Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.CCN(CC)CC.[C:34]1([N:40]=[C:41]=[S:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[C:34]1([NH:40][C:41]([NH:24][CH:22]2[CH2:23][CH:21]2[C:18]2[CH:19]=[CH:20][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)=[S:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NC1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(C4CC4NC(=S)Nc4ccccc4)cc3)n2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 33.2 %

Procedure:
The amine trifluoroacetate salt from Example 5 (0.064 g, 0.135 mmol) was dissolved in THF (0.5 mL). Et3N (0.037 mL, 0.27 mmol) was added, followed by phenyl isothiocyanate (0.020 mL, 0.15 mmol). The resulting dark yellow solution was heated to 80° C. and stirred for 4 h. The solution was cooled to 25° C., loaded directly onto a silica gel column and purified (gradient elution with 15% to 40% to 80% EtOAc in hexanes) to afford the product (0.0222 g, 33%) as a yellow oil: IR νmax 3380, 3218 (br), 1617, 1598, 1518, 1497, 1448, 1356, 1326, 1264, 1221, 1168, 1111, 1065, 986, 910, 851, 756, 732, 694 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.90 (br s, 1H), 7.78 (d, J=9.0 Hz, 2H), 7.46-7.32 (m, 5H), 7.31-7.21 (m, 5H), 3.10 (br s, 1H), 2.25 (br s, 1H), 1.51-1.30 (m, 2H); HRMS-ESI (m/z) [M]+ calcd for C25H20F3N5OS, 495.134; found, 495.1341.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:8][C:9]1[CH:10]=[C:11]([NH:12][C:5](=[O:7])[CH3:6])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
691 mL of acetic anhydride are added to a solution cooled to 10° C. of 1200 g (6.976 mol, 1 eq) of 3-bromoaniline in 6 L of dichloromethane in the presence of 1.07 L (7.67 mol, 1.1 eq) of triethylamine and 25.6 g (0.209 mol, 0.03 eq) of 4-(dimethylamino)pyridine. The reaction medium is stirred at room temperature for 4 hours and then hydrolyzed with 850 mL of 1N hydrochloric acid solution, and the phases are separated by settling. The organic phase is washed with 0.5N hydrochloric acid solution and then with water, and the solvent is evaporated off. After recrystallization from diisopropyl ether/heptane, 1506.1 g of N-(3-bromophenyl)acetamide are obtained in solid form. Yield=100%
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[CH:9][C:10]3[C:16](=[O:17])[CH:15]=[CH:14][NH:13][C:11]=3[N:12]=2)=[CH:3][CH:2]=1.[H-].[Na+].[H][H].[CH2:22](I)[CH3:23]>C(NC(C)C)(C)C.CN(C)C=O>[CH2:22]([N:13]1[C:11]2[N:12]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[N:8]=[CH:9][C:10]=2[C:16](=[O:17])[CH:15]=[CH:14]1)[CH3:23]
Reactant: O=c1cc[nH]c2nc(-c3ccncc3)ncc12
Reactant: CCI
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCn1ccc(=O)c2cnc(-c3ccncc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
C-1. 8-Ethyl-2-(4-pyridinyl)pyrido[2,3-d]pyrimidin-5(8H)-one--A mixture containing 12.7 g of 2-(4-pyridinyl)pyrido[2,3-d]pyrimidin-5(8H)-one, 2.74 g of 50% sodium hydride in mineral oil and 300 ml of dimethylformamide was stirred at room temperature until evolution of hydrogen ceased. The mixture was heated gently with stirring on a steam bath for 30 minutes, one drop diisopropylamine was added followed by 100 mg of sodium hydride and gentle heating with stirring was continued for another 45 minutes. The mixture was then cooled to room temperature and to it was added dropwise with stirring at room temperature 8.85 g of ethyl iodide. The reaction mixture was stirred at room temperature for three hours and then heated gently with stirring on a steam bath for 30 minutes. The solvent was then distilled off in vacuo and the residue was shaken well with a mixture of water and chloroform. The water layer was extracted several times with chloroform and the chloroform extracts were combined with the chloroform layer. The combined chloroform solution was dried over anhydrous sodium sulfate, the mixture filtered, and the filtrate treated with decolorizing charcoal and filtered. The chloroform was distilled off in vacuo and the remaining 12 g of solid residue was dissolved in 300 ml of hot isopropyl alcohol, the hot alcohol solution treated with decolorizing charcoal and filtered. The filtrate was concentrated to a volume of about 150 ml and cooled. The precipitated solid was collected, washed with a small quantity of cold isopropyl alcohol, and dried at 65° C. in vacuo to produce 6.8 g of 8-ethyl-2-(4-pyridinyl)pyrido[2,3-d]pyrimidin-5(8H)-one, m.p. 200°-202° C. Additional product was obtained from the mother liquor.
Reaction SMILES: N[C@@H](CC(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.B.O1CCCC1.[CH:27]1(/[CH:33]=[C:34](/[N:41]2[CH:45]=[N:44][CH:43]=[N:42]2)\[C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.Cl>ClCCCl>[CH:27]1(/[CH:33]=[C:34](/[N:41]2[CH:45]=[N:44][CH:43]=[N:42]2)\[CH:35]([OH:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC(C)(C)C(=O)/C(=C\C1CCCCC1)n1cncn1
Agent: B
Agent: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)C(O)/C(=C\C1CCCCC1)n1cncn1
Reaction time: 24 h

