Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=1.C1C(=O)N([Br:35])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:35][CH2:27][C:25]1[CH:24]=[CH:23][C:4]2[S:5][C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=3)=[C:2]([Cl:1])[C:3]=2[CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2sc3ccc(CBr)cc3c2Cl)ccc1-c1ccccc1
Yield: 38 %

Procedure:
To a solution of 3-chloro-5-methyl-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene (110 mg, 0.273 mmol) in CCl4 (3 ml) is added NBS (49 mg, 1 eq.). The mixture is heated at reflux for 15 minutes before AIBN (4.5 mg, 0.1 eq.) is added. The reaction is further heated at reflux overnight. The mixture is filtered through Celite and washed with CCl4. The filtrate is concentrated and purified by column chromatography (EtOAc/Hexane, gradient) to give 50 mg of 5-bromomethyl-3-chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene in 38% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:13]=1.[H-].[Na+].Br[CH2:27]/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[NH:10][C:11]([CH2:27]/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[C:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:13]=1
Reactant: COC(=O)/C=C/CBr
Reactant: O=C(OCc1ccccc1)c1c[nH]c(Cc2ccccc2Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/Cc1[nH]c(Cc2ccccc2Br)nc1C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a stirring solution of phenylmethyl 2-[(2-bromophenyl)methyl]imidazole-4-carboxylate in dimethyl foramide (0.1M) was added sodium hydride (1.2 eq) The reaction was allowed to stir for 10 mins. followed by addition of methyl 4-bromocrotonate continued stirring for 18 hr. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was extracted with 10% hydrochloric acid and the aqueous layer was neutralized with saturated sodium carbonate. The aqueous layer eas extracted with ethyl acetate and dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (50% EtOAc/Hexane). EI-MS m/z 406/408 (M+H)+
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[Cl:15])=[O:10].[NH:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:31]([C:33](O)=[O:34])[CH3:32].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:30]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[C@H:31]([C:33]([NH:2][C@H:3]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[Cl:15])=[O:10])=[O:34])[CH3:32]
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
At 0° C. the solution of 88 mg (0.2 mmol) of HCl.Lys(ClZ)-OBzl in 5 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 38 mg (0.2 mmol) of Boc-Ala-OH, 30 mg (0.22 mmol) of 1-hydroxybenzotriazole and 45 mg (0.22 mmol) of dicyclohexylcarbodiimide in 5 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 5 h and TLC (chloroform/methanol, 30:1) indicated complete disappearance of Boc-Ala-OH. The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 20 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (30 ml×3), saturated NaCl in water (30 ml×3) and KHSO4 in water (5%, 30 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated to provide 112 mg (98%) of the title compound as a colorless powder. Mp94–96° C., FAB-MS (m/e) 575[M+H]+, 475[M-Boc]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH3:12][N:13]([CH3:30])[S:14]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]=[C:28]=[O:29])(=[O:26])=[O:25])(=[O:16])=[O:15]>C(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:28]([NH:27][S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][S:14]([N:13]([CH3:30])[CH3:12])(=[O:15])=[O:16])(=[O:25])=[O:26])=[O:29])[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: CN(C)S(=O)(=O)Oc1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2OS(=O)(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
To a suspension of 0.46 g (0.003 mole) 2-amino-4,6-dimethoxypyrimidine in 5 ml methylene chloride was added 1.2 g (0.004 mole) 2-(dimethylaminosulfonyloxy)benzenesulfonyl isocyanate. The reaction exothermed (18°-26° C.) and was then stirred at room temperature 3 hours. The solvent was evaporated under reduced pressure. The resultant mixture was triturated with diethyl ether and filtered to give 1.2 g of a white solid, m.p. 165°-168° C. The infrared spectrum shows absorption bands at 1710, 1380, 1170 cm-1.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[C:28]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.CCN(P1(N(CC2C=CC=CC=2)CCCN1C)=NC(C)(C)C)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1>C1COCC1>[C:28]1([CH2:34][C:35]([NH:25][C:23]2[S:24][C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:15][C:11]4[CH:10]=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:26])([F:1])[F:27])=[CH:4][CH:5]=5)[N:14]=[CH:13][N:12]=4)[C:21]=3[N:22]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1Cc1ccccc1
Solvent: C1CCOC1
Solvent: C=Cc1ccccc1
Product: O=C(Cc1ccccc1)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1

