Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:7][S:6][CH:5]=[N:4][CH:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:9].CCN(CC)CC.[N:33]([CH2:36][C:37](Cl)=[O:38])=[N+:34]=[N-:35]>C(Cl)Cl>[N:33]([C@H:36]1[C:37](=[O:38])[N:4]2[CH:3]([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)=[O:9])[C:2]([OH:1])([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:7][S:6][C@H:5]12)=[N+:34]=[N-:35]
Reactant: CC(=O)OCC1(O)CSC=NC1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=NCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC1(O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
p-Nitrobenzyl 5-hydroxy-5-acetoxymethyl-5,6-dihydro-4H-1,3-thiazine-4-carboxylate (1.27 g., 3.45 mMol) and Et3N (0.58 ml., 4.16 mMol) in anhydrous CH2Cl2 (50 ml.) is stirred under a N2 atomsphere at room temperature while a solution of N3CH2COCl (0.36 ml., 4.13 mMol) in anhydrous CH2Cl2 (20 ml.) is added dropwise over 90 min. After stirring 30 more min., the solution is washed twice with H2O and brine, dried with MgSO4, filtered, and evaporated in vacuo. The residual oil us chromatographed on a column of Baker silica gel. Elution with 3:1 PhH-EtOAc yields p-nitrobenzyl 7α-azido-3-hydroxy-3-acetoxymethyl-cepham-4-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][N:16]([C:18]([N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[O:19])[CH2:15][CH:14]([C:26]([O:28]C)=[O:27])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CC(C)([O-])C.[K+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][N:16]([C:18]([N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[O:19])[CH2:15][CH:14]([C:26]([OH:28])=[O:27])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C1CC(c2ccc(C(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1

Procedure:
According to General Method 4A, 0.55 g (1.01 mmol) of the compound from Example 84A was reacted with 1.14 g (10.1 mmol) of potassium tert-butoxide. This gave 455 mg of crude product in 78% purity (LC-MS), which was reacted without any further purification steps. Yield: 550 mg (73% of theory)
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1>[Cu]>[Cl:15][C:14]1[C:9]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:10][CH:11]=[C:12]([C:16]([F:18])([F:17])[F:19])[CH:13]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Sc1ccccc1
Agent: [Cu]
Product: FC(F)(F)c1cnc(Sc2ccccc2)c(Cl)c1
Reaction time: 1 h
Yield: 99 %

Procedure:
26 g (0.233 mol) of 98.7% pure thiophenol, 50 g (0.226 mol) of 97.8% pure 2,3-dichloro-5-trifluoromethylpyridine and 14.7 mg (0.23 mmol) of copper powder were reacted by the method of Example 1, except that the reaction time was only 1 h and the reaction temperature was 160-170° C. The yield was 99%.
Reaction SMILES: [OH:1][C:2]1([CH3:20])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[N:18]([CH3:19])[CH:17]=[CH:16][C:11]3=[N:12][C:13]=2[C:14]#[N:15])[CH2:4][CH2:3]1.[CH3:21][Mg]Br.CCOCC.[BH4-].[Na+]>C1COCC1>[NH2:15][CH:14]([C:13]1[N:12]=[C:11]2[CH:16]=[CH:17][N:18]([CH3:19])[C:10]2=[CH:9][C:8]=1[N:5]1[CH2:6][CH2:7][C:2]([CH3:20])([OH:1])[CH2:3][CH2:4]1)[CH3:21]
Reactant: Cn1ccc2nc(C#N)c(N3CCC(C)(O)CC3)cc21
Reactant: C[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(N)c1nc2ccn(C)c2cc1N1CCC(C)(O)CC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-(4-hydroxy-4-methylpiperidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (245 mg, 0.906 mmol) in THF (5 mL) at 0° C. was slowly added 3M methylmagnesium bromide in ether (1.21 mL, 3.63 mmol). The resulting yellow solution was stirred at 0° C. for 2.5 hours. The reaction was quenched with MeOH (5 mL) and stirred for 15 minutes at RT. Sodium borohydride (68.6 mg, 1.81 mmol) was added. The reaction was stirred for 1 hour, quenched with 1M HCl (5 mL), and then stirred for an additional 15 minutes. The mixture was subsequently diluted with EtOAc and washed with saturated aqueous NaHCO3 (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C16H24N4, 289; found 289.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:3]([CH2:8][Br:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a room temperature solution of 3-bromo-2-methylpyridine (2.60 g, 15.1 mmol) and N-bromosuccinimide (NBS) (2.90 g, 16.3 mmol) in CCl4 is added benzoyl peroxide (150 mg, 1.08 mmol). The mixture is heated at reflux for 7 hours, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (EtOAc) (3×30 mL). The combined organic layers are washed with brine (3×30 mL), dried over magnesium sulfate, filtered and concentrated. LCMS analysis indicated starting material and the desired product. The residue is dissolved in CCl4 (40 mL) and NBS (1.7 g, 9.6 mmol) and benzoyl peroxide (100 mg, 0.72 mmol) is added, and the mixture is warmed at reflux. After 24 hours, the mixture is cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers are washed with brine (3×30 mL), dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography eluting with a mixture of dichloromethane in hexanes (25:75, then 3:7) to afford 3-bromo-2-bromomethyl-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:49]([CH3:50])=[CH:48][C:39]([O:40][CH2:41][CH2:42][NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:51][C:37]1[CH:38]=[C:39]([O:40][CH2:41][CH2:42][NH:43][S:44]([CH3:47])(=[O:45])=[O:46])[CH:48]=[C:49]([CH3:50])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(OCCNS(C)(=O)=O)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCNS(C)(=O)=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and N-(2-(4-bromo-3,5-dimethylphenoxy)ethyl)methanesulfonamide following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.59 min; Mass spectrum (ESI+): m/z=584 [M+H]+.
Reaction SMILES: Br[C:2]1[CH2:6][C:5](C)(C)[CH2:4][C:3]=1[Br:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:9][C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1(C)CC(Br)=C(Br)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(C2=C(Br)CCC2)cc1
Yield: 24.1 %