Procedure:
In a nitrogen atmosphere, a solution of 0.485 g (1.8 mmoles) of (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol in 5 ml of 1,2-dichloroethane was added dropwise at -78° C. to a solution comprising 1.8 ml (1.8 mmoles) of 1.00M borane-tetrahydrofuran solution and 2 ml of 1,2-dichloroethane, and the temperature of the mixture was raised from -78° C. to room temperature over about 2 hours. Thereafter, a solution of 0.31 g (1.2 mmoles, E/Z=99.9/0.1) of (E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-one in 3 ml of 1,2-dichloroethane was added dropwise to this solution, and stirring was carried out for 24 hours. The reaction product was decomposed with addition of 6 ml of 2N hydrochloric acid to the solution, and after removing (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol hydrochloride by filtration, the organic layer was washed with water and concentrated under reduced pressure. The residue was purified on a column packed with 2 g of silica gel with chloroform as a developing solvent to obtain (-)-(E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol. The conversion was 100%, and the composition of the product was: E-form alcohol, 99.1% and Z-form alcohol, 0.9%. The enantiomer ratio of the E-form alcohol was: (+)-isomer, 16.3% and (-)-isomer, 83.7%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12](I)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Li])CCC.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH:28]=[O:29].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH3:19])[C:12]([CH:28]([C:27]2[CH:26]=[C:25]([Cl:24])[CH:32]=[C:31]([Cl:33])[CH:30]=2)[OH:29])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1I
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)c1nc(COCc2ccccc2)n(C)c1C(O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.4 %

Procedure:
In 30 ml of dry tetrahydrofuran was dissolved 3.31 g (8.94 mmol)of 2-benzyloxymethyl-5-iodo-4-isopropyl-1-methylimidazole (4c), followed by addition of 5.78 ml (9.83 mmol)of n-butyllithium (1.70 M hexane solution)at -70° C. over 30 minutes. Then, after 5 minutes, a solution of 1.56 g (8.91 g)of 3,5-dichlorobenzaldehyde dissolved in 10 ml of dry tetrahydrofuran was added at -70° C. over 30 minutes. After 1 hour, the mixture was left to cool to room temperature, and an aqueous solution of ammonium chloride was added thereto, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate/methylene chloride 10:1)to give 1.25 g of [2-benzyloxymethyl-5-isopropyl-3-methyl-3H-imidazol-4-yl]-(3,5-dichlorophenyl)-methanol (56) (yield 33.3%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[C:13]([C:25]#[C:26][CH:27]2[CH2:29][CH2:28]2)([C:21]([F:24])([F:23])[F:22])[O:12][C:11]1=[O:30])(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:7][CH2:8][CH2:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[C:13]([C:25]#[C:26][CH:27]2[CH2:29][CH2:28]2)([C:21]([F:22])([F:24])[F:23])[O:12][C:11]1=[O:30]
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)OC(C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN1C(=O)OC(C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.5 mg of 7 was added 500 μL of dichloromethane and 500 μL of trifluoroacetic acid. The mixture was allowed to stir at room temperature for 30 minutes and concentrated under reduced pressure to give 3 mg of 8 as a thick oil (M+H, 359).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH2:38][CH2:39][NH2:40])[CH:35]=[CH:36][CH:37]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:40]([CH2:39][CH2:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:13])=[O:14]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: NCCc1cccc(C(F)(F)F)c1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(CCc2cccc(C(F)(F)F)c2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(3-Trifluoromethyl-phenyl)-ethylamine. MS (ESI): 501.4 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:21]=[CH:20][C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([N+:11]([O-:13])=[O:12])[O:10][C:6]=2[CH:5]=1.[CH2:22](I)[CH3:23].O>C(COC)OC>[CH2:22]([O:3][C:4]1[CH:21]=[CH:20][C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([N+:11]([O-:13])=[O:12])[O:10][C:6]=2[CH:5]=1)[CH3:23]
Reactant: O=[N+]([O-])c1oc2cc(O)ccc2c1-c1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1

