Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH:21](Br)[CH3:22]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH:21]([N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2)[CH3:22]
Reactant: CC(Br)c1cc(F)ccc1F
Reactant: O=C1CNc2ncc(I)cc2N1
Product: CC(c1cc(F)ccc1F)N1C(=O)CNc2ncc(I)cc21

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.030 g) was alkylated with 2,5-difluoro-alpha-bromoethylbenzene as in General Procedure 1 to give the title compound as a yellow solid. LCMS: m/z=415.93 (M+H+)
Reaction SMILES: C[O-].[Na+].[OH:4][CH2:5][CH:6]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[N:22]=[CH:21]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](OCC)=[O:16])[CH:10]=1.O.C([NH2:31])=O>>[C:15]([C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH:6]([N:20]2[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[N:22]=[CH:21]2)[CH2:5][OH:4])[CH:14]=[CH:13][CH:12]=1)(=[O:16])[NH2:31]
Reactant: CCOC(=O)c1cccc(CCC(CO)n2cnc(C(N)=O)c2)c1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cccc(CCC(CO)n2cnc(C(N)=O)c2)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
Sodium methoxide (39 mg, 0.72 mmol) was added to a stirred solution of 1-{1-hydroxy-4-[3-(ethoxycarbonyl)phenyl]-2-butyl}-imidazole-4-carboxamide (obtained in Example 10(1))(60 mg, 0.18 mmol) in formamide (1.5 ml), and the reaction mixture was stirred at 110° C. for 3 h. After cooling, the reaction mixture was poured into water (5 ml). The residue was purified by HP-20 (16 cc) column chromatography eluting with water/2-propanol (9:1) and lyophilized to give 1[4-(3-carbamoylphenyl)-1-hydroxy-2-butyl]imidazole-4-carboxamide (39.2 mg, 71.6%) as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:24][N:23]=[CH:22][CH:21]=1)=[CH:16][CH:15]=3.[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35]Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:21]=[CH:22][N:23]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[N:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: COCCOCCl
Product: COCCOCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 10 above, with the compound from Example 39 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-5-yl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and methoxyethoxymethyl chloride.
Reaction SMILES: [C:1]1([C:6]2[C:15]([CH:16](O)[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[C:14]([CH:28]([CH3:30])[CH3:29])[CH:13]=[C:12]3[C:7]=2[C:8](=[O:33])[CH2:9][C:10]([CH3:32])([CH3:31])[O:11]3)[CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)C.[Pd]>[CH:1]1([C:6]2[C:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=3)=[C:14]([CH:28]([CH3:29])[CH3:30])[CH:13]=[C:12]3[C:7]=2[C:8](=[O:33])[CH2:9][C:10]([CH3:31])([CH3:32])[O:11]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)c1cc2c(c(C3=CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cc2c(c(C3CCCC3)c1Cc1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 8 h

Procedure:
A mixture of 60 mg (130 μmol) of 5-cyclopent-1-en-1-yl-6-{hydroxy[4-(trifluoromethyl)phenyl]-methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 36A) and 14 mg of palladium-on-carbon (10%) in 10 ml of ethanol is stirred under a hydrogen atmosphere at atmospheric pressure overnight. The suspension is filtered through Celite, the filter cake is washed with ethanol and the solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 40:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[CH3:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: Cc1ccc(N=C=O)cc1C
Product: Cc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)cc1C