Procedure:
According to the procedure described in Example 67, the title compound was prepared by using 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (0.19 g, 0.5 mmol), phenylacetyl chloride (0.13 mL, 1 mmol, Aldrich), and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine, polymer bound (BEMP resin) (0.34 g, 0.75 mmol) in THF (5 mL). Purification by silica gel chromatography (1:4 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 507 (M+1). Mp: 188.6-191.0° C.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([CH3:20])=[C:18]([S:21][CH3:22])[C:17]([C:23]#[N:24])=[N:16]1.O>CO.CC(O)C.OS(O)(=O)=O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([CH3:20])=[C:18]([S:21]([CH3:22])=[O:1])[C:17]([C:23]#[N:24])=[N:16]1
Reactant: OO
Reactant: CSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: Cc1c(S(C)=O)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C

Procedure:
30% Hydrogen peroxide (1.82 ml) was added to a stirred solution of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylthio-1H-pyrazole-3-carbonitrile (6.2 g) in methanol, containing i-PrOH/H2SO4 catalyst (5.31 ml) described by Drabowicz, et al (above) at 0-5° C. The mixture was allowed to warm to 20° C. over 17 hours. Additional hydrogen peroxide (5.46 ml) was added in three portions over the next 24 hours, along with the catalyst (5 ml). After stirring for a further 60 hours water was added to give 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (6.72 g) as a yellow oil (91.7% area purity by HPLC) having a retention time of 3.61 minutes on a 25.0 centimeter by 4.6 millimeter SUPELCOSIL LC-18 column, eluting with CH3CN/H2O (3:1) solvent at 1 ml/minute.
Reaction SMILES: C([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[CH2:10][S:9]1(=[O:20])=[O:19])C1C=CC=CC=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].N1CCCCC1.[H][H]>N1C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH:10]2[C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:8][S:9]2(=[O:19])=[O:20])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C1CS(=O)(=O)N(Cc2ccccc2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: [H][H]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C2C(=O)c3ccccc3NS2(=O)=O)CC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 24 %

Procedure:
1-Benzyl-2,2-dioxo-2,3-dihydro-1H-2,1-benzothiazin-4-one (1.51 g, 5.26 mmol) was dissolved in pyridine (50 mL). N-tert-Butoxycarbonyl-4-piperidinone (1.24 g, 6.33 mmol) was added to the mixture followed by piperidine (110 μL, 1.11 mmol). Molecular sieves were added to the mixture. Reaction stirred at room temperature for 40 hours. Reaction mixture was filtered over celite. Filtrate was concentrated in vacuo. Residue was purified by silica gel chromatography. The major component was isolated and the fractions concentrated in vacuo. Residue was dissolved in methanol (50 mL). A catalytic amount of 50% wet 10% palladium on carbon was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 55 psi of hydrogen gas. Reaction shook at room temperature for 2 hours. Reaction mixture was filtered over celite. Fresh catalyst was added to the filtrate. Reaction vessel was placed on a Parr apparatus and charged with 55 psi of hydrogen gas. Reaction shook at room temperature for 1 hour. Mixture was filtered over celite. A third batch of fresh catalyst was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 55 psi of hydrogen gas. Reaction shook at room temperature for 7.5 hours. Catalyst was filtered off. Filtrate was concentrated in vacuo. Silica gel chromatography afforded the title compound as pale yellow solid in 24% yield. MS m/e (M−H)−=379.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:31][C:6]2[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28](O)=[O:29])[CH:23]=4)[CH:17]=3)=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:32])[CH2:3]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(Cl)CCl.O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:1][C:2]1([CH3:33])[CH2:31][C:6]2[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[O:29])[CH:23]=4)[CH:17]=3)=[C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[S:9][C:5]=2[C:4](=[O:32])[CH2:3]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4ccnc(C(=O)O)c4)c3)c2C1
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4ccnc(C(=O)N5CCOCC5)c4)c3)c2C1
Yield: 48.5 %

