Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14](OC)=[O:15])=[C:6]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:15][CH2:14][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2
Reactant: COC(=O)c1[nH]c2cc(OC)c(OC)cc2c1-c1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(CO)[nH]c3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
A solution of methyl 5,6-dimethoxy-3-(4-methoxyphenyl)indole-2-carboxylate (0.25 g) in tetrahydrofuran (10 ml) was dropwise added to a suspension of lithium aluminum hydride (LiAlH4) (56 mg) in tetrahydrofuran (10 ml) at room temperature, followed by stirring for 2 hours at room temperature. After adding water, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from acetone to give 2-hydroxymethyl-5,6-dimethoxy-3-(4-methoxyphenyl)-indole (0.145 g, 63%) as colorless prisms.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[C:11]([O:15]C(=O)CC)(=[O:14])[CH2:12][CH3:13].C([O-])(=O)CC.[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[C:12]([CH3:13])[C:11]([OH:15])=[O:14]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CCC(=O)OC(=O)CC
Agent: CCC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=Cc1ccc(F)c(F)c1)C(=O)O
Temperature: 135 °C

Procedure:
A mixture of 2.88 g (0.02 mol) of 3,4-difluorobenzaldehyde, 3.24 g (0.025 mol) of propionic anhydride and 0.92 g (0.02 mol) of sodium propionate under nitrogen is heated at 135° C. with a magnetic stirrer for 20 hours. The reaction mixture is poured onto 50 ml of water. A solid precipitates that dissolves when 50 ml of saturated K2CO3 is added with stirring. The basic solution is extracted with ether (2×100 ml). The aqueous phase is then poured into an excess of concentrated HCl and ice. The precipitated white solid is filtered and dried to give 3,4-difluoro-α-methylcinnamic acid, M.P. 122-125° C.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]3[C:15]4[CH:21]=[CH:20][C:19]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=5)=[CH:18][C:16]=4[S:17][C:13]=3[C:12]([C:32]#[N:33])=[CH:11][N:10]=2)=CC=1.[OH:36]S(O)(=O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O>[NH2:8][C:9]1[C:14]2[C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=4)=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([C:32]([NH2:33])=[O:36])=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(-c5ccc(S(C)(=O)=O)cc5)ccc4c23)cc1
Reactant: O=S(=O)(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc3c(c2)sc2c(C(N)=O)cnc(N)c23)cc1

Procedure:
A solution of 1-[(4-methoxybenzyl)amino]-7-[4-(methylsulfonyl)phenyl][1]benzothieno[3,2-c]pyridine-4-carbonitrile in conc. H2SO4 (45 equiv) was stirred at room temperature for 2 h and then poured into H2O. The mixture was neutralized with K3PO4, filtered, washed with H2O and dried. The crude product was purified by flash chromatography on silica gel, eluted with 10% MeOH in EtOAc to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:11][NH:10][C:9]1=S)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH:26]([OH:32])[C:27]([O:30][CH3:31])([CH3:29])[CH3:28]>C(O)C.[Hg](Cl)Cl>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C@H:12]1[CH2:11][NH:10][C:9](=[N:24][CH2:25][CH:26]([OH:32])[C:27]([O:30][CH3:31])([CH3:29])[CH3:28])[C@@H:8]([NH:7][C:6](=[O:23])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=S
Reactant: COC(C)(C)C(O)CN
Agent: Cl[Hg]Cl
Solvent: CCO
Product: COC(C)(C)C(O)CN=C1NC[C@H](c2cccc(F)c2F)C[C@@H]1NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl[(3S,5S)-5-(2,3-difluorophenyl)-2-thioxopiperidin-3-yl]carbamate (400 mg, 1.17 mmol) in ethanol (11.7 mL) was added 1-amino-3-methoxy-3-methylbutan-2-ol (389 mg, 2.92 mmol) and mercury (II) chloride (412 mg, L52 mmol). The mixture was stirred 20 min, filtered, and concentrated giving the crude title compound. MS 442.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][C:3]=1[F:10].O=[C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:10])[NH:8][C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:14][C:13]2=1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Reactant: NNc1ccc(Br)c(F)c1
Product: CC(C)C(=O)NC1CCc2[nH]c3cc(F)c(Br)cc3c2C1

Procedure:
Prepare the title compounds by essentially following the procedure as described in Preparation 4 (Method 2) with (4-bromo-3-fluoro-phenyl)-hydrazine (Preparation 12) and N-(4-oxo-cyclohexyl)-isobutyramide, to obtain a tan solid containing a 65:35 mixture of isomers in 20% overall yield. MS (ES): m/z 353, 355 (M+H), 351, 353 (M−H); HPLC (Method A): Rt=2.22 min, (95%).