Procedure:
Under nitrogen, 1.3 g (5.1 mmol) of 1,2-dibromo-4,4-dimethylcyclopentene (Step 8) was reacted with 600 mg (4.3 mmol) of 4-fluorophenylboronic acid (Lancaster) in 23 mL of toluene, 15 mL of ethanol, and 10 mL of 2M Na2CO3 in the presence of 250 mg (5 mol %) of Pd(PPh3)4. The reaction was vigorously stirred at reflux overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (Na2SO4), and reconcentrated. Purification by silica gel chromatography (MPLC) with hexane gave 250 mg of 1-(2-bromocyclopenten-1-yl)-4-fluorobenzene (38 in Synthetic Scheme X when R1 and R2 =CH3, R5 =F, R3, R4, R6, and R7 =H) as a pale yellow oil which was reacted with 200 mg (1.2 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 1) in 5.2 mL of toluene, 3.4 mL of ethanol, and 2.2 mL of 2M Na2CO3 in the presence of 40 mg (5 mol %) of Pd(PPh3)4. The reaction was vigorously stirred at reflux for 6 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (Na2SO4), and reconcentrated. Purification by silica gel chromatography (MPLC) with hexane gave 120 mg of 1-[2-(4-fluorophenyl)-4,4-dimethyl cyclopenten-1-]-4-(methylthio)benzene (41 in Synthetic Scheme X when R1 and R2 =CH3, R5 =F, R10 =SCH3, R3, R4, R6, R7, R8, R9, R11, and R12 =H) as an oil: NMR (CDCl3) δ1.20 (s, 6H0, 2.42 (s, 3H), 2.63 (s, 4H), 6.90 (t, J=8 Hz, 2H), 7.00-7.18 (m, 4H), 7.30-7.60 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:26]([CH2:39][CH3:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CC(=O)CC.C(O)C.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:40][CH2:39][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCCCC(Br)CC
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCC(C)=O
Solvent: O
Product: O=C(O)CCCCCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
1,4,5-Triphenylimidazol-2-one was treated with ethyl 9-bromo-undecanoate and potassium carbonate in butanone, followed by sodium hydroxide in ethanol and water, to give after work-up the title compound, m.p. 83°-84° C. Found: C, 77.5; H, 7.3; N, 5.4%; C32H36N2O3 requires: C, 77.4; H, 7.3; N, 5.6%
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]2[C:25]3[CH2:24][CH2:23][N:22](C(=O)C(F)(F)F)[CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][C:16]=2[Cl:32])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([S:5][CH2:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]2[C:25]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][C:16]=2[Cl:32])=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)SCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)SCc1ccc(CNc2c(Cl)ccc3c2CCNCC3)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
Dissolve 6-[(6-tert-butylthiomethyl-pyridin-3-ylmethyl)-amino]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.46 g, 9.24 mmol) in methanol (20 mL). Add a solution of potassium carbonate (5.1 g, 37 mmol) in water (10 mL) and stir at room temperature for 12 h. Remove methanol in vacuo, dilute the residue with water, and extract the aqueous phase with DCM. Purify the crude mixture by SCX chromatography (20 g) eluting with methanol and a solution of NH4OH (40 mL) in methanol (140 mL). Concentrate in vacuo to obtain pure 6-[(6-tert-butylthiomethyl-pyridin-3-ylmethyl)-amino]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.6 g, 100%). MS (APCI+) m/z: 390 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C([O-])([O-])=O.[K+].[K+].I[CH:30]([CH3:32])[CH3:31].O>CN(C=O)C>[CH:30]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:32])[CH3:31]
Reactant: CC(C)I
Reactant: NCCCCNS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCCNS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 3 h