Procedure:
82 mg of solid yellow 3-{4-[3-(3,4-dimethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3,4-dimethylphenyl isocyanate.
Reaction SMILES: Cl.C([S:5][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[CH2:28][CH2:27]2)=[O:25])[CH2:7]1)(=O)C>O1CCOCC1>[SH:5][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C@H:8]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:36])[CH2:30][CH2:31]2)=[O:25])[CH2:7]1
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
600 ml of a 10% w/v methanolic solution of hydrogen chloride were added to a solution of 140 g of (2S,4S)-4-acetylthio-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step 90(b)(ii) or 90(c)(ii) above] in 150 ml of 1,4-dioxane, and the resulting mixture was stirred at 50° C. for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with 1500 ml of ethyl acetate. The dilute solution was neutralized with an aqueous solution of sodium hydrogencarbonate and washed, in turn, with 300 ml of water and with 300 ml of an aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol ranging from 30:1 to 20:1 by volume as the eluent, to give 96.44 g of the title compound, as a colorless powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound thus obtained were identical with those of the compound prepared as described in step 90(a)(iii) above.
Reaction SMILES: C(S[C:4]1[NH:5][C:6](=[O:14])[C:7]2[CH2:12][S:11][CH:10]([CH3:13])[C:8]=2[N:9]=1)C.Cl.CC(O)=[O:18]>O>[CH3:13][CH:10]1[C:8]2[NH:9][C:4](=[O:18])[NH:5][C:6](=[O:14])[C:7]=2[CH2:12][S:11]1
Reactant: CCSc1nc2c(c(=O)[nH]1)CSC2C
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CC1SCc2c1[nH]c(=O)[nH]c2=O
Yield: 80 %

Procedure:
To a suspension of 2-(ethylthio)-7-methylthieno[3,4-d]pyrimidin-4(3H,5H,7H)-one (3.96 g, 17.3 mmol) in water (20 mL) was added 2.0 mL of conc. HCl and 4.0 mL of AcOH. The mixture was heated to reflux overnight then cooled and the precipitated solid collected by filtration, washed with water and methanol, evaporated and dried to obtain 7-methylthieno[3,4-d]pyrimidine-2,4(1H,3H,5H,7H)-dione as a white solid (2.52 g, 80%). Without further purification, the crude product was used directly in the next step.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1>>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([S:1][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OCc1cccc(S)c1
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(Sc2cccc(CO)c2)nc1
Yield: 75.8 %

Procedure:
Using the method of Preparation 155 using (3-mercaptophenyl)methanol (10.0 g, 71.3 mmol) and 6-chloronicotinonitrile (19.8 g, 142.7 mmol) affords the title compound (13.1 g, 76%): 243 (M+H, 100%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][C:53]=1[F:65])#[N:51]>CN(C=O)C>[C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=2)=[CH:54][C:53]=1[F:65])#[N:51]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: N#Cc1ccc(-c2cccc(N)c2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(C#N)c(F)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 78 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-cyano-3′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 81% yield: LCMS (ESI) m/z 415 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1S[CH:20]=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(C=O)[O:25]C=1>>[CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[O:25][CH:20]=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccco1
Reactant: COC(=O)/C(=C/c1cccs1)NC(=O)OCc1ccccc1
Product: COC(=O)/C(=C/c1ccco1)NC(=O)OCc1ccccc1

Procedure:
A method similar to that used for the preparation of (99a) was used except that 2-furylcarboxaldehyde (288 mg) was used as the aldehyde component to afforded the desired product (530 mg). 1H NMR (300 MHz, CDCl3) δ 3.788 (s, 3H), 5.17 (s, 2H), 6.29 (m, 1H), 6.46 (m, 1H), 6.73 (br., 1H), 6.94 (s, 1H), 7.37 (m, 6H). LC/MS: 2.27 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[NH:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[O:29]([NH2:31])[CH3:30].C([O-])(=O)C.[Na+]>CO.C([O-])(O)=O.[Na+]>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18](=[NH:19])[CH:17]=[CH:16][C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1](=[N:31][O:29][CH3:30])[CH3:2])=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)=[CH:22][CH:23]=1
Reactant: CC(=O)c1ccc(-c2ccc(C=CC(=N)Nc3ccc(Cl)cc3)cc2)cc1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CON=C(C)c1ccc(-c2ccc(C=CC(=N)Nc3ccc(Cl)cc3)cc2)cc1
Yield: 9 %