Reaction SMILES: C[Mg]Br.[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:15]([C:19]1[N:20]=[C:21]([C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]4[C:42]5[C:37](=[CH:38][C:39]([CH2:43]I)=[CH:40][CH:41]=5)[C:36]([C:45]#[N:46])=[CH:35]4)=[CH:29][C:27]=3[CH:28]=2)[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([C:19]1[N:20]=[C:21]([C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]4[C:42]5[C:37](=[CH:38][C:39]([CH2:43][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])=[CH:40][CH:41]=5)[C:36]([C:45]#[N:46])=[CH:35]4)=[CH:29][C:27]=3[CH:28]=2)[S:22][CH:23]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(CI)ccc54)ccc3o2)n1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc2c(c1)c(C#N)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
A mixture of 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(chloromethyl)indole-3-carbonitrile (0.65 g) and potassium iodide (0.91 g) in acetone (5 ml) was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure and the residue was dissolved with dichloromethane. After removal of the resulting insolble mass by filtration, and the filtrate was evaporated under reduced pressure to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(iodomethyl)indole-3-carbonitrile (0.88 g). Methyl magnesium bromide (1M) in tetrahydrofuran solution (15 ml) was added dropwise to diethyl malonate (5.41 g) under ice-cooling. After the mixture was stirred at room temperature for 1.5 hours, 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(iodomethyl)indole-3-carbonitrile (0.88 g) was added to the mixture. After several hours, the resulting mixture was partitioned between diluted hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give ethyl 3-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-3-cyanoindol-5-yl}-2-(ethoxycarbonyl)propionate (0.78 g).
Reaction SMILES: [Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:5]=[C:4]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:23][C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2c(Br)cc(O)cc21
Reactant: Cc1ccc(SCCCCCl)cc1
Product: Cc1ccc(SCCCCOc2cc(Br)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 4 from 8-bromo-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.
Reaction SMILES: [CH3:1][C:2]1[C:6]([I:7])=[C:5]([CH3:8])[NH:4][N:3]=1.CC1C=CC(S(O[CH2:20][C@@H:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].O1CCOCCOCCOCCOCCOCC1.CN(C=O)C>>[CH3:26][C:23]1([CH3:27])[O:22][C@H:21]([CH2:20][N:3]2[C:2]([CH3:1])=[C:6]([I:7])[C:5]([CH3:8])=[N:4]2)[CH2:25][O:24]1
Reactant: Cc1n[nH]c(C)c1I
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(C[C@@H]2COC(C)(C)O2)c(C)c1I
Temperature: 70 °C

Procedure:
A mixture of 3,5-dimethyl-4-iodopyrazole (200.0 mg, 0.9008 mmol), ((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (515.9 mg, 1.802 mmol), K2CO3 (136.9 mg, 0.9909 mmol), 1,4,7,10,13,16-hexaoxacyclooctadecane (23.81 mg, 0.09008 mmol) and DMF (4 mL, 50 mmol) was heated to 70° C. overnight. The material was extracted in EtOAc, and washed with water (3×). The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 20-30% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:29](=[O:30])[NH:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: O=C=NC1CCCCC1
