Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]3[N:19]([CH2:20][CH2:21]O)[C:18]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[N:17][N:16]=3)[N:9]=2)[CH:7]=1.CCN(S(F)(F)[F:35])CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]3[N:19]([CH2:20][CH2:21][F:35])[C:18]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[N:17][N:16]=3)[N:9]=2)[CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCn1c(SCc2noc(-c3cc(Cl)ccc3F)n2)nnc1-c1cccs1
Solvent: C1CCOC1
Product: FCCn1c(SCc2noc(-c3cc(Cl)ccc3F)n2)nnc1-c1cccs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
To a cooled (−15° C.) solution of 2-{3-[5-(5-chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-[1,2,4]triazol-4-yl}-ethanol (46 mg, 0.11 mmol) in anhydrous THF (15 ml) was dropwise added DAST (32 ml, 0.24 mmol). The mixture was stirred at room temperature for 1.5 h and was then quenched with MeOH (1 ml). The solvent was removed under reduced pressure and the residue was partitioned between brine and EtOAc. The aqueous layer was extracted with EtOAc (2×20 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (EtOAc:heptane 2:1) and preparative HPLC afforded the title compound as a white solid (11 mg, 22%). 1H NMR (CDCl3) d (ppm): 8.05 (dd, 1H), 7.52 (m, 3H), 7.20 (m, 1H), 7.16 (m, 1H), 4.75 (t, 1H), 4.63 (m, 3H), 4.45 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](=[S:15])[NH:12][C:13]=2[CH3:14])[CH:2]=1.CI.[O-][CH2:20]C.[Na+]>C(O)C>[CH3:20][S:15][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:13]([CH3:14])[N:12]=1
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1Cc1cccnc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSc1nc(C)c(Cc2cccnc2)c(=O)[nH]1

Procedure:
Treatment of 5-(3-pyridylmethyl)-6-methyl-2-thiouracil with methyl iodide and sodium ethoxide in ethanol at 0° followed by acidification gave 2-methylthio-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone m.p. 208°-211°.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH2:16][CH2:15]2.O>CN(C=O)C>[Br:8][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([F:9])[CH:11]=1)[NH:18][C:17](=[O:20])[CH2:16][CH2:15]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2cccc(F)c2N1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(Br)cc(F)c2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
NBS (0.62 g, 3.5 mmol) dissolved in DMF (5 mL) was added to a solution of 8-fluoro-3,4-dihydro-1H-quinolin-2-one (0.52 g, 3.2 mmol) in DMF (5 mL) dropwise at 0° C. The resulting reaction mixture was stirred at room temperature for 12 hr before it was treated with water. The precipitated solid was collected through filtration, washed with ether, and dried over vacuum to afford title compound (0.65 g, 85% yield) as a white solid. MS: 244.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=O)[N:6]([CH3:8])[CH:7]=1)#[N:2].[NH2:11]CC1N(C)C(C#N)=CC=1>>[NH2:11][CH2:9][C:5]1[N:6]([CH3:8])[CH:7]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: Cn1c(C#N)ccc1CN
Reactant: Cn1cc(C#N)cc1C=O
Product: Cn1cc(C#N)cc1CN

Procedure:
5-Aminomethyl-1-methylpyrrole-3-carbonitrile were prepared starting from 4-cyano-1-methylpyrrole-2-carbaldehyde similar to the synthesis of 5-aminomethyl-1-methylpyrrole-2-carbonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2.[OH-].[K+].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.[Na+].[I-]>CN(C=O)C.O>[CH3:27][O:26][C:24]([C:23]1[CH:28]=[CH:29][C:20]([CH2:19][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH:10]=[C:9]([S:12]([OH:15])(=[O:13])=[O:14])[CH:8]=[CH:7]3)=[CH:21][CH:22]=1)=[O:25]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=S(=O)(O)c1ccc2cccc(O)c2c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(COc2cccc3ccc(S(=O)(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.9 %

