Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH:1]1([NH:7][C:8]2[S:9][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)NC1CCCCC1
Solvent: CCO
Product: CCOC(=O)c1csc(NC2CCCCC2)n1

Procedure:
To a suspension of 0.25 g (1.6 mmol) of N-cyclohexylthiourea in 2.5 mL of ethanol was added 0.31 g of ethyl bromopyruvate. The reaction was heated at reflux for 17 hr then evaporated to leave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C@H:5]1[CH2:10][C@@H:9]([CH:11]=CC2C=CC=CC=2)[O:8][C:7]([CH3:20])([CH3:19])[O:6]1.[O:22]=[O+][O-]>CO>[CH3:20][C:7]1([CH3:19])[O:6][CH:5]([CH2:4][C:3]([O:2][CH3:1])=[O:21])[CH2:10][CH:9]([CH:11]=[O:22])[O:8]1
Reactant: COC(=O)C[C@H]1C[C@@H](C=Cc2ccccc2)OC(C)(C)O1
Reactant: O=[O+][O-]
Solvent: CO
Product: COC(=O)CC1CC(C=O)OC(C)(C)O1
Temperature: 25 °C

Procedure:
Cis-2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-acetic acid methyl ester (prepared in Example 1) was dissolved in methanol (10 mL) and ozone was passed through the solution at -78° C. until the color of the solution turned blue. The reaction mixture was purged with nitrogen to remove excess ozone then dimethyl sulfide was added and the temperature was allowed to warm up to room temperature. The reaction was evaporated in vacuo and the residual oil was purified by chromatography on silica gel using diethyl ether-hexane (3:1) as the eluent to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH2:10]([SH:14])[CH2:11][CH2:12][SH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]2[S:14][CH2:10][CH2:11][CH2:12][S:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C=O)n1
Reactant: SCCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C2SCCCS2)n1
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 51.7 %

Procedure:
A solution of 6-methyl-2-pyridinecarboxaldehyde (100 g), 1,3-propanedithiol (285 g) and para-toluenesulphonic acid (11.8 g) in toluene (2.6 liters) is heated to boiling for 12 hours 40 minutes, the water formed being removed by azeotropic distillation. After being cooled to a temperature in the region of 20° C., the reaction mixture is poured into a mixture of distilled water (1 liter) and ice (500 g), and approximately 10N aqueous potassium hydroxide solution is then added dropwise. After decantation, the organic solution is washed with approximately 5N aqueous potassium hydroxide solution, and 3 times with distilled water (1700 cc in total), dried over anhydrous magnesium sulphate and concentrated to dryness under reduced pressure (25 mm Hg; 3.25 kPa) at 50° C. The product obtained (160.2 g) is chromatographed on neutral silica gel (980 g; 0.063-0.200 mm) contained in a column 8 cm in diameter. The product is eluted with a mixture of cyclohexane and ethyl acetate (70:30 by volume), collecting 300-cc fractions. Fractions 9 to 23 are combined and concentrated to dryness under reduced pressure (25 mm Hg; 3.25 kPa) at 50° C. 2-(6-Methyl-2-pyridyl)-1,3-dithiane (90.2 g), m.p. 74° C., is thereby obtained.
Reaction SMILES: [C:1]([C:3]1[N:4]=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:11][OH:12].C(N(CC)CC)C>CO>[OH:12][N:11]=[C:1]([C:3]1[N:4]=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)[NH2:2]
Reactant: NO
Reactant: Cc1ccc(C#N)nn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(C(N)=NO)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyano-6-methyl pyridazine (U.S. Pat. No. 5,914,319) (0.77 g, 6.4 mmol) was dissolved in methanol (20 mL), then hydroxylamine hydrochloride (0.66 g, 9.6 mmol) and triethylamine (1.3 mL, 9.6 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was chilled in an ice-bath, then the solid was collected by filtration, washed with methanol and dried to give the title compound as a pale yellow solid (0.84 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C@@H:24]([OH:25])[CH2:23][CH2:22][C@@:21]2([CH3:26])[C@H:3]1[CH2:4][CH2:5][C:6]1[C:7]3[C@:17]([CH3:27])([CH2:18][CH2:19][C:20]=12)[C@@H:10]([C@H:11]([CH3:16])[CH2:12][CH2:13][CH2:14][OH:15])[CH2:9][CH:8]=3.C[N+]1([O-])CCOCC1.CCOCC>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[O:25]=[C:24]1[CH2:23][CH2:22][C@@:21]2([CH3:26])[C@@H:3]([CH2:4][CH2:5][C:6]3[C:7]4[C@:17]([CH3:27])([CH2:18][CH2:19][C:20]=32)[C@@H:10]([C@H:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[O:15])[CH2:9][CH:8]=4)[C:2]1([CH3:1])[CH3:28]
Reactant: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](CCC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CCC(=O)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A suspension of 4,4-dimethyl-5α-chola-8,14-dien-3β,24-diol (500 mg, 1.29 mmol), N-methylmorpholine-N-oxide (600 mg, 5.2 mmol), TPAP (45 mg, 0.13 mmol) and crushed molecular sieves (2 g) in dichloromethane (5 mL) was stirred for 30 minutes at room temperature. Addition of ether (15 mL) and filtration through kieselguhr gave a dark brown solution which was concentrated under reduced pressure and purified by chromatography (Eluant: 3 hexane: 1 ethyl acetate) to give the 3-oxo-4,4-dimethyl-5α-chola-8,14-dien-24-aldehyde (345 mg, 70%) as a white solid with melting point 96.5-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([CH2:28][C:29]#[N:30])=[N:9]1.[N-:31]=[N+:32]=[N-:33].[Na+].[NH4+].[Cl-].CN(C=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([CH2:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[N:9]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CC#N)nn3-c3ccccc3Cl)s2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(Cc4nnn[nH]4)nn3-c3ccccc3Cl)s2)c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 77.8 %