Procedure:
4′-Bromobiphenyl-4-sulfonic acid (4-amino-butyl) amide (0.6 g) was dissolved in DMF (30 mL). K2CO3 (1 g) was added followed by 2-iodo-propane (0.3 mL). The mixture was stirred for 3 hrs, poured into water, extracted with ether and dried. Addition of petrol and evaporation caused the title compound to precipitate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:36])[CH2:26][C:27]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](C3N(C)C=CN=3)[S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C([C:54]3[N:55]([CH3:59])[CH:56]=[CH:57][N:58]=3)SC=12.CCCCCCCCCCCCN>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:36])[CH2:26][C:27]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:56]3[N:55]([CH3:59])[CH:54]=[N:58][CH:57]=3)[S:17][C:10]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4cccnc4)cc3F)c2s1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: CCCCCCCCCCCCN
Product: Cn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4cccnc4)cc3F)c2s1
Yield: 33 %

Procedure:
Following the procedure described above for the compound 40 (example 17, step 2, scheme 14) but substituting the amine 9 for the amine 12, title compound 41 was obtained in 33% yield (scheme 14) 1H NMR (DMSO-d6) δ (ppm): 10.58 (s, 1H), 10.44 (s, 1H), 8.74 (d, 1H), 8.49 (d, 1H), 8.27 (dd, 1H), 8.05 (m, 1H), 7.86 (m, 2H), 7.77 (s, 1H), 7.48 (t, 1H), 7.42 (m, 2H), 7.35 (q, 1H), 6.63 (d, 1H), 3.88 (s, 3H), 3.54 (s, 2H). MS (m/z): 502.7 (M+H).
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[N:10]=[C:11]([O:21][CH2:22][CH3:23])[C:12]([C:16]([O:18]CC)=O)=[N:13][C:14]=1[Cl:15].[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28][NH2:29])[CH3:25]>CCCCCC>[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28][NH:29][C:16]([C:12]1[C:11]([O:21][CH2:22][CH3:23])=[N:10][C:9]([NH2:8])=[C:14]([Cl:15])[N:13]=1)=[O:18])[CH3:25]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)c1nc(Cl)c(N)nc1OCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOc1nc(N)c(Cl)nc1C(=O)NCCN(CC)CC
Temperature: 25 °C

Procedure:
To 8 ml. of toluene were added 0.8 g. of ethyl 5-amino-6-chloro-3-ethoxypyrazine-2-carboxylate and 0.8 g. of N,N-diethylethylenediamine and the mixture was refluxed for 20 hours. After the reaction was over, the reaction mixture was cooled to room temperature and then extracted with 20 ml. of a 1 N aqueous hydrochloric acid solution. The extract was neutralized with dilute aqueous ammonia under ice-cooling and then extracted three times each time with 30 ml. of chloroform. The extracts were combined, washed with water dried, and then the solvent was distilled off under reduced pressure. By washing the residue obtained with 30 ml. of n-hexane, 0.53 g. of colorless crystals of N-(2-diethylaminoethyl)-5-amino-6-chloro-3-ethoxypyrazine-2-carboxamide was obtained. The colorless acicular crystals obtained by recrystallizing the product from a mixture of benzene and n-hexane melted at 147°-148° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([O:13]C(=O)C)[CH2:7]2)(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.O>[OH:13][CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=2)[CH2:9]1
Reactant: CC(=O)OC1Cc2ccc(C(C)=O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(c1)CC(O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A solution of acetic acid 5-acetyl-indan-2-yl ester (Compound E-24; 1.50 g, 6.87 mmol) in dioxane (7 mL) was treated with 1.0 N sodium hydroxide (NaOH; 7.7 mL), and the solution was stirred at room temperature overnight. The solution was diluted with H2O (25 mL) and was extracted with CH2Cl2 (2×). The combined extracts were dried (MgSO4) and concentrated to give the title compound (1.06 g, 88%): 1H NMR δ 7.85 (s, 1H), 7.79 (m, 1H), 7.33 (d, J=7.7 Hz, 1H), 4.76 (m, 1H), 3.29-3.21 (m, 2H), 3.00-2.94 (m, 2H), 2.59 (s, 3H), 1.73 (d, J=5.3 Hz, 1H); ELMS m/z 176 (M+, 76), 161 (100).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[S:1]1[C:5]2[CH2:6][N:7]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1ccc2c(c1)Cc1ccsc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3sccc3Cc3ccccc32)cn1