Reactant: O=C1c2ccccc2SCCC1CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)OCC1CCSc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (283 mg, 1.36 mmol) in 17 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.21 ml, 1.5 mmol) and cyclohexyl isocyanate (682 μl, 5.56 mmol). The mixture was stirred at 80° C. for 24 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 190 mg (42%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[Br:16]N1C(=O)CCC1=O>ClCCl>[Br:16][C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cncc(-c2ccnc3ccnn23)c1
Solvent: ClCCl
Product: Brc1cnn2c(-c3cccnc3)ccnc12
Temperature: 0 °C

Procedure:
A mixture of 1.96 g. of 7-(3-pyridyl)pyrazolo[1,5-a]-pyrimidine and 1.97 g. of N-bromosuccinimide in 100 ml. of dichloromethane is heated on a steam bath for 15 minutes. The mixture is poured into ice cold 2.5 N sodium hydroxide. The organic layer is separated and dried then is passed through a column of hydrous magnesium silicate. The column is washed with dichloromethane and the eluent is concentrated and diluted with hexane to give 1.8 g. of the product of the example, m.p. 243°-244° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:17][C:16]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:15]=3[C:14](=[O:23])[NH:13][C:12]=2[CH:24]=1)(=O)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:15]2[C:14](=[O:23])[NH:13][C:12]3[CH:24]=[C:8]([CH2:7][CH2:6][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:9]=[CH:10][C:11]=3[NH:17][C:16]=2[CH:18]=1
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1Nc2cc(CCN3CCOCC3)ccc2Nc2cc(Cl)ccc21
Temperature: 50 °C

Procedure:
A mixture of Example 641A (360 mg, 0.98 mmol) in DMF (5 mL) was treated with morpholine (200 μL) and heated at 50° C. for 24 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel to provide the title compound. MS (ESI) m/e 358 (M+H)+; 1H NMR (300 MHz, DMSO-d.6 □ 9.84 (s, 1H), 7.97 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.91 (dd, J=8.5, 2.0 Hz, 1H), 6.81-6.89 (m, 3H), 3.55-3.58 (m, 4H), 2.57-2.62 (m, 2H), 2.37-2.45 (m, 6H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:25]1[CH:26]=[C:27]2[N:34]([CH3:35])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>C1COCC1>[CH3:35][N:34]1[C:27]2[N:28]([C:29](=[O:31])[N:30]=[C:25]([O:3][CH2:4][C:5]3[CH:6]=[N:7][C:8]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=4)=[C:9]([CH:12]=3)[C:10]#[N:11])[CH:26]=2)[CH2:32][CH2:33]1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)cnc1Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1cnc(Oc3cccc(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (6.46 mg, 0.162 mmol), 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)nicotinonitrile (31.7 mg, 0.108 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (20 mg, 0.11 mmol).
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]([CH3:23])=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])C=C.C(O)(=O)C.C1([SiH3])C=CC=CC=1>C(Cl)Cl.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>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[C:10]1[CH:11]=[C:12]([C:14]2[C:15]([CH3:23])=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)[S:13][C:9]=1[C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: C=CCn1ccnc1-c1sc(-c2c(C)nn3ccccc23)cc1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nn2ccccc2c1-c1cc(-c2ccc(Cl)cc2Cl)c(-c2ncc[nH]2)s1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 1-allyl-2-[3-(2,4-dichlorophenyl)-5-(tributylstannyl)-2-thienyl]-1H-imidazole (180 mg, 0.29 mmol) in DMF (4.0 mL) was