Procedure:
A mixture of 0.04 g (0.11 mmol) of 3-(4′-acetyl-biphenyl-4-yl)-N-(4-chloro-phenyl) -acrylamidine, 0.028 g (0.33 mmol) of methoxylamine hydrochloride and 0.027 g (0.33 mmol) of sodium acetate in 3 mL of methanol was heated under microwave (100 W, 5 min). Diluted with 20 mL of NaHCO3, it was extracted with two 10 mL portions of ethyl acetate. The combined organic extracts were washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC eluting with 70% ethyl acetate in hexanes plus 1% NH4OH to give 0.004 g of N-(4-chloro-phenyl)-3-[4′-(1-methoxyimino-ethyl)-biphenyl-4-yl]-acrylamidine.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:5]2[CH2:6][N:7]([CH3:11])[C:8](=[O:10])[CH2:9][N:4]2[N:3]=1.Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:20][C:18]1[CH:19]=[C:14]([NH:1][C:2]2[CH:12]=[C:5]3[CH2:6][N:7]([CH3:11])[C:8](=[O:10])[CH2:9][N:4]3[N:3]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CN1Cc2cc(N)nn2CC1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1Cc2cc(Nc3cc(Br)cn(C)c3=O)nn2CC1=O
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A 100-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 313d (300 mg, 1.8 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (482 mg, 1.8 mmol), cesium carbonate (1.17 g, 3.6 mmol), and 1,4-dioxane (20 mL). After bubbling nitrogen through the suspension for 10 minutes, xantphos (104 mg, 0.18 mmol) and tris(dibenzylideneacetone)dipalladium(0) (82 mg, 0.090 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×30 m). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 313e (390 mg, 61%) as a yellow solid.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[C:6]([Sn](C)(C)C)=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1>ClCCl>[Br:1][C:10]1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COc1ccc(C(F)(F)F)nc1[Sn](C)(C)C
Reactant: BrBr
Solvent: ClCCl
Product: COc1cnc(C(F)(F)F)cc1Br

Procedure:
Prepared from bromine (0.21 ml, 4 mmol) and a solution of 3-methoxy-6-trifluoromethyl-2-trimethylstannylpyridine (0.7 g, 2.0 mmol) in dichloromethane (10 ml) according to the method of Description 42 to afford 4-bromo-3-methoxy-6-trifluoromethylpyridine as a yellow solid.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].Cl.Cl[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH2:30][CH3:31])[C:25]([CH3:32])=[CH:24][N:23]=1.[OH-].[Na+]>O>[CH2:30]([O:29][C:26]1[C:25]([CH3:32])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:13]=[C:12]4[C:8](=[CH:7][C:5]=3[N:6]=2)[C:9]([CH3:18])([CH3:17])[C:10](=[O:16])[C:11]4([CH3:14])[CH3:15])[C:27]=1[CH3:28])[CH3:31]
Reactant: CCOc1c(C)cnc(CCl)c1C
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C

Procedure:
7.8 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one were suspended in 200 ml of alcohol and treated while cooling with ice with 7.1 g of 2-chloromethyl-4-ethoxy-3,5-dimethylpyridine hydrochloride. Thereafter, a solution of 2.4 g of sodium hydroxide in 100 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 500 ml of methylene chloride. The solution was washed firstly with 250 ml of 1.5N sodium hydroxide solution and then with 3×250 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 150 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 5,7-dihydro-2-[[(4-ethoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one of melting point 179°-180°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.Cl.[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]([NH2:41])[CH3:40].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]([NH:41][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=1)=[O:22])[CH3:40]
Reactant: CC(N)c1ncco1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
A round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.22 mmol) and 1-oxazol-2-yl-ethylamine dihydrochloride (91 mg, 0.39 mmol). DMF (1 ml) was added followed by N,N-diisopropylethylamine (0.25 ml, 1.43 mmol) and HATU (92 mg, 0.24 mmol). The light yellow solution was stirred at room temperature for 48 h. Water was added and the resulting suspension was filtered. The solid was washed with water and petroleum ether then dried under high vacuum to afford 108 mg (90%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide as an off-white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:22]4[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=[C:18]([N:25](CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)[C:17]=4[N:16]=[CH:15]3)[O:10][N:9]=2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:22]4[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=[C:18]([NH2:25])[C:17]=4[N:16]=[CH:15]3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c3c2ncn3Cc2cc(-c3ccc(F)cc3)no2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)c2ncn(Cc3cc(-c4ccc(F)cc4)no3)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N,N-bis(4-methoxybenzyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (2.0 g, 3.5 mmol) in trifluoroacetic acid (20 mL) was stirred at room temperature for 16 hours. The trifluoroacetic acid was removed under reduced pressure, and the residue was triturated with aqueous hydrochloric acid (25 mL of 6 N) and ethanol (20 mL) for 30 minutes. The resulting mixture was adjusted to pH 14 with the addition of 50% (w/w) aqueous sodium hydroxide and stirred at 0° C. for 30 minutes. A solid was present and was isolated by filtration and purified by column chromatography on silica gel (eluting with 5% to 10% CMA in chloroform). The resulting solid was dried under high vacuum at 100° C. for 18 hours to provide 0.708 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine as a white powder, mp 244.0-246.0° C.
Reaction SMILES: Br[CH:2]([CH3:5])[C:3]#[N:4].[CH3:6][C:7]1([CH3:18])[O:12][C:11](=[O:13])[NH:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]1=2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:6][C:7]1([CH3:18])[O:12][C:11](=[O:13])[N:10]([CH2:5][CH2:2][C:3]#[N:4])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]1=2
Reactant: CC(Br)C#N
Reactant: CC1(C)OC(=O)Nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OC(=O)N(CCC#N)c2ccccc21

