Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[I:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[I:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:13][CH:12]=1
Reactant: Ic1ccc(I)cc1
Reactant: OC1CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Ic1ccc(OC2CN3CCC2CC3)cc1
Temperature: 110 °C

Procedure:
3-Hydroxy quinuclidine (Aldrich, 2.54 g, 20 mmol) in toluene (anhydrous, Aldrich, 50 mL) was treated with 1,4-diiodobenzene (Aldrich, 7.9 g, 24 mmol), Cul (Strem Chemicals, 0.38 g, 2 mmol), 1,10-phenanthroline (Aldrich, 0.72 g, 4 mmol), and Cs2CO3 (Aldrich, 8.15 g, 25 mmol), heated at 110° C. for 40 hours. The reaction mixture was allowed to cool to room temperature, diluted with chloroform (100 mL), and washed with water (2×10 mL). The organic phase was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as oil (3.7 g, yield, 56%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.56 (m, 1H), 1.64–1.80 (m, 2H), 1.90–2.08 (m, 1H), 2.10–2.21 (m, 1H), 2.60–3.00 (m, 5H), 3.34–3.40 (m, 1H), 4.46 (m, 1H), 6.73 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8, Hz, 2H), ppm. MS (DCl/NH3) m/z 330 (M+H)+.
Reaction SMILES: NOS(O)(=O)=O.C(OC(=O)[NH:13][CH2:14][CH2:15][C:16](=[S:23])[N:17]=[C:18]([N:20](C)C)[CH3:19])(C)(C)C.N1C=CC=CC=1.Cl>CO.C(O)C>[CH3:19][C:18]1[N:17]=[C:16]([CH2:15][CH2:14][NH2:13])[S:23][N:20]=1
Reactant: CC(=NC(=S)CCNC(=O)OC(C)(C)C)N(C)C
Agent: Cl
Agent: NOS(=O)(=O)O
Solvent: c1ccncc1
Solvent: CCO
Solvent: CO
Product: Cc1nsc(CCN)n1
Temperature: 25 °C

Procedure:
Hydroxylamine-O-sulfonic acid (0.68 g, 6.0 mmol) in methanol (5 ml) is added to a stirred solution of [2-(1-Dimethylamino-ethylidenethiocarbamoyl)-ethyl]-carbamic acid tert-butyl ester (1.43 g, 5.0 mmol) and pyridine (0.83 ml, 10 mmol) in ethanol (25 ml). After stirring the reaction for 18 hours at room temperature the solvent is removed in vacuo and the residue is partitioned between water and DCM. The organic extract is separated, dried (MgSO4), and the solvent is removed to give a colourless oil which is dissolved in ethanol (20 ml). Aqueous HCl (2M, 10 ml) is added and the mixture is heated at reflux for 1 hour. After cooling to room temperature the solvent is removed. The product is dissolved in aqueous NaHCO3 and the free base is extracted with ethyl acetate. The organic extract is dried (MgSO4) and the solvent removed to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19](I)[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6].N1C=CC=C[C:24]=1C1C=CC=CN=1.[CH3:35][S:36]SC>CN(C)C=O.[Zn].[Ni](Br)Br>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([S:36][CH3:35])[C:20]=1[O:21][CH3:24])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6]
Reactant: CSSC
Reactant: O=C(c1cc(Cl)c(O)c(I)c1)N1CS(=O)(=O)c2ccccc21
Reactant: c1ccc(-c2ccccn2)nc1
Agent: Br[Ni]Br
Agent: [Zn]
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1SC
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
3-(3-chloro-4-hydroxy-5-iodobenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (1.19 g) was dissolved in N,N-dimethylformamide (9 mL), and 2,2′-bipyridine (32 mg), a zinc powder (262 mg), nickel bromide (45 mg) and dimethyl disulfide (0.09 mL) were added to the solution, and then the mixture was stirred at 80° C. for 1.5 hours. After the reaction solution was filtered, 1N hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in N,N-dimethylformamide (6 mL). Potassium carbonate (828 mg) and dimethylsulfuric acid (0.38 mL) was added to the solution, and then the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (203 mg) as a yellow crystal.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1>>[CH3:19][C:18]1([CH3:20])[C:14]([CH3:13])([CH3:28])[O:15][B:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)=[CH:23][CH:22]=2)[O:17]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Yield: 90 %