Procedure:
A mixture of [1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]acetonitrile (136 mg, 0.3 mmol), NaN3 (59 mg, 0.9 mmol), NH4Cl (49 mg, 0.9 mmol), and anhydrous DMF (5 mL) was stirred in a sealed vial at 120° C. for 24 h. The mixture was poured into water, and extracted with DCM. The combined extracts were washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-80% 20% MeOH/DCM) to give the title compound as a white solid (116 mg, 78%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.85-7.83 (m, 1H), 7.74-7.71 (m, 1H), 7.62-7.46 (m, 5H), 7.22 (d, 1H), 6.8 (d, 1H), 6.66 (s, 1H), 4.52 (s, 2H), 3.08 (s, 3H). MS(ES): 497 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][CH2:14][CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:16]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([O-])(=[O:27])C.[Na+]>ClCCl>[CH2:6]([O:13][CH2:14][CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:25]=[O:27])[CH:21]=2)[O:16]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(COCC2CCc3ccccc3O2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCC(COCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Phosphorous oxychloride (0.863 ml, 9.26 mmol) was added very slowly and under inert atmosphere on N-methylformanilide (1.14 ml, 9.26 mmol) and the mixture was left under stirring at room temperature for 30 minutes. After that 2-(benzyloxymethyl)chromane (1.569 g, 6.18 mmol) was added stirring at 65° C. for 1.5 h. Subsequently the mixture was diluted with dichloromethane (30 ml), added with a 15% sodium acetate solution (20 ml), the phases were separated and the organic phase was washed successively with a 1M hydrochloric acid solution and a sodium chloride saturated solution. After drying and removing the solvent by evaporation under reduced pressure, a residue was obtained which was purified by flash chromatography through a silica gel column. Eluting with hexane:ethyl acetate, 10:1, 0.921 g of the title product were recovered (53% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=[C:11]3[C:10]4[C:14](=[CH:15][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)[NH:13][C:12]3=[O:16])[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 8.7 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (30 mg, 0.15 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (40 mg) to give 5.9 mg (8.5%) of the title compound as a yellow-orange solid.
Reaction SMILES: C([O:5][C:6](=[O:20])[C@@H:7]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10]1)[CH3:8])(C)(C)C>C(O)(C(F)(F)F)=O>[O:19]=[C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]1[C@@H:7]([CH3:8])[C:6]([OH:20])=[O:5]
Reactant: C[C@@H](C(=O)OC(C)(C)C)n1cnc2ccccc2c1=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)O)n1cnc2ccccc2c1=O
Yield: 142.5 %