Procedure:
A mixture of Example 223 (55 mg, 0.12 mmol), morpholine (12 mL, 0.14 mmol), EDC (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole hydrate (3 mg, 0.02 mmol) in DCM (10 mL) was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (pH 2.5) to give the title compound (31 mg, 49%) as a yellow oil. δH (CDCl3) 8.82 (1H, dd, J 5.1, 0.6 Hz), 8.73 (1H, dd, J 5.1, 0.4 Hz), 8.30 (1H, d, J 1.1 Hz), 8.04 (1H, dd, J 5.1, 1.7 Hz), 7.91 (1H, s), 7.38 (1H, dd, J 4.9, 1.3 Hz), 3.90-3.81 (4H, m), 3.77-3.71 (4H, m), 3.70-3.65 (4H, m), 3.05-2.98 (4H, m), 2.51 (2H, s), 2.47 (2H, s), 1.05 (6H, s). LCMS (ES+) 533.3 (M+H)+.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[CH:14]=[N:15]O)=[CH:10][CH:9]=[CH:8][CH:7]=3.[ClH:17]>>[ClH:17].[ClH:17].[CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[CH2:14][NH2:15])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: ON=Cc1cn2c(ccc3ccccc32)n1
Agent: Cl
Product: NCc1cn2c(ccc3ccccc32)n1
Reaction time: 4 h

Procedure:
A solution of 1.0 g of imidazo-[1,2-a]-quinoline-2-carboxaldehyde oxime in 100 ml of 0.25N methanolic hydrogen chloride in the presence of 0.100 g of 10% palladized carbon was hydrogenated at atmosphere pressure for 4 hours and after 175 ml of hydrogen were absorbed, 0.200 g of additional catalyst were added thereto. The mixture was hydrogenated further at 50° C. under atmosphere pressure for 2 hours during which 62 ml of hydrogen were absorbed. The mixture was filtered through cellulose powder and the filtrate was concentrated under reduced pressure. Anhydrous ether was added to the concentrate which was then cooled in ice to induce crystallization. The mixture was filtered and the recovered product was dried at 50° C. under vacuo and was crystallization from a methanol-ether mixture to obtain 0.85 g of imidazo-[1,2-a]-quinoline-2-methanamine dihydrochloride in the form of hygroscopic colorless crystals melting at 320°-325° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(S[C:15](=[O:31])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>COCCOC.FC(F)(F)C([O-])=O.[Ag+]>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[NH:1][C:15](=[O:31])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18]
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)SC(C)(C)C
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: COCCOC
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)Nc1cc(O)ccc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Silver trifluoroacetate (1.3 g) was added in two portions over 20 minutes to a stirred solution of 3-amino-4-chlorophenol (0.5 g) and 2-(4-methanesulfonylbenzyl)-3-oxothiobutyric acid S-tert-butyl ester (0.8 g) in 1,2-dimethoxyethane (10 mL) at room temperature. The mixture was stirred at room temperature for 15 hours and then filtered through hyflo, washing with 1,2-dimethoxyethane. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 0:1 by volume) gave title compound as a pale peach solid, 0.75 g.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[C:9]([OH:18])=[CH:8][N:7]=1)(=[O:3])[CH3:2].FC(F)(F)C([O-])=O>N1C=CC=CC=1.[Cu]I>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]2[CH:12]=[CH:13][O:18][C:9]2=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(C#C[Si](C)(C)C)c(O)cn1
Agent: [Cu]I
Agent: O=C([O-])C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)OCc1cc2ccoc2cn1

Procedure:
{5-Hydroxy-4-[(trimethylsilyl)ethynyl]-2-pyridinyl}methyl acetate, trifluoroacetate) (10 g, 22 mmol) was dissolved in pyridine (200 ml) and treated with copper(I) iodide (5.2 g, 27 mmol) then heated under reflux for 18 hrs. The mixture was allowed to cool, evaporated to dryness and the residue partitioned between ethyl acetate and water. This mixture was filtered through kieselguhr to remove copper residues. The organic layer was separated from the filtrate, dried and chromatographed on silica gel, eluting with a gradient of 10-60% ethyl acetate in 40-60° C. petroleum ether. This gave furo[2,3-c]pyridin-5-ylmethyl acetate (1.15 g, 27%) and a less polar product [2-(trimethylsilyl)furo[2,3-c]pyridin-5-yl]methyl acetate (1.3 g, 23%) as oils.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([SH:12])[CH:6]=[CH:5]2.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C@@H:20]([OH:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].C(O)CO>C(OCC)(=O)C.[Cu]I.C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C@@H:20]([OH:22])[CH3:21])[CH:6]=[CH:5]2
Reactant: Sc1ccc2cc(Br)ccc2c1
Reactant: C[C@H](O)c1ccccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: OCCO
Product: C[C@H](O)c1ccccc1Sc1ccc2cc(Br)ccc2c1
Temperature: 80 °C
Yield: 87.2 %