Procedure:
To a suspension of 0.34 g (0.008 mole) of sodium hydride in 45 ml of glyme is added dropwise a solution of 2.0 g (0.008 mole) of 6-hydroxy-2-nitro-3-phenylbenzofuran in 20 ml of glyme. To this suspension is added 16 g (0.010 mole) of ethyl iodide and the mixture is heated to its reflux temperature and maintained at reflux for 5 hours. After cooling to 25° C. an additional 0.1 g of sodium hydride and 5 ml of ethyl iodide are added and the mixture is refluxed for about three hours. The mixture is poured into water and extracted with diethyl ether. The extracts are washed with water and saturated sodium chloride solution and dried. Concentration of the extracts provides a residue which is recrystallized from aqueous ethanol to provide yellow needles of 6-ethoxy-2-nitro-3-phenylbenzofuran, m.p. 109°-111° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([F:1])[CH:3]=1)=[O:16]
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ccc(F)c(F)c1
Product: COC(=O)C(=O)Nc1ccc(F)c(F)c1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 3,4-difluoroaniline and methyl chlorooxoacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:22][C:14]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)NC(=O)CCC2
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CCCC(=O)N2
Temperature: 25 °C

Procedure:
A suspension of 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (100 mg, 0.52 mmol), NBS (103 mg, 0.57 mmol) and BPO (ca. 5 mg) in carbon tetrachloride (1.5 mL) was heated at reflux for 3 hrs. The reaction mixture was allowed to cool to room temperature, diluted with DCM (20 mL), washed with water and dried over Na2SO4. Filtration and evaporation of the organic layer provided a solid residue, which was washed with n-hexane and dried in high vacuum. The title compound was obtained as a white crystalline product (140 mg, 100%).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10](Cl)[S:9][N:8]=2)=[CH:3][CH:2]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.O=O>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:10]2[S:9][N:8]=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:13])=[CH:2][CH:3]=3)[N:11]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nsc(Cl)n2)cc1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: O=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nsc(-c3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 31.2 %

Procedure:
A mixture of 3-(p-tolyl)-5-chloro-1,2,4-thiadiazole (0.50 g, 2.37 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II) chloride catalyst (1.41 g, 2.61 mmol) in anhydrous THF (20 ml) is cooled in an ice-water bath. To this mixture is added slowly 4-fluorophenyl-magnesium bromide (1.0M in THF, 2.5 ml, 2.49 mmol) with exclusion of both moisture and oxygen. The mixture is allowed to warm to room temperature and stirred for 13 hours under N2. The mixture is filtered through celite and concentrated. The residue is taken up in CHCl3 (50 ml) and washed with brine (50 ml×2). The organic layer is dried over magnesium sulfate and concentrated. The residue is purified on a silica gel column, eluting with 3:7 CHCl3:hexanes to yield 5-(4′-fluorophenyl)-3-(p-tolyl)-1,2,4-thiadiazole (0.20 g, 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7]O.C(O[CH:17](OCC)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C.FC(F)(F)[S:28](O[Si](C)(C)C)(=O)=O.O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:28][CH2:7][CH2:6]2
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C(OCC)OCC
Reactant: COc1ccc(CCO)cc1OC
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1SCCc2cc(OC)c(OC)cc21

