Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:29])[NH:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2)c1
Yield: 42.6 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with tert-butyl 2-(2-amino-N-phenylacetamido)acetate (1.25 g) and 3-methylphenyl isocyanate (0.63 g), and after recrystallization in acetonitrile, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate (0.8 g), m.p. 180° C., is obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[O:11][CH:12]=[CH:13][N:14]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[O:11][CH:12]=[CH:13][N:14]=1
Reactant: Ic1ccncc1NCc1ncco1
Reactant: OB(O)c1ccccc1Cl
Product: Clc1ccccc1-c1ccncc1NCc1ncco1

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-N-(oxazol-2-ylmethyl)pyridin-3-amine and 2-chlorophenylboronic acid after a reaction time of 5 hours at reflux. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100), then EtOAc:MeOH (100:0 to 90:10). Light yellow solid (93%). MS (ESI): m/z=286.074 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O:20]CC)=O)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O.[NH2:24][NH2:25]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([NH:24][NH2:25])=[O:20])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CCN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Yield: 19.2 %

Procedure:
A solution of ethyl 3-[4-(3-nitrophenyl)piperazino]propanoate D6 (3.00 g, 9.76 mmol) and hydrazine monohydrate (2.93 g, 2.85 mL, 58.56 mmol) in ethanol (30 mL) was refluxed for 24 hrs. The solvent was evaporated under reduced pressure, brine was added to the residue and the product was extracted several times with dichloromethane. The combined organic phases were dried over MgSO4 and the solvent was evaporated under reduced pressure to afford 3.00 g crude product as an orange semi-solid. Purification by flash chromatography (Silica gel 60 Å, 45 μm, 10% methanol in dichloromethane) afforded 0.55 g (19%) 3-[4-(3-nitrophenyl)piperazino]propanohydrazide D7.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])[CH3:9])=[O:7])=[CH:4][C:3]=1[N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>ClC1C=CC=CC=1>[CH:22]1([C:18]2[N:17]3[C:3]4[C:2]([NH:1][C:28](=[O:29])[C:21]3=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:5]([C:6]([N:8]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])[CH3:9])=[O:7])[CH:4]=4)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOCCN(C)C(=O)c1ccc(N)c(-n2ccnc2C2CCCCC2)c1
Solvent: Clc1ccccc1
Product: CCOCCN(C)C(=O)c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Temperature: 150 °C

Procedure:
4-Amino-3-(2-cyclohexyl-1H-imidazol-1-yl)-N-(2-ethoxyethyl)-N-methylbenzamide as synthesized in Production Example 50, 2.51 g, 1,1′-carbonyldiimidazole 1.32 g and chlorobenzene 32 mL were mixed, and under nitrogen atmosphere, the temperature outside the reactor was heated to 150° C. for 16 hours. Allowing the reaction liquid to cool off, the solvent was distilled off therefrom. To the residue ethyl acetate and brine were added and the organic layer was separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling the solvent off, the residue was crystallized from t-butyl methyl ether. Further heat-suspending the crystals in ethyl acetate for purification, 993 mg of the title compound was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:21])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.O>[C:23]1([CH2:22][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Reaction time: 0.17 h
Yield: 56.6 %

Procedure:
To a stirred suspension of sodium hydride (50% dispersion in mineral oil, 2.55 g) in tetrahydrofuran (100 mL) was added hexaethylene glycol (25 g). The reaction mixture was stirred at 5–15° C. for 10 minutes, then benzyl bromide (16.66 g) was added. The suspension was allowed to stand at 20° C. for 72 hours then the reaction mixture was diluted with water (250 mL) and extracted with cyclohexane (250+125 mL). Aqueous sodium chloride solution (15% w/w, 300 mL) was added to the aqueous phase and the resulting solution was extracted with ethyl acetate (3×250 mL). The combined ethyl acetate extracts were concentrated in vacuo to give the title compound as an orange oil (18.68 g). LC retention time 2.50 mins. Mass spectrum m/z 390 [MNH4+]
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])=O.[NH2:28][C:29]([NH2:31])=[S:30].C(OCC)(=O)C>CO.ClCCl>[NH2:31][C:29]1[S:30][CH:2]=[C:3]([C@@H:5]2[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[N:28]=1
Reactant: NC(N)=S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)CBr)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(N)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a solution of (2S,4R)-2-bromoacetyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (660 mg) in a mixture of methanol (20 ml) and dichloromethane (20 ml) was added thiourea (165 mg) at room temperature. After stirring at the same temperature for 3 hours, the mixture was poured into ethyl acetate, washed in turn with saturated aqueous sodium bicarbonate and brine. The dried organic layer was evaporated, and the resulting oil was crystallized from a mixture of n-hexane and methanol (100:1 V/V) to give (2S,4R)-2-(2-aminothiazol-4-yl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (550 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(OCC)(=O)C.N1C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[F:11])[NH:1][S:13]([CH3:12])(=[O:15])=[O:14])(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(N)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(NS(C)(=O)=O)ccc1F
Yield: 79.7 %