Procedure:
Alkylation of 2-Chloromethyl-quinoline with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A for Example 3.32 to give 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-quinoline in 90% yield. 1H NMR (400 MHz, MeOD) δ ppm 1.2 (s, 12 H) 5.3 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 1 H) 7.6 (dd, J=11.4, 8.6 Hz, 3 H) 7.7 (m, 1 H) 7.8 (dd, J=8.1, 1.5 Hz, 1 H) 7.9 (d, J=8.6 Hz, 1 H) 8.3 (d, J=8.6 Hz, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[N:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([NH:19][C:20]3[C:21](=[CH:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=3)[N:28]3[CH:29]=[CH:30][CH:31]=[C:32]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2cccc2)c(N)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)NC1(CCN(Cc3ccccc3)CC1)c1cccn1-2

Procedure:
510 g (0.027 mole) of 1-benzyl-4-piperidone and 2 ml. of glacial acetic acid are added to a solution of 50 g (0.027 mole) of 1-(2-amino-4-methoxy-phenyl)pyrrole [Example 19(b)] in 80 ml. of absolute ethanol. The solution is refluxed for 43 hours and concentrated to an oil which is washed with water. The oil is recrystallized from isopropanol to give 1'-benzyl-7-methoxy-4,5-dihydrospiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine], m.p. 123°-124° C.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[O:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:24]([NH2:26])=[O:25])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:33][C:34]1[C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36]>C1(C)C(CCO)=CC=CC=1>[NH2:36][C:35]1[C:34]([CH3:33])=[C:40]([C:2]2[C:14]3[C:13]4[C:8](=[CH:9][C:10]([C:15]([N:17]5[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]5)=[O:16])=[CH:11][CH:12]=4)[NH:7][C:6]=3[C:5]([C:24]([NH2:26])=[O:25])=[CH:4][CH:3]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(Br)c23)CC1
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Yield: 64.9 %

Procedure:
A suspension of 4-bromo-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 1-1, 300 mg, 0.722 mmol), tetrakis-(triphenylphosphine)palladium (33.4 mg, 0.029 mmol), 2 M aqueous sodium carbonate (0.9 mL, 1.806 mmol), and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate 50-1, 253 mg, 1.084 mmol) in toluene-ethanol (4:1, 15 mL) was purged with nitrogen for 5 min and then heated at reflux for 7.5 h. The mixture was concentrated and the residue was partitioned between chloroform and water. The aqueous phase was extracted with chloroform and the combined organic phases were washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with DCM-2 M methanolic ammonia, gradient from 100:0 to 95:5) to provide 4-(3-amino-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a white solid (207 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H) 8.16 (br. s., 1H) 7.97 (d, J=7.91 Hz, 1H) 7.78 (s, 1H) 7.48 (br. s., 1H) 7.08 (t, J=7.80 Hz, 1H) 6.81-6.97 (m, 4H) 6.49-6.65 (m, 1H) 3.12-3.25 (m, 4H) 2.92-3.10 (m, 4H) 2.76 (s, 3H) 1.70 (s, 3H). Mass spectrum m/z 442.2 (M+H)+.
Reaction SMILES: C(OP([CH:9]([CH:12]([CH3:14])[CH3:13])[C:10]#[N:11])(OCC)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O[CH2:26][CH:27]=[C:28]([CH2:30][CH2:31][CH:32]=[C:33]([CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[CH3:34])[CH3:29].O>C1(C)C=CC=CC=1>[CH3:14][CH:12]([C:9](=[CH:26][CH:27]=[C:28]([CH3:29])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:34])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[C:10]#[N:11])[CH3:13]
Reactant: CCOP(=O)(OCC)C(C#N)C(C)C
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C
Temperature: -70 °C
Yield: 94.9 %

