Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[C:15]([F:21])=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>C1COCC1.O.C(=O)(O)[O-].[Na+]>[Si:26]([C:19]1[C:18]([F:20])=[CH:17][N:16]=[C:15]([F:21])[C:14]=1[Cl:13])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: Fc1cnc(F)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)c1c(F)cnc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
A solution of diisopropylamine (78.52 g, 108.8 mL, 776.0 mmol) in THF (1.205 L) was cooled to −20° C. n-BuLi (2.5 M in hexanes) (298.4 mL of 2.5 M, 746.1 mmol) was added dropwise via cannula over 30 min at such a rate that the temperature was kept below −15° C. Once the addition was complete the cooling bath was removed and the reaction mixture was allowed to warm to 0° C. The reaction mixture was stirred for 15 min at 0° C., then re-cooled to −78° C. 3-chloro-2,5-difluoro-pyridine (95.963 g, 596.9 mmol) was added dropwise via cannula over 20 min at such a rate that the temperature was kept below −70° C. The reaction mixture was stirred for 45 min at −78° C. during which time the solution turned orange red. A solution of tert-butyl-chloro-dimethyl-silane (117.0 g, 776.0 mmol) in THF (133.9 mL) was added via cannula at such a rate to maintain the reaction temperature below −70° C. The reaction mixture was stirred at −78° C. for 90 minutes, during which time the solution turned to a deep red colour. Lc/Ms after this time indicated that the reaction was complete. A saturated ammonium chloride solution (300 ml) was then added and mixture was allowed to warm to ambient. The reaction mixture was diluted with water (200 ml) and saturated aqueous sodium bicarbonate (500 ml) and extracted with ethyl acetate (1.5 L then 500 ml). The combined organics were washed with brine (400 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to an oil (187 g). The crude was purified by flash chromatography (CombiFlash Companion XL, 1.5 kg column, 0.5-10% ethyl acetate in petroleum ether). This afforded the title compound as a pale yellow oil (113.8 g, 72%); 1H NMR (CDCl3) 0.46 (6H, d), 0.93 (9H, s), 7.84 (1H, d); 19F NMR (decoupled) −112.8, −74.6; MS ES (+) 264.95 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:19][O:20][CH2:21][O:22][CH3:23])([CH2:14][O:15][CH2:16][O:17][CH3:18])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:19][O:20][CH2:21][O:22][CH3:23])([CH2:14][O:15][CH2:16][O:17][CH3:18])[CH2:12][NH:11][CH2:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COCOCC1(COCOC)CN(C(=O)OC(C)(C)C)CC=C1c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCOCC1(COCOC)CNCC=C1c1ccc(F)cc1

Procedure:
To a dichloromethane solution (0.80 mL) of tert-butyl 4-(4-fluorophenyl)-5,5-bis[(methoxymethoxy)methyl]-5,6-dihydropyridine-1(2H)-carboxylate (40.0 mg, 0.0940 mmol) synthesized in Reference Synthesis Example 358, trifluoroacetic acid (40.0 μL, 0.538 mmol) was added at room temperature and the resultant mixture was stirred for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:10][CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3](OC1N(C3C=CC=CC=3)N=NN=1)[CH:4]=[CH:5]2.[K+].[Br-]>[Pd].C(O)(=O)C>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:10][CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[CH:3][CH:4]=[CH:5]2
Reactant: CN1CC[C@]23c4c5ccc(Oc6nnnn6-c6ccccc6)c4O[C@H]2C(=O)CC[C@@]3(OCCCc2ccccc2)[C@H]1C5
Agent: [Pd]
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: CN1CC[C@]23c4c5cccc4O[C@H]2C(=O)CC[C@@]3(OCCCc2ccccc2)[C@H]1C5
Reaction time: 17 h