Procedure:
5'-Amino-2'-fluoroacetophenone (28 g) was dissolved in a mixture of 100 ml of ethyl acetate and 15.9 g of pyridine, a solution of 23 g of methanesulfonyl chloride in 50 ml of ethyl acetate was added with ice-cooling and stirring and the mixture was made to react at room temperature for 3 hours. The reaction mixture was washed with water, dried, the solvent was evaporated therefrom and the residue was purified by silica gel column chromatography (eluting with chloroform) to give 33.7 g of 3'-acetyl-4'-fluoromethanesulfonanilide, m.p. 120°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][OH:20])[N:10]=1.[C:32](O)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[Cl:21][C:6]1[CH:5]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][O:20][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Reactant: O=C(O)c1ccncc1
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COC(=O)c2ccncc2)c1=O

Procedure:
Using the method described in Example 14 from 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile and isonicotinic acid: isonicotinic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester was obtained as a light yellow solid (43.6 mg, 23%); ES+-HRMS m/e calcd for C24H17N7O6Cl2 (M+H+) 570.0690, found 570.0686.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[NH2:11])=[O:3].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Li]>>[NH2:11][C:5]1[CH:6]=[CH:7][C:8]([Br:10])=[CH:9][C:4]=1[C:2]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)([OH:3])[CH3:1]
Reactant: CC(=O)c1cc(Br)ccc1N
Reactant: [Li]c1ccccn1
Product: CC(O)(c1ccccn1)c1cc(Br)ccc1N

Procedure:
Prepared from 2-amino-5-bromophenyl methyl ketone and 2-pyridyllithium generally according to the procedure described in example 1. 1H NMR (DMSO-d6): δ 8.5 (d, J=3.99 Hz, 1H), 7.77 (dt, J=7.77, 1.79 Hz, 1H), 7.64 (d, J=7.96 Hz, 1H), 7.30 (d, J=2.37 Hz, 1H), 7.21-7.25 (m, 1H), 7.06 (dd, J=8.49, 2.36 Hz, 1H), 6.47 (d, J=8.51 Hz, 1H), 6.18 (s, 1H), 5.26 (s, 2H), 1.8 (s, 3H); MS (ESI) m/z 293/295, 1 Br pattern ([M+H]+).
Reaction SMILES: FC1C=CC(C(=O)CBr)=CC=1.[C:12]([CH:14]([CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].FC1C=CC(C2NC=C(C(OCC)=O)C=2)=CC=1.[H-].[Na+].[F:49][C:50]1[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1>CN(C)C=O.O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[N:13]([S:56]([C:53]3[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=3)(=[O:58])=[O:57])[CH:12]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]=2)=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccc(F)cc1
Agent: CCOC(=O)c1c[nH]c(-c2ccc(F)cc2)c1
Agent: O=C(CBr)c1ccc(F)cc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Using 4-fluorophenacyl bromide instead of phenacyl bromide, a procedure as in Reference Example 1 was performed to synthesize ethyl 2-cyano-4-(4-fluorophenyl)-4-oxobutanoate, and procedures as in Reference Examples 2 and 3 were performed to synthesize ethyl 5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate. Sodium hydride (60% in oil, 0.58 g) was added to a solution (20 mL) of ethyl 5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (2.85 g) in N,N-dimethylformamide under ice-cooling. The mixture was stirred at the same temperature for 15 min, 4-fluorobenzenesulfonyl chloride (2.92 g) was added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as crystals (yield 4.66 g, 97%).
Reaction SMILES: C([O-])=O.[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[OH:16].[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21]([CH2:25]O)=[CH:20][N:19]=1.Cl>C(O)(=O)C>[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21]([CH2:25][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([OH:16])=[C:6]([O:5][CH3:4])[CH:15]=2)=[CH:20][N:19]=1
Reactant: Nc1ncc(CO)c(N)n1
Reactant: COc1ccc2ccccc2c1O
Agent: Cl
Agent: O=C[O-]
Solvent: CC(=O)O
Product: COc1cc(Cc2cnc(N)nc2N)c2ccccc2c1O
Yield: 31.5 %