Procedure:
To a solution of 2-(diethylphosphono)isovaleronitrile (8.72 g, 40 mmol) in toluene (75 ml) was gradually added a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (75 ml) with stirring at -70° C. under argon atmosphere. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to -70° C. again, and farnesol (5.88 g, 26.7 mmol) was added thereto with stirring, and the mixture was allowed to warm to room temperature. After addition of water, the organic layer was separated, washed with saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, and dried over MgSO4. The organic layer was separated from MgSO4 by filtration and concentrated to give a residue, which was purified with silica gel column chromatography (solvent: n-hexane/ethyl acetate=100:1) to obtain the aimed 2 -(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (7.23 g, 96%; 2Z:2E=25.6:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:34]=[CH:33][C:32]5OCO[C:28]=5[CH:27]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH:35]1[C:40]([CH:41]=O)=[CH:39][C:38]2[O:43][CH2:44][O:45][C:37]=2[CH:36]=1.[BH4-].[Na+]>CO>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][CH2:41][C:40]4[CH:35]=[CH:36][C:37]5[O:45][CH2:44][O:43][C:38]=5[CH:39]=4)=[CH:7][N:6]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:21]1)[C:26]1[CH:34]=[CH:33][CH:32]=[CH:28][CH:27]=1
Reactant: Nc1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(CCc1ccc(Oc2ccc(NCc3ccc4c(c3)OCO4)cn2)cc1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (1.04 g, 2.5 mmol) was dissolved in methanol (25 mL). To the resulting solution was added piperonal (0.39 g, 2.63 mmol), and this solution was refluxed overnight. The resulting reaction solution was cooled with ice, and then sodium borohydride (0.28 g, 7.50 mmol) was added. The resulting solution was stirred for 2 hours at room temperature. This reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (ethyl acetate), to thereby yield 0.80 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[NH:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>O=P(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13]([Cl:20])=[N:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC1=NS(=O)(=O)N(Cc2ccccc2)C(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: COC1=NS(=O)(=O)N(Cc2ccccc2)C(Cl)=N1

Procedure:
A stirred mixture of 2-benzyl-5-methoxy-2H-1,2,4,6-thiatriazin-3-one-1,1-dioxide (10.5 g) and PCl5 (12.2 g) in POCl3 (35 ml) is refluxed overnight. The reaction mixture is evaporated in vacuo at 50° C. affording the crude product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1C1C=CC=CC=1O.O.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[O:9]1[C:5]2[CH:6]=[CH:7][CH:11]=[CH:12][C:4]=2[N:10]=[C:8]1[C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:20])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1-c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc3ccccc3o2)cc1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
A solution of (2-hydroxyphenyl)-terephthalamic acid methyl ester (0.35 g, 1.3 mmol) in polyphosphoric acid (˜5 mL) was heated to reflux for 3 h. The solution was cooled to 0° C., water added (100 mL) and solid K2CO3 introduced until pH 7–9 was attained. The residue was diluted with ethyl acetate (2×100 mL) and the organic extract dried (MgSO4), filtered and concentrated to give cyclized methyl 4-(benzoxazol-2-yl)-benzoate (0.15 g, 45%) as a beige powder. 1H NMR (CDCl3) δ 3.98 (s, 3H), 7.40 (m, 2H), 7.61 (m, 1H), 7.81 (m, 1H), 8.20 (d, 2H, J=7.8 Hz), 8.34 (d, 2H, J=7.8 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:14]([C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=1)[CH2:15][CH3:16].CC(C)=O>C(#N)C.ClCCl>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:14][CH2:15][CH3:16])[N:22]=2)[CH:7]=1
Reactant: CCCc1cccc(N)n1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CC#N
Product: CCCc1cccc(Nc2cc(Cl)nnc2C(=O)OCC)n1
Temperature: 130 °C
Reaction time: 24 h
Yield: 28.7 %