Procedure:
Part A. A solution of 3,4-dimethoxyphenethyl alcohol (4.63 g, 25.4 mmol), ethyl diethoxyacetate (5.00 mL, 28.0 mmol) and trimethylsilyl trifluoromethanesulfonate (0.50 mL, 2.58 mmol) in acetonitrile (50 mL) wasstirred at ambient temperature for 12 hours, then heated to reflux for 18 hours. The solution was cooled, and poured into water (200 mL). This was extracted with ethyl acetate (2×200 mL), and the extracts were washed with brine (200 mL), combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was separated by flash chromatography (1:9 ethyl acetate/hexane--1:4 ethyl acetate/hexane) to afford the product, ethyl 6,7-dimethoxy-1,2,3,4-tetrahydro-2-thianaphthalene-1-carboxylate, as an oil (1.68 g, 6.31 mmol, 25%). 1H NMR (CDCl3): δ 6.92 (1H,s); 6.62 (1H, s); 4.32-4.22 (3H, m); 4.04-3.96 (1H, m); 3.87 (3H, s); 3.86 (3H, s); 2.90-2.79 (2H, m); 1.32 (3H, t, J=7.0 Hz). Mass spectrum (NH3 -CI/DDIP): m/z 269 (1%); 268 (7%); 267 (53%); 233 (5%); 193 (100%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:22]=4)[NH:17][C:16]=3[OH:30])=[N+:12]([O-])[CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P(Cl)(Cl)Cl>C(OCC)(=O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:22]=4)[NH:17][C:16]=3[OH:30])=[N:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1-c1c(O)[nH]c2ccc(-c3cccnc3)cc12
Solvent: CCOC(C)=O
Solvent: ClP(Cl)Cl
Product: Oc1[nH]c2ccc(-c3cccnc3)cc2c1-c1ccc(CN2CCOCC2)cn1
Yield: 2.6 %

Procedure:
To a solution of 3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-pyridin-3-yl-1H-indol-2-ol (200 mg, 0.6 mmol) in ethyl acetate (60 mL) was added phosphorus trichloride (0.4 mL). A yellow precipitate was formed and the mixture was refluxed for 3 h, and then diluted with ethyl acetate and washed with an aqueous saturated NaHCO3 solution. The aqueos layer was extracted with two portions of ethyl acetate and one portion of chloroform. The organic- layers were combined, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Xterra, 19×300 mm, eluent: water/acetonitrile, (0:100 to 100:0), gradient) affording 6 mg (3% yield) of the title compound as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.50 (br s, 1 H), 8.92 (d, J=2 Hz, 1 H), 8.49 (dd, J=4, 1 Hz, 1 H), 8.12-8.06 (m, 1 H), 8.02 (s, 1 H), 7.90-7.71 (m, 1 H), 7.71-7.67 (m, 2 H), 7.43 (dd, J=8, 5 Hz, 1 H), 7.20 (d, J=8 Hz, 1 H), 6.98 (d, J=8 Hz, 1 H), 3.63-3.53 (m, 4 H), 3.40-3.24 (m, 2 H), 2.42-2.34 (m, 4 H); MS (ES) m/z 388 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8](C3CCCCO3)[C:5]2=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][N:29]([CH:31]3[CH2:36][CH2:35]N(C(OC(C)(C)C)=O)CC3)[CH:30]=2)O1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=1>>[NH:7]1[CH2:6][CH2:35][CH:36]([CH2:31][N:29]2[CH:30]=[C:26]([C:10]3[C:4]4[C:5](=[CH:6][N:7]=[C:2]([C:49]5[CH:50]=[N:45][CH:46]=[CH:47][CH:48]=5)[CH:3]=4)[NH:8][N:9]=3)[CH:27]=[N:28]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Brc1cc2c(I)nn(C3CCCCO3)c2cn1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Product: c1cncc(-c2cc3c(-c4cnn(CC5CCNCC5)c4)n[nH]c3cn2)c1
Yield: 14 %