Procedure:
A solution of (2S)-2-(4-oxo-4H-quinazolin-3-yl)-propionic acid tert-butyl ester (1.434 g, 5.23 mmol) in TFA (25 mL) was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure and the residue was dissolved in dry DCM. This process was repeated several times to remove excess TFA. The gum was triturated with diethyl ether, filtrated and washed several times with diethyl ether to afford the sub-title compound as a white powder (1.626 g, 94%): 1H NMR (400 MHz DMSO-d6) δ 1.67 (3H, d), 5.26 (1H, q), 7.58 (1H, m), 7.71 (1H, d), 7.87 (1H, m), 8.15 (1H, m), 8.44 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:24]([C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[Cl:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccccc1Cl
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccccc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 50.4 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75 mg, 0.22 mmol), 2-Chlorobenzaldehyde (34.3 mg, 0.244 mmol), and Ammonium acetate (34.2 mg, 0.444 mmol) were reacted to produce 50.82 mg (50%) of the title compound. (300 MHz, DMSO-d6) 13.16 (s, 1H), 8.07 (s, 1H), 7.84 (m, 1H), 7.72 (s, 1H), 7.64 (m, 1H), 7.52 (m, 2H), 7.20 (s, 1H), 7.14 (d, J=9 Hz, 1H), 6.29 (s, 2H), 5.21 (t, J=17 Hz, 8.5 Hz, 1H), 2.86 (s, 1H), 2.77 (s, 1H), 2.57 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=460 (M+H), HPLC: 2.46 min. (G Method)
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27][CH3:28])=[O:26])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]=[CH:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C.C(OCC)(=O)C>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27][CH3:28])=[O:26])=[CH:12][C:13]=3[N:14]3[CH2:20][CH2:19][CH2:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC=Cc1ccccc1-3
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCc1ccccc1-3
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
Method A: Palladium on carbon (60 mg of 10%) was added to a solution of Example 1 (60 mg, 0.16 mmol) in 60 mL of ethanol and 10 mL of ethyl acetate. The reaction vessel was flushed with H2. The resulting mixture was stirred at room temperature under an atmosphere of hydrogen (balloon pressure) for 4 hours. The mixture was filtered and concentrated to provide the desired product (60 mg, 100% yield) as a colorless solid. ESI-MS m/z 373 (MH+); 1H NMR (500 MHz, CDCl3) δ 1.22 (m, 1H), 1.39 (m, 2H), 1.65 (m, J=12.51 Hz, 1H), 1.76 (d, J=8.85 Hz, 2H), 1.91 (d, J=11.90 Hz, 1H), 1.91 (d, J=11.90 Hz, 1H), 2.06 (m, 3H), 2.38 (m, 1H), 2.56 (m, 1H), 2.68 (dd, J=13.43, 6.71 Hz, 1H), 2.91 (m, 1H), 3.70 (m, 1H), 3.97 (m, 3H), 4.43 (dd, J=14.34, 6.71 Hz, 1H), 7.35 (m, 4H), 7.73 (dd, J=8.54, 1.53 Hz, 1H), 7.87 (d, J=8.54 Hz, 1H), 8.08 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25]C)=[O:24])[CH:20]=[CH:19][CH:18]=1.[CH2:27]([Zn]CC)[CH3:28]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:27]([C:7]1[C:2]([F:1])=[C:3]([C:17]2[N:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[CH:19][CH:18]=2)[C:4]([F:16])=[CH:5][CH:6]=1)[CH3:28]
Reactant: CC[Zn]CC
Reactant: COC(=O)c1cccc(-c2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2F)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1ccc(F)c(-c2cccc(C(=O)O)n2)c1F
Temperature: 70 °C