Procedure:
A mixture of ethyl 4,6-dichloropyridazine-3-carboxylate (0.80 g, 3.62 mmol) and 6-propylpyridin-2-amine (739 mg, 5.43 mmol) was dissolved in acetonitrile (4 mL) and heated at 130° C. After 24 h, the reaction mixture was cooled and concentrated in vacuo, then purified by chromatography (silica, 80 g, 0 to 3% acetone in dichloromethane over 15 min, then 3 to 10% acetone in dichloromethane over another 15 min) to give ethyl 6-chloro-4-(6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (335 mg, 1.04 mmol, 29%) as a pale yellow crystalline solid after drying under high vacuum at room temperature. LC-MS 321.1 [M+H]+.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[C:21]([F:22])([F:24])[F:23])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
A solution of vanillin (1.65 g, 10.86 mmol) and 4-fluoro-3-trifluoromethyl-benzonitrile (10.26 mmol) in DMF (15 mL) was treated with K2CO3 (2.83 g, 21.72 mmol), and the mixture was heated in an oil bath at 80° C. for 12 h. The reaction was cooled to RT and partitioned between EtOAc and H2O. The organic phase was washed with water (3×), dried over Na2SO4 and concentrated in vacuo. Silica gel chromtagraphy (EtOAc/hexanes) afforded the title compound. 1H NMR (400 Hz, CDCl3) δ 10.00 (s, 1H), 8.00 (m, 1H), 7.68 (dd, 1H), 7.58-7.53 (m, 2H), 7.29 (d, 1H), 6.75 (d, 1H), 3.83 (s, 3H); LC/MS (m/z) [M+1]+ 322.1 (calculated for C16H11F3NO3, 322.06).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][C:35]=1[F:36])[O:17][C:18]1[N:23]=[C:22]2[S:24][C:25]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])=[N:26][C:21]2=[CH:20][CH:19]=1.C(N(CC)CC)C.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:51]=[CH:50][C:49]([CH2:52][NH2:53])=[CH:48][CH:47]=1>O1CCCC1.C(OCC)(=O)C>[F:36][C:35]1[CH:34]=[CH:33][C:16]([O:17][C:18]2[N:23]=[C:22]3[S:24][C:25]([NH:27][C:28]([CH:30]4[CH2:32][CH2:31]4)=[O:29])=[N:26][C:21]3=[CH:20][CH:19]=2)=[CH:15][C:14]=1[NH:13][C:1](=[O:12])[NH:53][CH2:52][C:49]1[CH:48]=[CH:47][C:46]([C:45]([F:44])([F:54])[F:55])=[CH:51][CH:50]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 116.8 %

Procedure:
To a solution of bis(trichloromethyl) carbonate (30 mg, 0.102 mmol) in tetrahydrofuran (2 mL) was added dropwise a suspension of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.290 mmol) produced in Example 16(vi) and triethylamine (80 μL, 0.580 mmol) in tetrahydrofuran (2 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. 1-[4-(Trifluoromethyl)phenyl]methanamine (50 μL, 0.348 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate (20 mL), and washed successively with aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (5 mL). The solid precipitated in the organic layer was collected by filtration to give the title compound (65 mg, 41%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([CH3:29])[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+].CO.C(Cl)(Cl)Cl>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([CH3:29])[N:16]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2ccc(C)nc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: COc1ccc(-c2ccc(C)nc2-c2ccc(O)cc2)cc1
Yield: 8905.6 %