Procedure:
As described for Example 1, 9,10-dihydro-4-H-thieno[2,3-c][1]benzazepine in dichloromethane, in the presence of triethylamine is reacted with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a non-crystalline yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH:16]3[CH2:18][CH:13]1[CH2:14][N:15]3CC1C=CC=CC=1)[N:8]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])[CH:7]=[C:6]([C:34]([OH:36])=[O:35])[C:5]2=[O:37]>C(O)C.Cl.[Pd]>[CH:13]12[CH2:18][CH:16]([NH:15][CH2:14]1)[CH2:17][N:12]2[C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:37])[C:6]([C:34]([OH:36])=[O:35])=[CH:7][N:8]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])=[CH:3][C:2]=1[F:1]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(N3CC4CC3CN4Cc3ccccc3)c(F)cc2c1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(N3CC4CC3CN4)c(F)cc2c1=O
Reaction time: 2 h
Yield: 72.5 %

Procedure:
2.57 g (5 08 m Mol) of 6-fluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-4-oxo-7-(5-benzyl-2,5-diazabicyclo(2.2.1)-hept-2-yl)quinoline-3-carboxylic acid was dissolved in 170 ml of absolute ethanol containing 18 g of HCl and to the solution was added 2.1 g 10% Pd/c and the resultant hydrogenated at 15 psi and 60° C. for 2 hrs. After filtration of the catalyst the volatiles were removed under reduced pressure. The resulting residue was taken up in 80 ml of water and the pH adjusted to 7. The resulting suspension was heated for 20 mins. at 60° C. After cooling the precipitated was filtered and recrystallized from DMF to give 1.53 g (69.5%) of product as a hydrate, mp 198° C.-204° C. dec.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[C:25]([Mg]Br)#[C:26][CH3:27].[NH4+].[Cl-]>C1COCC1>[C:21]([O:20][C:18]([NH:3][CH2:4][CH2:5][N:6]([CH2:7][C:2](=[O:1])[C:25]#[C:26][CH3:27])[C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC#C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A 150-mL round-bottomed flask was charged with 4-benzyl 1-tert-butyl 2-oxo-1,4-piperazinedicarboxylate (1.41 g, 4.22 mmol) and THF (5 mL). 1-Propynylmagnesium bromide (0.5 M in THF, 20.0 mL, 10.0 mmol, Sigma-Aldrich, St. Louis, Mo.) was added at 0° C. slowly. The mixture was stirred at 0° C. for 2 h. Saturated aqueous NH4Cl (40 mL) was added and the aqueous phase was extracted with EtOAc (200 mL, then 2×100 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica, 0 to 50% EtOAc in hexanes) to afford benzyl (2-((tert-butoxycarbonyl)amino)ethyl)(2-oxo-3-pentyn-1-yl)carbamate (1.55 g) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:64])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:35][CH:34]=1>CN(C=O)C>[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:64][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:37][CH:38]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C

Procedure:
Analogously to Example 7, 106 mg (0.56 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 201 mg (1.05 mmol) of EDC and 95 mg (0.7 mmol) of HOBT in 4.6 ml of DMF and 293 t (2.1 mmol) of TEA are reacted with 0.35 mmol of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane to form the title compound: m.p: 227-229° C.; HPLC20-100 : tRet =14.5; FAB MS (M+H)+ =697.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]2)=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([N:25]([CH:35]2[CH2:37][CH2:36]2)CC2C=CC(OC)=CC=2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.FC(F)(F)C([O-])=O>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]2)=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][CH:35]2[CH2:36][CH2:37]2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(CO)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCOC(CO)C2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.5 %

Procedure:
To a round bottom flask charged with (+/−)-2-((2-chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (35.2 mg, 0.06 mmol) in dichloromethane (200 μl) was added anisole (32.8 μl, 0.300 mmol), followed by trifluoroacetic acid (185 μl, 2.400 mmol). The reaction mixture was stirred at room temperature ON. LCMS indicated primarily the trifluoroacetate product was present. Excess TFA was removed in vacuo. The residue was treated with toluene and concentrated in vacuo (2×). The crude solid was treated with 2 N NH3/MeOH (˜1.5 mL)—a solid immediately precipitated out. After 20 min, the solid was isolated by vacuum filtration. LCMS indicated the solid was the desired alcohol product. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 15-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. (+/−)-2-((2-Chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.5 mg) was isolated.