Procedure:
A mixture of 4,5α-epoxy-17-methyl-14β-[(3-phenylpropyl)oxy]-3-[(1-phenyl-1H-tetrazol-5-yl)oxy]morphinan-6-one (6.20 g, 11.00 mmol), 10% Pd/C catalyst (2.48 g) and 100 ml glacial acetic acid was hydrogenated at 50 psi and 40° C. for 17 h. After filtering off the catalyst, the filtrate was reduced down to a volume of 30 ml, 150 ml of ice/water mixture was added to it and after alkalising with conc. NH4OH it was extracted with CH2Cl2 (1×100 ml, 3×75 ml). The combined organic phases were washed with saturated NaCl solution (4×200 ml), dried over Na2SO4 and evaporated down. The evaporation residue (4.15 g of yellowish oil, DC pure) was crystallised out of a little methanol and in this way 3.20 g (72%) of the compound 53 was obtained as colourless crystals. Fp. 105-109° C.; MS (CI): 404 (M++1); IR (KBr): 1721 (C═O) cm−1; 1H-NMR (DMSO-d6): δ 7.29-7.16 (m, 5 arom. H), 7.04 (t, J=8.0 Hz, 1 arom. H), 6.73 (d, J=8.0 Hz, 1 arom. H), 6.64 (d, J=8.0 Hz, 1 arom. H), 4.75 (s, 1H, C5-H), 2.28 (s, 3H, N17-CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[Cl:1])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1ccccc1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
A mixture of 2-chloro-4-nitroaniline (15.0 g, 86.9 mmol), triethylamine (13.3 ml, 95.6 mmol) and benzoyl chloride (11.1 ml, 95.6 mmol) were heated in toluene (200 ml) at reflux for 2 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature overnight, causing precipitation of a white solid. The solid was collected by suction filtration, washed with toluene (3×50 ml) and dried in vacuo. The crude product was taken up in dichloromethane (300 ml) and washed with 2.0 N aqueous hydrochloric acid (3×100 ml), water (100 ml), saturated aqueous sodium bicarbonate solution (3×100 ml) and water (100 ml). Drying of the organic layer over magnesium sulphate, followed by solvent evaporation in vacuo, yielded N-benzoyl 2-chloro-4-nitroaniline (6.83 g, 28% yield) as a yellow crystalline solid:
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH:4]([CH3:7])[CH2:5][CH3:6].COC(=O)[C@H]([C@H](CC)C)N.OCCN.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[C:29]([CH3:36])[CH:28]=1)=[O:26]>>[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]2[NH:8][C@@H:3]([CH:4]([CH2:5][CH3:6])[CH3:7])[CH2:2][S:35]2)=[C:29]([CH3:36])[CH:28]=1)=[O:26]
Reactant: CCC(C)[C@H](N)CO
Reactant: COC(=O)c1ccc(N=C=S)c(C)c1
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Solvent: NCCO
Product: CCC(C)[C@H]1CSC(=Nc2ccc(C(=O)OC)cc2C)N1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Methoxycarbonyl-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(4-methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH3:24])[C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN(C=O)C>[CH3:24][N:12]([CH2:11][C:10]1[CH:25]=[CH:26][CH:27]=[C:8]([C:5]2[CH:4]=[N:3][C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:7][CH:6]=2)[CH:9]=1)[C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C1CNCCN1
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (2.35 g) was dissolved in DMF (50 ml), and piperazine was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc, and then the organic layer was dried over MgSO4 and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 10% MeOH/CHCl3) to obtain tert-butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (1.8 g).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[Cl:14][CH2:15][C:16](=[O:21])[C:17](Cl)=[N:18][OH:19]>C(#N)C>[Cl:14][CH2:15][C:16]([C:17]1[CH2:1][CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:19][N:18]=1)=[O:21]
Reactant: C=Cc1ccccc1
Reactant: O=C(CCl)C(Cl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(CCl)C1=NOC(c2ccccc2)C1
Reaction time: 1 h

Procedure:
To a mixture of styrene (6.79 g, 65.3 mmol) and sodium bicarbonate (32.1 g, powder) in acetonitrile (100 mL), 3-chloro-N-hydroxy-2-oxo-propanimidoyl chloride (i.e. the product of Example 7, Step B) (10 g, 64.1 mmol) was added in 10 portions over 20 minutes. The reaction mixture was then stirred for additional 1 h and filtered. The filtered solid was rinsed with acetonitrile, and the combined filtrates were concentrated under reduced pressure to leave an oil, which was triturated first with hexanes and then with 1-chlorobutane to give 13.6 g of the title compound as a white solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)=O.O.[NH2:19]N>CCO>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[N:19]1
Reactant: COC(=O)c1ccc(C(=O)/C=C/N(C)C)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2cc[nH]n2)cc1
Temperature: 50 °C

Procedure:
To a solution of crude (E)-methyl 4-(3-(dimethylamino)acryloyl)benzoate (28.1 mmol) in EtOH (100 mL) was added hydrazine monohydrate (1.50 mL, 30.9 mmol) and the reaction was heated at 50° C. for 24 hours. The reaction temperature was then increased to 60° C. for 24 hours. Additional hydrazine monohydrate (1.5 mL) was added, and the reaction was heated at 60° C. for an additional 6 hours. The reaction was cooled, concentrated, and dried in a vacuum oven at 45° C. overnight to yield methyl 4-(1H-pyrazol-3-yl)benzoate as an orange solid (8.15 g, quantitative): mp 106° C. (dec); 1H NMR (400 MHz, CDCl3) δ 8.15-8.05 (m, 2H), 7.91-7.83 (m, 2H), 7.65 (d, J=2.4 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 3.94 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 166.91, 136.89, 131.83, 130.13, 129.37, 125.50, 103.35, 52.14, 22.46; EIMS m/z 202.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH3:17][C:18]1([CH3:25])[O:22][CH:21]([CH2:23][OH:24])[CH2:20][O:19]1.[H-].[Na+].[Cl-].[Na+]>C(OC)(C)(C)C.CN(C)C=O>[CH3:17][C:18]1([CH3:25])[O:22][CH:21]([CH2:23][O:24][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:3]=2)[CH2:20][O:19]1
Reactant: Clc1nc(SCOCc2ccccc2)ns1
Reactant: CC1(C)OCC(CO)O1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC1(C)OCC(COc2nc(SCOCc3ccccc3)ns2)O1
Reaction time: 2 h
Yield: 70 %