added [3-bromo-2-methylpyrazolo[1,5-a]pyridine (50 mg, 0.2 mmol) (azeotroped from toluene) and Bis(triphenylphosphine)palladium(II) chloride (8.5 mg, 0.012 mmol). The resulting mixture was degassed and stirred for 1 h at 100° C. under an atmosphere of argon. The reaction mixture was allowed to cool, concentrated and the residue was partially purified by silica gel column chromatography (40 g, eluting with 30% EtOAc in hexanes to EtOAc to give 3-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]-2-methylpyrazolo[1,5-a]pyridine, 82 mg. To a solution of [A] 3-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]-2-methylpyrazolo[1,5-a]pyridine (70 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium(0) (8.5 mg, 0.0074 mmol) and acetic acid (0.4 mL, 7 mmol) in DCM (1.5 mL) was added slowly phenylsilane (0.1 mL, 0.8 mmol) and the reaction mixture stirred at 40° C. for 2 h. The reaction mixture was concentrated and the product was purified by column chromatography on silica gel eluting with 1-3% MeOH in DCM. The product was further purified by preparative hplc, formic acid gradient. The title compound was isolated as a colorless lyophilized solid, 25 mg. LC/MS (FA) ES+ 425.0, 427.6, 428.4, 429.3. 1H NMR (400 MHz, d4-MeOH) δ: 8.48 (d, J=8.3 Hz, 1H), 7.85-7.87 (m, 1H), 7.50-7.60 (m, 1H), 7.31-7.39 (m, 3H), 7.18 (s, 1H), 7.04 (s, 2H), 6.90-6.95 (m, 1H), 2.62 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]=[CH:7][N:8]([C@H]3C[C@@H](CO)[C@H](O)[C@@H]3O)[C:9]=2[N:10]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>CS(C)=O.CO>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
A mixture of 2-amino-9-[(1S,2R,3S,4S)-2,3-dihydroxy-4-(hydroxymethyl)-cyclopentyl]-1,9-dihydro-6H-purin-6-one (60.0 g, 0.213 mol) and benzyl bromide (60.9 mL, 0.512 mol) in DMSO (300 mL) was stirred at room temperature for 18 h. Concentrated HCl aqueous solution (150 mL) was added to the reaction mixture and stirring was continued for 45 min. The resulting mixture was poured into MeOH (1800 ml). The solution was neutralized with 2 M NaOH solution. The resulting white precipitate was collected by filtration, washed with water, and dried under vacuum to afford the product (48 g, 93.3%). LCMS calculated for C12H12N5O (M+H): 242.1; found: 242.1.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[CH:26])[CH2:20][CH2:19][C:18]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>N1CCCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:20][CH2:19][C:18]4([O:21][CH2:22][CH2:23][O:24]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Brc1ccccn1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: O
Product: COc1ccc(C2(C#Cc3ccccn3)CCC3(CC2)OCCO3)cc1OC1CCCC1

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.15 g, 0.42 mmol) and 2-bromopyridine (0.040 mL, 0.42 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)-palladium(0) (0.02 g, 4%), copper(I) iodide (0.005 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80° C. for 0.5 h. Water was added and the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(2-pyridylethynyl)cyclohexane as a white foam. mp 41°-42° C. 1H-NMR (400 MHz, CDC3) δ 8.58 (d, J=4.6 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.21 (m, 2H), 7.17 (d, J=8.5 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.81 (m, 1H), 3.99 (s, 4H), 3.84 (s, 3H), 2.25 (m, 2H), 2.15 (m, 4H), 1.8-2.0 (m, 8H), 1.59 (m, 2H).