Procedure:
A mixture of 6-bromo-2-naphthyl hydrosulfide (Example 5 Step 2, 1.80 g, 7.53 mmol), (1S)-1-(2-iodophenyl)ethanol (1.82 g, 7.34 mmol), copper(I) iodide (70 mg, 0.37 mmol) and potassium carbonate (2.02 g, 14.6 mmol) was degassed then isopropyl alcohol (10 mL) and ethylene glycol (0.82 mL, 14.7 mmol) added. The reaction was heated to 80° C. overnight. The cooled reaction mixture was diluted with ethyl acetate (40 mL), filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a 10-20% ethyl acetate/isohexane gradient to give solid (1S)-1-{2-[(6-bromo-2-naphthyl)thio]phenyl}ethanol (2.30 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.94 (1H, s), 7.68 (1H, dd, J 1.4, 7.8), 7.64 (1H, d, J 8.7 Hz), 7.58-7.50 (3H, m), 7.43-7.39 (1H, m), 7.36 (1H, dd, J 1.4, 7.8 Hz), 7.30 (1H, dd, J 1.8, 8.6 Hz), 7.27-7.23 (1H, m), 5.44 (1H, q, J 6.3 Hz), 1.46 (3H, d, J 6.4 Hz); m/z (ES+) 341, 343 [(M-OH)+].
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]#[C:17][Si](C)(C)C)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]([NH:22]C(=O)C(C)(C)C)[NH:3]1.C(O)(=O)C>CO.O>[NH2:22][C:4]1[NH:3][C:2](=[O:1])[C:11]2[C:10]3[CH:12]=[C:13]([C:16]#[CH:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(C#C[Si](C)(C)C)cc3c2c(=O)[nH]1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: C#Cc1ccc2ccc3nc(N)[nH]c(=O)c3c2c1
Yield: 58.5 %

Procedure:
A solution of N-(1,2-dihydro-1-oxo-9-(trimethylsilylethynyl)benzo[f]quinazolin-3-yl)pivalamide (0.24 g, 0.61 mmol) and K2C03 (0.50 9'3.6 mmol) in methanol (-50 ml) was stirred at reflux for 2.5 hours. The solution was then diluted with water (-20 ml) acidified with acetic acid, and the resulting solid filtered and dried at 900 C under reduced pressure. The solid was resuspended in ethanol (- 20 ml), filtered, and dried to give 3-amino-9-ethynyl benzo[f]quinazolin- 1(2H)-one (0.084 g) as a tan solid. 1H NMR (DMSO-d, 200 MHz) δ: 4.26 (s, 1H, ethynyl CH), 6.63 (br s, 2H, NH2), 7.32 (d, J=9 Hz, 1H, Ar'), 7.47 (dd, J=8,2 Hz, 1H, Ar), 7.87 (d, J=8 Hz, IH, Ar), 8.02 (d, J =9 Hz, 1H, Ar), 9.78 (s, 1H, Ar), 11.34 (br s, 1H, NH). Mass spectrum (CI-CH4): 236 (M+1, 100%). Anal. Calculated for C1-4H9N3 0: (, 71.48; H, 3.86; N, 17.86. Found: C, 71.30; H, 3.92; N, 17.68.
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:6]=1[NH:23][CH:24]([CH3:29])[C:25](OC)=[O:26])([O-:4])=[O:3]>CO>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:6]=1[NH:23][CH:24]([CH3:29])[C:25]([NH2:1])=[O:26])([O-:4])=[O:3]
Reactant: N
Reactant: COC(=O)C(C)Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CO
Product: CC(Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(N)=O