Procedure:
10.2 mL (123 mmol) of bromopropionitrile is added dropwise to a solution of 20.0 g (112 mmol) of 4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 17.4 g (126 mmol) of potassium carbonate in 250 mL of acetonitrile and the mixture is refluxed overnight. Another 4 mL (48 mmol) of bromopropionitrile is added and the mixture is refluxed for another 2 hours. The solid is suction filtered, the filtrate is evaporated down, and the residue is recrystallized from diisopropylether. White solid. Yield: 22.8 g (88%); mass spectroscopy: [M+H]+=231.
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:6]=[C:7]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[O:16])=[O:12])[CH:8]=[CH:9][CH:10]=1.[OH-].[Li+].FC(F)(F)C(O)=O>O.C(#N)C>[NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:6]=[C:7]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CCNC(=O)CNC(=O)c1cccc(NC=NN)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NN=CNc1cccc(C(=O)NCC(=O)NCCC(=O)O)c1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
The compound of Example 96 (500 mg) was dissolved in water/acetonitrile (1:1) followed by the addition of lithium hydroxide (200 mg). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) triflouroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) to result in 375 mg of a white solid. MS and 1H-NMR were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][C:10](=[O:12])[CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:9][C@H:10]([OH:12])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C1CC(c2ccc(Br)cc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: O[C@H]1C[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 3-(4-bromo-phenyl)-cyclobutanone (3 g, 13.3 mmol) (J. Med. Chem., 43:721-735(2000)), in anhydrous ether (100 mL) cooled to −20° C. was dropwise added lithium aluminum hydride (1M in THF, 15 mL). The mixture was then allowed to warm to room temperature and stirred for 4 hours. The reaction was slowly quenched with NaOH (1M, 0.8 mL), H2O (0.8 mL) and NaOH (1M, 0.8 mL) sequentially. After stirring for about 30 minutes, the mixture was filtered through a layer of diatomaceous earth and washed with extra ether (100 mL). The filtrate was evaporated under reduced pressure to provide a colorless oil as the title compound (3.01 g, 100%). 1H NMR (300 MHz, CDCl3) δ 2.0 (m, 2 H), 2.76 (m, 2 H), 2.92 (m, 1 H), 4.28 (m, 1 H), 7.09 (d, J=9 Hz, 2 H), 7.41 (d, J=9 Hz, 2 H); (DCl/NH3) m/z 244 (M+NH4)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:18])[CH2:12][NH:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)=[CH:5][C:4]=1[Br:19]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:18])[CH2:12][NH:13][CH:14]2[CH2:15][CH2:16][CH2:17]2)=[CH:5][C:4]=1[Br:19]
Reactant: N#Cc1cc(C(=O)CNC2CCC2)cc(Br)c1N
Agent: Cl
Product: N#Cc1cc(C(O)CNC2CCC2)cc(Br)c1N

Procedure:
m.p. of the hydrochloride: 215°-216° C. (decomp.), was prepared from 4'-amino-3'-bromo-5'-cyano-2-cyclobutylaminoacetophenone analogous to Example 48.