Procedure:
To a solution of methyl 6-(2,6-difluoro-3-(trifluoromethylsulfonyloxy)-phenyl)picolinate (1.0 equiv.) in toluene (0.15 M) was added Pd(dppf)Cl2-DCM (0.1 equiv.) followed by diethyl zinc (3.0 equiv.). The solution turned from orange to bright yellow. The reaction was heated to 70° C. for 2 hours at which time, LC/MS analysis indicated a mixture of 1:3:1 ratio of hydrolyzed product, desired product and unknown by-product. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with 1N NaOH (2×). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide a brown oil. The oil was redissolved in THF and treated with 1N NaOH for one hour. The reaction was then diluted with ethyl acetate and washed with 1N NaOH (2×). The basic washings were combined, acidified with concentrated HCl and extracted with ethyl acetate (3×). The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide 6-(3-ethyl-2,6-difluorophenyl)picolinic acid as a light brown oil in >99% yield. LC/MS=264.1 (M+H), Rt=0.88 min.
Reaction SMILES: Cl[C:2]1C=C(N2CCN(C)CC2)C=C[C:3]=1N.[Cl:16][C:17]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[NH:30][C:31]1[N:32]=[CH:33][C:34]2[CH:40]=[CH:39][C:38](=[O:41])[N:37]([C:42]3[CH:43]=[C:44]([NH:48][C:49](=O)[O:50]C(C)(C)C)[CH:45]=[CH:46][CH:47]=3)[C:35]=2[N:36]=1>>[Cl:16][C:17]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[NH:30][C:31]1[N:32]=[CH:33][C:34]2[CH:40]=[CH:39][C:38](=[O:41])[N:37]([C:42]3[CH:43]=[C:44]([NH:48][C:49](=[O:50])[CH:2]=[CH2:3])[CH:45]=[CH:46][CH:47]=3)[C:35]=2[N:36]=1
Reactant: CN1CCN(c2ccc(N)c(Cl)c2)CC1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(=O)n(-c5cccc(NC(=O)OC(C)(C)C)c5)c4n3)c(Cl)c2)CC1
Product: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4Cl)nc32)c1

Procedure:
The title compound was prepared according to the procedures described for Example 1, starting from 2-chloro-4-(4-methylpiperazin-1-yl)aniline (Aurum Pharmatech LLC, Wowell, N.J.). tert-Butyl (3-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (15a): m/z (ESI, +ve ion) 562.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:19])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.C([O-])(O)=O.[Na+]>CC(C)=O>[OH:19][C:9]1([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: COc1ccc(C2(O)CCC3(CC2)OCCO3)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(C2(O)CCC(=O)CC2)cn1

Procedure:
8-(6-Methoxy-pyridin-3-yl)-1,4-dioxa-spiro[4.5]decan-8-ol (4.00 g, 15.7 mmol) as prepared in the previous step was treated with 1N HCl (˜16 mL) in acetone (20 mL) at room temperature for 4 hours. The reaction was neutralized with saturated NaHCO3 solution and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a pale yellow solid.
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[O:19]([CH2:26][CH:27]1[CH2:29][O:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[OH:28][CH:27]([CH2:26][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:29][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:4]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:2]=[CH:1][C:6]1=2
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: c1ccc(OCC2CO2)cc1
Product: CCOC(=O)c1cc2c3ccccc3n(CC(O)COc3ccccc3)c2cn1

Procedure:
Following Representative Procedure 1, the title compound ethyl 9-(2-hydroxy-3-phenoxypropyl)-9H-pyrido[3,4-b]indole-3-carboxylate was prepared from Ethyl 9H-pyrido[3,4-b]indole-3-carboxylate and phenoxymethyloxirane in 67% yield.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)N>C(O)(=O)C.C(OCC)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CCOCC
Solvent: CC(=O)O
Product: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 150 °C
Yield: 70.1 %