Procedure:
The formate of 2-methoxy-1-naphthol (J. E. Oatis, Jr., M. P. Russell, D. R. Knapp and T. Walle, J. Med. Chem. 1981, 24, 309) (7.23 g, 30.3 mmol), 2,4-diamino-5-hydroxymethylpyrimidine (4.35 g, 30.3 mmol), concentrated hydrochloric acid (4.2 mL) and glacial acetic acid (60 mL) were refluxed 2 hr. The resulting dark solution was evaporated to dryness and the residue dissolved in water and neutralized with ammonia. The resulting tan precipitate (5.2 g) was recrystallized from aqueous ethanol containing a slight excess of hydrochloric acid to give title compound as tan powder (2.83 g, 28%); mp ca. 290°-300° dec. Anal. Calcd for C16H16N4O2.HCl: C, 57.75; H, 5.15; N, 16.84; Cl, 10.65. Found: C, 57.62; H, 5.21; N, 16.79; Cl, 10.61.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[C:22]([C:26]1[CH:27]=[C:28](O)[CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1)([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[Br:20][C:28]1[CH:27]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=1
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1

Procedure:
A 1000 mL three-neck, round-bottom flask was equipped with a mechanical stirrer, a pressure-compensating dropping funnel, and a reflux condenser. A nitrogen gas flow adapter with overpressure valve was attached on top of the reflux condenser. A slight nitrogen flow guaranteed an inert gas atmosphere in the apparatus. The flask was charged with 181 g triphenylphosphine (690 mmol) and 160 mL acetonitrile (HPLC grade). The white suspension was cooled in an ice bath for 15 minutes. While stirring, dropwise addition of 101.5 g bromine (635 mmol) took place within 40 minutes. After bromine addition, the ice bath was removed. 124 g of 3,5-di-tertbutylphenol (601 mmol) and 140 mL acetonitrile were added in one portion. The orange/white suspension converted into an orange solution upon heating. The mechanical stirrer was replaced by an egg-shape stir bar. The solution was stirred at gentle reflux temperature for three hours.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([N:32]1[CH:36]=[C:35]([CH2:37][OH:38])[N:34]=[CH:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+:39]([C:42]1[CH:43]=[C:44](O)[CH:45]=[CH:46][CH:47]=1)([O-:41])=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N+:39]([C:42]1[CH:47]=[C:46]([CH:45]=[CH:44][CH:43]=1)[O:38][CH2:37][C:35]1[N:34]=[CH:33][N:32]([C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:36]=1)([O-:41])=[O:40]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of diethyl azodicarboxylate (2.1 mL) in tetrahydrofuran (THF) (40 mL) was added (1-trityl-1H-imidazole-4-yl)methanol (2.23 g, prepared as described in J. Med. Chem. (1977)20:721) and 3-nitrophenol (2 g). To this mixture at 0° C. was added dropwise a solution of triphenyl phosphine (3.44 g) in THF (60 mL). The reaction mixture was stirred at room temperature overnight. After evaporation of the solvent the residue was chromatographed on silica gel eluting with ethyl acetate:hexane (40:60) to isolate 4-(3-nitro-phenoxymethyl)-1-trityl-1H-imidazole (2 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:5]([CH3:15])=[C:4]([CH3:16])[N:3]=1>C(O)C.[Pd]>[CH3:15][C:5]1[CH:6]=[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[N:3][C:4]=1[CH3:16]
Reactant: CCOC(=O)C=Cc1cc(C)c(C)nc1Cl
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cnc(C)c(C)c1
Yield: 77.1 %