Procedure:
To 3 g of N,N-dimethylformamide, 350 mg of 5-chloro-3-benzyloxymethylthio-1,2,4-thiadiazole and 169 mg of 2,2-dimethyl-1,3-dioxolane-4-methanol were dissolved, and added 56 mg of sodium hydride (60% in oil) at about 0° C., followed by stirring at same tempareture for 2 hours. Then, to the reaction mixture, t-butylmethylether and saturated sodium chloride aqueous solution were added, and separeted to two layers. The organic layer was dried by anhydrous sodium salfate, and concentrated. The residue obtaind was subjected to column chromatography to obtain 330 mg of 5-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy-3-benzyloxymethylthio-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[NH:17][CH:18]=3)=[CH:12][CH:11]=[C:10]([O:27][CH3:28])[C:8]=2[N:9]=1>Cl.CO>[CH3:1][O:2][C:3](=[O:29])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[N:15]=[C:16]([NH2:19])[NH:17][CH:18]=3)=[CH:12][CH:11]=[C:10]([O:27][CH3:28])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(-c3c[nH]c(NC(=O)OC(C)(C)C)n3)c2s1
Agent: Cl
Solvent: CO
Product: COC(=O)Nc1nc2c(OC)ccc(-c3c[nH]c(N)n3)c2s1
Yield: 16 %

Procedure:
0.04 g of [7-(2-tert-butoxycarbonylamino-1H-imidazol-4-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester (0.0001 Mol) were heated to 60° C. in HCl/MeOH (2.5 M, 2 ml). After evaporation of the solvent the residue was dissolved in water (5 ml) and the pH was adjusted to 8 with sat. NaHCO3. The water was evaporated and the residue triturated in ethyl acetate where a precipitation formed. This was isolated and dried to yield the title compound as a grey solid (16%); F.p.: 225-235° C.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15](O)=[O:16].C(N(CC)CC)C.Cl.[CH3:31][NH:32][OH:33]>CN(C)C=O.C(OCC)(=O)C.C(OCC)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15]([N:32]([CH3:31])[OH:33])=[O:16]
Reactant: CNO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)N(C)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
Pivaloyl chloride (23.5 g, 195 mmol) was added dropwise to a stirred solution of 3,4-dimethoxycinnamic acid (40 g, 192 mmol) and triethylamine (54.4 ml, 390 mmol) in N,N-dimethylformamide (600 ml) at -30° C. To the resulting mixture was added a solution of N-methylhydroxylamine hydrochloride (15.9 g, 190 mmol) in N,N-dimethylformamide (50 ml). The mixture was allowed to warm slowly to room temperature. Ethyl ether (600 ml) was added, and the precipitated triethylamine hydrochloride filtered off. The filtrate was concentrated in vacuo to leave a yellow oil, which was dissolved in 400 ml ethyl acetate. Additional triethylamine hydrochloride was removed by filtration, and the filtrate seeded and allowed to stand at room temperature overnight. The precipitated product was collected by filtration, dried in vacuo, and recrystallized from methanol-water to provide 19.0 g of the named compound as a white powder, mp 149.5°-150.5° C.
Reaction SMILES: [CH2:1]([N:8]1[N:17]=[CH:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH2:33]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([N:8]1[N:17]=[CH:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:19][CH2:20][N:21]([CH2:33][CH2:32][CH:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:22][CH2:23]3)=[CH:13][CH:14]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2cc(N3CCNCC3)ccc2cnn1Cc1ccccc1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Product: O=c1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)ccc2cnn1Cc1ccccc1

Procedure:
The title compound was prepared using the compound prepared in step (e) of Example 137 and 3,3-diphenylpropyl bromide as starting compounds according to the method described in WO 9854135.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:26][C:27]1[S:31][CH:30]=[N:29][CH:28]=1>>[CH3:26][C:27]1[S:31][C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[N:29][CH:28]=1
Reactant: Cc1cncs1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: Cc1cnc(C(=O)c2cn(-c3cccc(-c4ccccc4C#N)c3)cn2)s1