Procedure:
Following the Suzuki coupling procedure of Example 159, 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate were reacted. The product was subsequently reacted with 3-pyridineboronic acid pinacol ester by the Suzuki coupling procedure of Example 10 and deprotected by the procedure of Example 229. The mixture was purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 25 mg (14%) of 186 over three steps. ESI MS m/z 360.1 (M+1). 1H NMR (400 MHz, DMSO) 9.44 (d, J=2.1 Hz, 1H), 9.15 (d, J=1.0 Hz, 1H), 8.64-8.54 (m, 4H), 8.17 (s, 1H), 7.53 (dd, J=8.0, 4.8 Hz, 1H), 4.08 (d, J=7.2 Hz, 2H), 2.91 (d, J=12.0 Hz, 2H), 2.41 (t, J=10.9 Hz, 2H), 1.98 (s, 1H), 1.45 (d, J=11.2 Hz, 2H), 1.18-1.05 (m, 2H)
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].CS(C)=O.[C:11]([N:14]1[CH2:41][CH2:40][CH2:39][C@H:15]1[C:16]([NH:18][C@H:19]([C:21]([N:23]1[CH2:38][CH2:37][CH2:36][C@H:24]1[C:25]([NH:27][CH:28]([CH3:35])[CH:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31])=[O:26])=[O:22])[CH3:20])=[O:17])(=[O:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([N:14]1[CH2:41][CH2:40][CH2:39][C@H:15]1[C:16]([NH:18][C@H:19]([C:21]([N:23]1[CH2:38][CH2:37][CH2:36][C@H:24]1[C:25]([NH:27][CH:28]([CH3:35])[C:29]([OH:3])([OH:34])[C:30]([O:32][CH3:33])=[O:31])=[O:26])=[O:22])[CH3:20])=[O:17])(=[O:13])[CH3:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)C(O)C(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(O)(O)C(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of oxalyl chloride (0.12 ml, 1.43 mmol) in methylene chloride (1.5 ml) under an argon atmosphere and cooled in a dry ice-acetone bath was added dropwise a solution of dimethylsulfoxide (0.20 ml, 2.86 mmol) in methylene chloride (1.5 ml). After 5 minutes, a solution of the product of example 59 (0.32 g, 0.72 mmol) in methylene chloride (1.5 ml) was added and the reaction mixture stirred for 25 minutes. Triethylamine (0.50 ml, 3.58 mmol) was added and the reaction mixture warmed to room temperature. The reaction mixture was placed directly onto a silica gel column and eluted with methylene chloride-methanol. Evaporation of the appropriate fractions on a rotary evaporator, addition of water (3 ml) to the residue and evaporation gave the above-named product.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][S:5][CH2:4]1.S(Cl)(Cl)(=O)=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][S:5][CH:4]=1
Reactant: COC1CSC=C1C(N)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: COc1cscc1C(N)=O
Yield: 75 %

Procedure:
1.59 parts of 3-methoxy-dihydrothiophene-4-carboxylic acid amide are reacted with 0.88 part by volume of sulfuryl chloride in 25 parts by volume of carbon tetrachloride in the course of 2 hours at 0° C. The end product is isolated from the reaction mixture by the method described in Example 1c. 1.17 parts (75% of theory) of 3-methoxythiophene-4-carboxylic acid amide are obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([O:24]C)=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CO.Cl>O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Yield: 83 %

Procedure:
A mixture of 1-benzyl-3-(5-methoxycarbonyl-2-furyl)-1H-indazole (1.46 g, 4.39 mmol), 15% aqueous KOH solution (100 mL) and methanol (100 mL) was heated to reflux for 4 h. The resultant solution was allowed to cool and then diluted with H2O (300 mL). The solution was acidified to pH 2 by the addition of conc. HCl and the precipitate collected by vacuum filtration. The off-white solid was washed with H2O and air dried. Recrystallisation of the crude solid (EtOH) gave the product as fine off-white needles (1.16 g, 83%): mp 205-206.5° C. (lit mp 200-202° C.); 1H-NMR (DMSO) 5.34 (s, 2H), 6.67 (d, 1H, J 3.6 Hz), 6.89-7.00 (m, 7H), 7.08 (m, 2H), 7.89 (d, 1H, J 8.0 Hz); 13C-NMR (CDCl3) 52.55, 109.06, 110.91, 119.84, 120.91, 121.22, 122.57, 127.49, 127.69 (2C), 128.02, 128.99(2C), 134.69, 137.40, 140.72, 144.41, 151.75, 159.67; MS (EI) M+; Anal. (C19H14N2O3) C, calcd 73.19; found 73.18, H, calcd 7.17; found 7.16, N, calcd 14.23; found 14.13.