the reaction mixture was filtered, and the filtrate was concentrated to dryness to afford title product which was used for the next step directly. (m=460.0 mg, yield=92.6%.) 1HNMR: (400 MHz, d6-DMSO) δ 3.89 (s, 3H), 7.09 (t, J=6.0 Hz, 1H), 7.15 (d, J=6.8 Hz, 1H), 7.24 (m, 1H), 7.36 (dd, J1=9.6 Hz, J2=15.6 Hz, 1H), 7.55 (m, 2H), 8.55 (d, J=8.0 Hz, 1H), 9.61 (s, 1H).
Reaction SMILES: C(N1C=C(C(=O)C=C(O)C(OC)=O)C(=O)N(CC2C=CC=CC=2)C1=O)C1C=CC=CC=1.[F:32][C:33]([F:70])([F:69])[C:34]1[CH:68]=[CH:67][C:37]([CH2:38][N:39]2[CH:44]=[C:43]([C:45](=[O:53])[CH:46]=[C:47]([OH:52])[C:48]([O:50]C)=[O:49])[C:42](=[O:54])[N:41]([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][CH:57]=3)[C:40]2=[O:66])=[CH:36][CH:35]=1>>[F:70][C:33]([F:32])([F:69])[C:34]1[CH:68]=[CH:67][C:37]([CH2:38][N:39]2[CH:44]=[C:43]([C:45](=[O:53])[CH:46]=[C:47]([OH:52])[C:48]([OH:50])=[O:49])[C:42](=[O:54])[N:41]([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([C:62]([F:63])([F:64])[F:65])=[CH:58][CH:57]=3)[C:40]2=[O:66])=[CH:36][CH:35]=1
Reactant: COC(=O)C(O)=CC(=O)c1cn(Cc2ccc(C(F)(F)F)cc2)c(=O)n(Cc2ccc(C(F)(F)F)cc2)c1=O
Agent: COC(=O)C(O)=CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Product: O=C(O)C(O)=CC(=O)c1cn(Cc2ccc(C(F)(F)F)cc2)c(=O)n(Cc2ccc(C(F)(F)F)cc2)c1=O
Yield: 68.2 %

Procedure:
The title compound was synthesized using a similar procedure to that described in Example 2, except that methyl 4-(1,3-dibenzyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)-2-hydroxy-4-oxobut-2-enoate was replaced with methyl 4-[1,3-bis(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl]-2-hydroxy-4-oxobut-2-enoate (3d). The title compound was recrystalized from hexane and ethyl acetate (3:1). The yield was 68.2%. Mp. 176-178° C. 1HNMR (DMSO-d6): 14.98 (br, s, 1H), 14.02 (br, s, 1H), 8.99 (s, 1H), 7.72 (d, 2H, J=8.0 Hz), 7.66 (d, 2H, J=8.5 Hz), 7.59 (d, 2H, J=8.5 Hz), 7.57 (s, 1H), 7.51 (d, 2H, J=8.0 Hz), 5.26 (s, 2H), 5.09 (s, 2H). 13CNMR (DMSO-d6): 185.8, 169.3, 163.1, 159.9, 151.3, 150.2, 141.2, 140.5, 128.4 (q, J=31.5 Hz), 128.3, 128.2, 127.9 (q, J=31.7 Hz), 125.4 (q, J=3.8 Hz), 125.2 (q, J=3.8 Hz), 124.2 (q, J=272.3 Hz), 124.1 (q, J=271.8 Hz), 108.0, 100.7, 52.6, 43.9. FAB-HRMS: [M+H]+ calcd. for C24H17F6N2O6 543.0991, found 543.1003.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:23]([O:25][CH3:26])=[O:24])[CH2:10][S:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][N+:14]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)(=O)C>[NH2:14][CH2:13][CH:12]([S:11][CH2:10][C@H:9]([C:23]([O:25][CH3:26])=[O:24])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](CSC(C[N+](=O)[O-])c1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](CSC(CN)c1ccccc1)NC(=O)OC(C)(C)C
Yield: 79.2 %

Procedure:
10% palladium on carbon (3.04 g) was added to a solution of methyl N-(tert-butoxycarbonyl)-S-(2-nitro-1-phenylethyl)-D-cysteinate (1.00 g, 2.60 mmol) in acetic acid (50 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (50 psi). After 18 h the mixture was filtered, concentrated, and saturated aqueous sodium carbonate was added. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the title compound (0.73 g). MS 355 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:10]S(O)(=O)=O>>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[N+:6]([O-:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nccnc1Cl
Product: N#Cc1c(Cl)ncc[n+]1[O-]
Temperature: 0 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
2-Chloro-3-cyanopyrazine (5.00 g, 35.94 mmol) was dissolved in 35 ml concentrated H2SO4 under nitrogen and cooled to 0° C. To this was added 11.65 g (43.95 mmol) K2S2O8 portionwise. The flask was fitted with a CaCl2 drying tube, the reaction mixture allowed to warm to rt and stir for 24 h. After partitioning between CHCl3 and ice water, the separated aqueous phase was extracted with CHCl3. The combined organics were washed with water, saturated NaHCO3, brine and dried over MgSO4. Concentration gave 2.01 g (36%) of the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, 1H), 8.38 (d, 1H). MS (DCI/NH3) m/e 173 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.[CH:21]([Zn]C(C)C)([CH3:23])[CH3:22]>C1COCC1>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([CH:21]([CH3:23])[CH3:22])[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Reactant: CC(C)[Zn]C(C)C
Solvent: C1CCOC1
Product: CCSc1ccccc1-c1nc2cc(C(C)C)cnc2n1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 6-bromo-2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (348 mg), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (41 mg), and THF (5 mL), diisopropyl zinc (1 M in toluene, 2 mL) was added at room temperature. The mixture was stirred at room temperature for 4 hours, washed with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 290 mg of 2-(2-ethylsulfanyl-phenyl)-6-isopropyl-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 147).