Procedure:
This compound is prepared by method C using compound 12d and 5-methylthiazole
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=1.[OH2:10]>OS(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: N#Cc1nccnc1Cl
Reactant: O
Agent: O=S(=O)(O)O
Product: N#Cc1c(Cl)ncc[n+]1[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Chloro-3-cyanopyrazine (5.00 g, 35.94 mmol) in concentrated H2SO4 (35 mL) at 0° C. was treated portionwise with K2S2O8 (11.65 g, 43.95 mmol), warmed to room temperature, stirred for 24 hours, treated with water, and extracted with chloroform. The organic extract was washed sequentially with water, saturated NaHCO3 and brine, dried (MgSO4) and concentrated to provide the title compound. MS (DCI/NH3) m/e 173 (M+NH4)+.
Reaction SMILES: [CH:1]([CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH2:29][C:30]1[CH2:34][CH2:33][C:32](=[O:35])[CH:31]=1>C(OCC)C.CN(C)C=O>[CH2:7]([O:6][C:4]([C:3]1[CH:1]=[N:29][C:30]2[CH2:34][CH2:33][C:32](=[O:35])[C:31]=2[CH:9]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: NC1=CC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cnc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 2-formyl-3-oxopropanoate (3.2 g, 22 mmol) in diethyl ether (25 mL) was teated with triethylamine (3.5 mL, 25 mmol) at about 0° C. The mixture was stirred at room temperature for about 1 h before the diethyl ether was removed in vacuo. To the residue was added a solution of p-toluenesulfonyl chloride (4.5 g, 23.6 mmol) in N,N-dimethylformamide (60 mL) at about 0° C. The mixture was stirred for about 5 h while being allowed to warm to room temperature. 3-Aminocyclopent-2-en-1-one (1.75 g, 18 mmol) was added and the mixture was heated to about 85-90° C. over night. The mixture was cooled to room temperature and was concentrated in vacuo. The residue was diluted with chloroform (200 mL), washed with sodium carbonate solution, filtered through Celite, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using dichloromethane/methanol/ammonium hydroxide (95:4.5:0.5) as the mobile phase to provide the title compound: 1H NMR (300 MHz, CDCL3): δ 1.42 (t, J=8.0 Hz, 3H), 2.82 (t, J=8.0 Hz, 2H), 3.38 (t, J=8.0 Hz, 2H), 4.42 (q, J=8.0 Hz, 3H), 8.60 (s, 1H), 9.40 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: OCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(OCc2ccccn2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-(hydroxymethyl)pyridine and DBU in dioxane. ES-MS m/e (%): 395 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1/[C:11](/[C:14]1[C:19](F)=[C:18]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[CH:17]=[CH:16][N:15]=1)=[N:12]/[OH:13]>C1COCC1.CN(C=O)C.C(Cl)Cl>[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[C:19]2[O:13][N:12]=1
Reactant: O/N=C(/c1ccc(F)cc1Cl)c1nccc(-c2cncnc2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1ccc(-c2noc3c(-c4cncnc4)ccnc23)c(Cl)c1
Temperature: 70 °C
Yield: 33.3 %

Procedure:
To a suspension of sodium hydride (5.69 mg, 0.142 mmol) in THF (Ratio: 1.8, Volume: 1.075 ml) was added dropwise (Z)-(2-chloro-4-fluorophenyl)(3-fluoro-4-(pyrimidin-5-yl)pyridin-2-yl)methanone oxime (0.029 g, 0.084 mmol) in DMF (Ratio: 1.0, Volume: 0.597 ml) slowly. The reaction mixture was heated at 70° C. for 3 hr, and then allowed to cool to room temperature. The reaction was quenched with H2O. The reaction mixture was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, concentrated, and further dried under high vacuum to afford a brown residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 0-80% EtOAc in hexanes over 15 min, tr=3 min) gave the title compound (10.3 mg, 0.028 mmol, 33.9% yield) as a yellow solid. ESI MS (M+H)+=327.0.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C@@H:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[C@H:10]1[OH:23])#[N:2].[CH2:24](Br)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:3]=[C:4]1[N:8]([CH2:24][CH3:25])[CH2:7][CH2:6][N:5]1[C@@H:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:21])([CH3:22])[C@H:10]1[OH:23])#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCNC2=NC#N)[C@@H]1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1=NC#N
Temperature: 63 °C
Yield: 68.2 %

Procedure:
A mixture of trans-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6carbonitrile (0.78 g), ethyl bromide (1.08 g) and potassium carbonate (1.38 g) in N,N-dimethylformamide (7.8 ml) was heated for 3 hours at 63° C. The reaction mixture was poured into ice-water (50 ml), and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was recrystallized from ethanol to give trans-4-(2-cyanoimino-3-ethylimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.58 g).