Procedure:
Ethyl 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylate (32.7 g) in ethanol (500 ml) was hydrogenated at 25°-30° and 344 kPa using palladium-on-charcoal catalyst (5%, 3 g). The mixture was filtered and the filtrate was evaporated to an oil which was partitioned between chloroform and 2N hydrochloric acid. The aqueous phase was made basic with aqueous sodium hydroxide, extracted with chloroform and the chloroform extracts were evaporated to give ethyl 3-(5,6-dimethyl-3-pyridyl)propionate (21.8 g, 80%) as an oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:21][OH:22])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=1)[CH2:21][O:22][C:24]1[CH:25]=[C:26]2[NH:33][CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1
Reactant: OCc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1nc(OCc2ccc(Oc3cccc(C(F)(F)F)c3)c(Cl)c2)cc2n1CCN2

Procedure:
Prepared in a manner similar to that described for E65 using sodium hydride (13.87 mg, 0.347 mmol), (3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol in THF (8 mL) and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (62.8 mg, 0.231 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C@@H:7]([CH3:20])[C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:23][S:24]([CH2:27][C:28](O)=[O:29])(=[O:26])=[O:25].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:28](=[O:29])[CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[C@@H:7]([CH3:20])[C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: C[C@@H]1Nc2ccc(Br)cc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)CC(=O)O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2cc(Br)ccc2N1C(=O)CS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a 0° C. solution of tert-butyl(2S,3S)-7-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (130 mg, 351 μmol) and 2-(methylsulfonyl)acetic acid (53.4 mg, 386 μmol) in pyridine (3.51 ml) was added phosphoryl chloride (64.3 μl, 702 μmol). The reaction was stirred at 0° C. for 30 min, then quenched by the addition of H2O and extracted with EtOAc. The combined organic layers were washed with 1 N aq. citric acid, H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(2S,3S)-7-bromo-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (161 mg, 94%) as a white solid. MS m/z 512/514 (MNa)+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:16][C@H:17]([CH2:21][CH3:22])[C:18]([NH2:20])=[O:19])=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:29]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[N:7]=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[C:3]([C:1]([NH2:2])=[O:29])=[N:4][CH:5]=1)[CH2:21][CH3:22]
Reactant: CC(=O)O
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2cc(C)ns2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2cc(C)ns2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound (R)-2-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)butanamide (106 mg, 0.334 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (38 mg). MS found for C13H17N7O2S as (M+H)+ MS 336.2; UV 206.0, 275.0, 323.1 nm; t 0.365 min. 1H NMR: (CD3OD) δ 7.70 (s, 1H), 6.88 (s, 1H), 4.65 (br.s, 1H), 2.45 (s, 3H), 2.18-2.05 (m, 1H), 1.96-1.87 (m, 1H), 1.10 (t, 3H).
Reaction SMILES: [Na].[F:2][CH2:3][CH2:4][OH:5].Br[CH2:7][C:8]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>O1CCCC1.O>[N+:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][O:5][CH2:4][CH2:3][F:2])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: OCCF
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(COCCF)c1
Yield: 17.5 %

Procedure:
Under a dry nitrogen atmosphere 1.1 gram (0.047 mole) of sodium metal was added to a stirred, cold (0° C.) solution of 3.0 grams (0.046 mole) of 2-fluoroethanol in 50 ml of dry tetrahydrofuran. After the sodium had dissolved, the solution was heated at reflux, and a solution of 5.0 grams (0.023 mole) of 3-bromomethylnitrobenzene in 10 ml of dry tetrahydrofuran was added dropwise. This mixture was heated at reflux for 24 hours and then was cooled. The reaction mixture was diluted with water, then was extracted with diethyl ether. The organic extract was washed with an aqueous, saturated, sodium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with n-hexane:diethyl ether (4:1), to yield 0.8 gram of 2-fluoroethyl 3-nitrobenzyl ether as an oil.