Procedure:
Ammonia was led at room temperature for 28 hours into a solution of 11.7 g of the methyl 2-[N-{2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl}amino]propionate, obtained according to Example I, in 100 ml of methanol. After evaporating to dryness under reduced pressure and recrystallizing from acetonitrile, an orange crystalline substance was obtained having a melting-point of 187° C. Elementary analysis: 47.67% C (calculated 47.60), 3.24% H (calculated 3.25) and 10.24% N (calculated 10.41).
Reaction SMILES: [C:1]([C@@H:3]([NH:22][C:23]([C:25]1([NH:31]C(=O)OC(C)(C)C)CCC[CH2:27][CH2:26]1)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[C:14]3=[N:15][CH:16]=2)=[CH:7][CH:6]=1)#[N:2].[CH:39]([OH:41])=O.[C:42](#N)C>CO.O>[NH2:31][C:25]1([C:23]([NH:22][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:12]=[C:13]4[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[C:14]4=[N:15][CH:16]=3)=[CH:7][CH:6]=2)=[O:24])[CH2:26][CH2:27][O:41][CH2:39][CH2:42]1
Reactant: O=CO
Reactant: CN1Cc2cc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCCCC4)cc3)cnc2C1=O
Reactant: CC#N
Solvent: CO
Solvent: O
Product: CN1Cc2cc(-c3ccc(C[C@@H](C#N)NC(=O)C4(N)CCOCC4)cc3)cnc2C1=O
Temperature: 50 °C

Procedure:
To (S)-tert-butyl 4-(1-cyano-2-(4-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)phenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 32, step (iv), 0.186 g) was added formic acid (9.6 mL) and the mixture heated to 50° C. for 15 min. The mixture was allowed to cool to room temperature and diluted with methanol, and then evaporated to dryness. The residue was suspended in methanol, filtered and the filtrate was evaporated. The residue from the filtrate was purified by reversed phase HPLC (Waters X-Bridge column) eluting with methanol in aqueous 0.1% trifluoroacetic acid. The fractions containing the desired compound were combined and evaporated, and the residue combined with the solid collected during the filtration. The purified compound was dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organics were dried to over magnesium sulfate and evaporated, triturated with diethyl ether and evaporated to afford a white solid. The solid was suspended in water (2.2 mL) and acetonitrile (0.11 mL) and stirred at room temperature for 3 days. The resulting solid was collected by filtration and washed with water and then dried under vacuum at 50° C. to afford the titled compound (56 mg).
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[NH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=1.[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1>C(O)(=O)C.O>[C:5]([C:19]1([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)[CH2:22][CH2:21][CH2:20]1)#[N:6]
Reactant: CNC(=O)c1ccc(N)cc1F
Reactant: O=C1CCC1
Reactant: C[Si](C)(C)C#N
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(NC2(C#N)CCC2)cc1F
Temperature: 80 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
TMS-CN (29.7 g, 300 mmol) was added to a mixture of N-methyl-2-fluoro-4-aminobenzamide 4a (16.8 g, 100 mmol) and cyclobutanone (14 g, 200 mmol) in 90% acetic acid (200 mL). The reaction mixture was stirred at 80° C. for 24 h. The mixture was cooled and diluted with water (200 mL). The suspension was extracted with ethyl acetate (3×200 mL). Combined organic layers were washed with brine (4×100 mL), dried (MgSO4) and concentrated in vacuo to dryness. The residue was triturated with a mixed solvent of hexanes and ethylether (20 mL-20 mL) to remove cyclobutanone cyanohydrin. The solid was collected by filtration, affording the title compound 6a (20 g, 84% yield). MS (ES-API Negative): 246 (M−H)−. 1H NMR (CDCl3, 500 MHz): δ 7.92 (1H, dd, J=8.4, 8.4 Hz), 6.76 (1H, q, J=4.3 Hz), 6.48 (1H, dd, J=8.3, 1.9 Hz), 6.29 (1H, dd, J=14.3, 1.9 Hz), 4.72 (1H, br s), 2.97 (3H, d, J=4.4 Hz), 2.85-2.75 (2H, m), 2.4-2.35 (2H, m), 2.3-2.15 (1H, m), 1.95-1.85 (1H, m).