Procedure:
The 2-(4-benzyloxyphenyl)-3-(4-methoxyphenyl)-6-methylpyridine (14 g, .37 mmol) and ammonium formate (3.5 g, 55 mmol) were stirred in 1 L of EtOH, then 5% Pd/ C (5.8 g, 3 mmol Pd) was added and the reaction mixture warmed to 50°-55° C. The reaction mixture was stirred at 55° C. for 1 h at which time the TLC (MeOH/ CHCl3, 1:9) indicated the starting material was consumed. After cooling, the reaction mixture was filtered, concentrated, and the residue triturated with Et2O to give 9.6 g (90% yield) of white solid: mp 190° C.; 1H NMR (CDCl3) d 2.66 (s, 3H, Pyr-CH3), 3.82 (s, 3H, OCH3), 6.53-6.56 (d, 2H, J=8 Hz, ArH), 6.80-6.83 (d, 2H, J=8 Hz, ArH), 7.06-7.18 (m, 6H, ArH, ArOH), 7.59-7.62 (d, 1H, J=8 Hz, ArH); MS(FD) 291(M+). Anal. Calcd for C19H17NO2 : C, 78.33; H, 5.88; N, 4.81. Found: C, 78.11; H, 5.93; N, 4.72.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C([N:30]([CH2:34][CH3:35])C(C)C)(C)C.[I-].[Na+].[CH2:38]([OH:40])C>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][NH:30][CH2:34][CH2:35][CH2:38][OH:40])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2)=[O:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCCl)ccc1Cl
Reactant: CCO
Agent: [I-]
Agent: [Na+]
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCNCCCO)ccc1Cl
Temperature: 120 °C

Procedure:
To a solution of 2-chloro-5-[3-chloropropoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.25 g, Example 3a) and N,N-diisopropylethylamine (0.54 ml) in ethanol (5 ml) was added sodium iodide (0.08 g) and 1-propanolamine (0.24 ml). The reaction vessel was sealed and reaction mixture heated at 120° C. for 24 h. The reaction mixture was then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and sodium hydrogencarbonate solution, and the aqueous phase extracted with additional ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by NPHPLC (eluting with 0-25% ethanol in dichloromethane) to give 2-chloro-5-[3-(3-hydroxy-propylamino)-propoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide as a semi-solid. This compound was converted to the hydrochloride salt by stirring with 4M HCl in dioxane and concentrated under reduced pressure to leave the title compound as a white solid (0.036 g).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]SC1SCC(=O)N=1.C(#N)C.[NH:27]1[CH:31]=[N:30][N:29]=[N:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:28]1[N:29]=[N:30][CH:31]=[N:27]1
Reactant: c1nnn[nH]1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1ccc(OCCCCCCn2ncnn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stir overnight at room temperature 300 mg. of the iodide prepared in Examples 2 and 3, 3 ml. acetonitrile, 63 mg. 1-H-tetrazole and 274 mg. cesium carbonate in a reaction flask. Add an additional. 189 mg. 1-H-tetrazole and 100 mg. cesium carbonate, let stir one week at room temperature. Work up the reaction mixture in methylene chloride with a water wash. Elute on a coarse silica column with methylene chloride then ethyl aetate/methylene chloride. Isolate two fractions of the title compound, the less polar fraction and the more polar fraction. one of the fractions is the 1-substituted tetrazole and the other fraction is the 2-substituted tetrazole.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([CH2:20][CH3:21])[CH:19]=[C:13]4[NH:12][C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([CH2:20][CH3:21])[CH:19]=[C:13]4[N:12]([C:27](=[O:28])[C:26]4[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=4)[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1cc2[nH]c3c(cnc4c3cnn4CC)c(=O)n2n1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CCc1cc2n(C(=O)c3ccc(Cl)cc3)c3c(cnc4c3cnn4CC)c(=O)n2n1

Procedure:
By treating the product of Example 25 with 4-chlorobenzoyl chloride according to the procedure of Example 2, 3,9-diethyl-3,11-dihydro-11-(4-chlorobenzoyl)-6H-pyrazolo-[1,5-a]pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one is obtained.