Procedure:
A suspension of N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (500 mg, 2.24 mmol) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (564 mg, 2.24 mmol) in acetic acid (2.5 ml) was heated under microwave at 150° C. for 2 minutes. The crude mixture was diluted with diethyl ether and the precipitated solid was filtered, rinsed with ether and dried under vacuum to give the title compound as a white solid (675 mg, 70%); NMR spectrum: 3.79 (t, 2H), 4.31 (t, 2H), 5.26 (s, 2H), 7.18 (t, 1H), 7.25 (d, 1H), 7.29-7.33 (m, 2H), 7.44-7.49 (m, 1H), 7.57 (d, 1H), 7.87 (s, 1H), 8.27 (s, 1H), 8.47 (s, 1H); Mass Spectrum: 430 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:14])[N:4]([CH3:15])[CH:5]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: Oc1ncc(N2CCOCC2)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(N2CCOCC2)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 3-bromo-5-morpholinopyridin-2-ol (1.0 equiv.) in DMF (0.1 M) was added potassium carbonate (2.0 equiv.) and iodomethane (1.0 equiv.). The solution was stirred at room temperature for 3 hours. Partitioned between water and ethyl acetate, the organic phase was washed with brine, dried with sodium sulfate, filtered and concentrated to dryness. Isolated 3-bromo-1-methyl-5-morpholinopyridin-2(1H)-one in 87% yield. LCMS (m/z) (M+H)=273.0/275.0, Rt=0.41 min.
Reaction SMILES: [N:1]#[C:2]Br.[C:4]([NH:19][NH2:20])(=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O1CCOCC1.O>[NH2:1][C:2]1[O:18][C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:19][N:20]=1
Reactant: CCCCCCCCCCCCCC(=O)NN
Reactant: N#CBr
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCCCc1nnc(N)o1

Procedure:
Cyanogen bromide (2.9 g, 0.027 mol) was added to a mixture of the compound prepared in Step 1 above (6.1 g, 0.025) and KHCO3 (2.8 g, 0.028 mol) in dioxane/water (1:1, 50 mL) at room temperature. The mixture was refluxed for 1 hour, allowed to cool, filtered, washed with dioxane/water (1:1, 20 mL), then water (50 mL), and dried in vacuo. The solid was recrystallized from chloroform to yield 4.16 g, m.p. 147°-150° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[NH:7][C:8](=[O:14])[C:9]([O:11]CC)=O)([O-:3])=[O:2].[CH3:18][NH:19][CH3:20]>C(Cl)Cl>[CH3:18][N:19]([CH3:20])[C:9]([C:8]([NH:7][C:6]1[CH:15]=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:14])=[O:11]
Reactant: CNC
Reactant: CCOC(=O)C(=O)Nc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: CN(C)C(=O)C(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A solution of 11.91 gm. (0.05 mole) of ethyl 3-nitro-oxanilate in 500 ml. of methylene chloride is cooled to 5° in an ice bath. There is added slowly, 25 ml. of dimethylamine and the mixture stirred for two hours in an ice-bath. The ice-bath is removed and the mixture allowed to stand at room temperature overnight.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:39])C(=O)C1>C(Cl)Cl.O>[Cl:39][C:7]1[N:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)[C:9]2[C:5]([C:6]=1[S:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[F:11]
Reactant: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: CCCn1cc(-n2c(Cl)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1
Reaction time: 16 h
Yield: 63.5 %

Procedure:
To a stirred solution of compound 4 (150 mg, 0.32 mmol) in CH2Cl2 (3 mL) under inert atmosphere was added NCS (87 mg, 0.65 mmol) at RT. After 16 h stirring, NCS (87 mg, 0.65 mmol) was added again at RT and stirred for additional 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with water (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 7% EtOAc/n-Hexane to afford compound 5 (100 mg, 62%) as a brown solid. 1H NMR (500 MHz, CDCl3): δ 7.89 (s, 1H), 7.80-7.79 (m, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.28-7.26 (m, 3H), 7.17-7.14 (m, 1H), 4.33 (q, J=7.5 Hz, 2H), 4.18 (t, J=7.5 Hz, 2H), 2.00-1.95 (m, 2H), 1.36 (t, J=7.5 Hz, 3H), 0.98 (t, J=7.5 Hz, 3H); LC-MS (ESI): 97.6%; m/z 492.4 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 5.07 min; 5 mM NH4OAc: ACN; 0.8 mL/min).