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].CO.[N+](=[CH2:22])=[N-]>CCOCC>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([O:10][CH3:22])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of BOC-L-Gln (20 g, 81 mmol) in 50 mL of EtOAC and MeOH at 0° C. was added diazomethane in 250 mL of Et2O with stirring. The resulting yellow solution was stirred at 0° C. for 5 minutes and then warmed up to room temperature and stirred for 20 minutes. Argon gas was then bubbled through the yellow reaction mixture to remove excess diazomethane. The crude product was concentrated and purified by crystallization from methyl-tert-butyl ether. Yield 100%. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.96 (m, 1H), 2.21 (m, 1H), 2.36 (m, 2H), 3.76 (s, 3H,), 4.34 (m, 1H), 5.32 (m, 1H), 5.44 (bs, 1H), 6.16 (bs, 1H). Anal. (C11H20N2O5) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[N+:11]([C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16])([O-:13])=[O:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=2[N+:11]([O-:13])=[O:12])=[O:7])=[CH:9][CH:10]=1
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Cc1cc(C)c(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2-nitro-4,6-dimethylaniline as a light yellow solid as described in Example 1. 1H NMR (CDCl3): 9.09 (s, 1H), 8.97 (d, J=2.4, 1H), 8.22-8.18 (m, 1H), 7.60 (d, J=1.2, 1H), 7.50 (d, J=8.1, 1H), 7.42 (s, 1H), 2.43 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]3[C:19]([OH:25])=[C:20]([C:22]([NH2:24])=[O:23])[S:21][C:5]2=3)[CH2:3][CH2:2]1.C1(N2C3C(=CC(F)=C(F)C=3OC)C(=O)C(C(OCC)=O)=C2S)CC1.C1(N2C3C(=CC(F)=C(F)C=3)C(=O)C3C(O)=C(C(N)=O)SC2=3)CC1.[NH:73]1[CH2:77][CH2:76][C@@H:75]([C:78]([NH2:81])([CH3:80])[CH3:79])[CH2:74]1.Cl>N1C=CC=CC=1.CO>[NH2:81][C:78]([C@@H:75]1[CH2:76][CH2:77][N:73]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]4[C:19]([OH:25])=[C:20]([C:22]([NH2:24])=[O:23])[S:21][C:5]=4[N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:74]1)([CH3:80])[CH3:79]
Reactant: CC(C)(N)[C@@H]1CCNC1
Reactant: COc1c(F)c(F)cc2c(=O)c3c(O)c(C(N)=O)sc3n(C3CC3)c12
Agent: CCOC(=O)c1c(S)n(C2CC2)c2c(OC)c(F)c(F)cc2c1=O
Agent: Cl
Agent: NC(=O)c1sc2c(c1O)c(=O)c1cc(F)c(F)cc1n2C1CC1
Solvent: c1ccncc1
Solvent: CO
Product: COc1c(N2CC[C@@H](C(C)(C)N)C2)c(F)cc2c(=O)c3c(O)c(C(N)=O)sc3n(C3CC3)c12
Temperature: 100 °C
Yield: 29 %

Procedure:
The starting material, 9-cyclopropyl-6,7-difluoro-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carboxamide, is prepared from ethyl 1-cyclopropyl-6,7-difluoro-2-mercapto-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate. (See US 2008071086, and Hashimoto, et al., 2007) using a procedure analogous to that describing the preparation of 9-cyclopropyl-6,7-difluoro-3-hydroxyl-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carboxamide. ((Chiba, et al., JP 03-223289) 1H NMR: δ 0.98-1.03 (m, 2H), 1.24-1.31 (m, 2H), 3.86-3.93 (m, 1H), 4.04 (d, J=1.5 Hz, 3H), 7.88 (dd, J=10.0 Hz, 8.5 Hz, 1H). 19F NMR: δ −145.5 (d, J=22.5 Hz, 1F), −139.4 (d, J=22.5 Hz, 1F). LCMS: m/z calcd for C16H12F2N2O4S ([M]+) 366. found ([M+H]+) 367. The title compound is prepared as follows. (R)-2-(Pyrrolidin-3-yl)propan-2-amine (175 mg, 1.4 mmol) is added to a mixture of 9-cyclopropyl-6,7-difluoro-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carboxamide (100 mg, 0.3 mmol) in pyridine (9 mL). The reaction mixture is heated at 100° C. for 24 h, cooled to rt, and evaporated under reduced pressure. The resulting residue is purified by preparative HPLC using mass-based fraction collection to provide the desired mass only fractions. The fractions containing product were combined and lyophilized. The resulting solid was treated with a solution of 1.25 M HCl in methanol (3 mL), evaporated, and triturated with diethyl ether. This step was repeated three times. The solid was dissolved in water and lyophilized to afford the desired product (40 mg, 29%, HCl salt).