Procedure:
8-Hydroxynaphthalene-2-sulfonic acid (110 mg, 0.49 mmol), KOH (110 mg, 1.96 mmol), methyl 4-(bromomethyl)benzoate (112 mg, 0.49 mmol) and NaI (7.4 mg, 0.49 mmol) were stirred in DMF (1.0 mL) at room temperature for 1 h and then at 60° C. for 72 h. The reaction mixture was cooled to room temperature, diluted with water and purified using preparative HPLC to give the title compound (60 mg, 31%). MS(ESI−) m/z 371.3 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([CH2:8][Br:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccnc1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccnc1Br

Procedure:
Synthesized from 2-bromo-3-methylpyridine (5.00 g, 29.1 mmol), NBS (5.69 g, 32.0 mmol) and DBPO (352 mg, 1.46 mmol) in CCl4 according to Method A. Yield: 2.87 g, 11.4 mmol, 39%. This compound was directly used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH2:14][OH:15])=[C:12]([CH3:16])[N:11]=[C:10]3[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:9]=23)[CH:5]=[CH:4][N:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH:14]=[O:15])=[C:12]([CH3:16])[N:11]=[C:10]3[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:9]=23)[CH:5]=[CH:4][N:3]=1
Reactant: CCn1ncc2c(-c3ccnc(Cl)c3)c(CO)c(C)nc21
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCn1ncc2c(-c3ccnc(Cl)c3)c(C=O)c(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A mixture of [4-(2-chloro-4-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (30 mg), pyridinium chlorochromate (34.2 mg), sodium acetate (5.7 mg) in DCM (2 ml) was stirred at room temperature for 2 hours. The reaction mixture was diluted with diethylether and filtrated through celite pad. After evaporation of filtrate, the residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:4) to give 4-(2-chloro-4-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (29 mg) as a white crystal.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](N)[CH:8]=2)[CH:3]=[N:2]1.F[B-](F)(F)F.[H+].N([O-])=[O:18].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:18])[CH:8]=2)[CH:3]=[N:2]1
Reactant: O=N[O-]
Reactant: Nc1ccc2cn[nH]c2c1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [H+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2cn[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Indazol-6-amine (24.33 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) was dissolved in water (100 mL) and 48% by weight of tetrafluoroboric acid solution (242 mL; manufactured by Sigma-Aldrich Co.). After cooling to 0° C., an aqueous solution of sodium nitrite [20 mL (sodium nitrite (13.87 g; manufactured by Kanto Chemical Co., Inc.) was dissolved in water (20 mL) to give the solution] was added dropwise thereto for 10 minutes, followed by stirring at 0° C. for 30 minutes. The precipitate from the reaction solution was filtered and washed with chloroform. Thus-obtained precipitate was dissolved in acetic acid (250 mL) and stirred for 10 minutes at 50° C., 10 minutes at 110° C., and 10 minutes at 130° C. The reaction solution was cooled and added with a saturated aqueous solution of sodium carbonate, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then dried. Thereafter, the solvent was evaporated under reduced pressure. Thus-obtained residue was dissolved in ethanol (240 mL), added with an aqueous solution of 2 mol/L-sodium hydroxide (365 mL), followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 2 mol/L-hydrochloric acid (200 mL), water and a saturated aqueous solution of ammonium chloride were added to the residue to obtain pH 7 approximately, and the extraction was carried out with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue, chloroform was added, and then the insoluble matters were filtered, washed with chloroform to obtain the target compound as a crude product (13.5401 g).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:40]([CH3:42])[CH3:41])[C:8]2[O:12][C:11]([C:13]3[CH:38]=[CH:37][C:16]([C:17]([NH:19][CH2:20][C:21]4([CH3:36])[O:25][C:24](=[O:26])[N:23](CC5C=CC(OC)=CC=5)[CH2:22]4)=[O:18])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH:39]=1)#[N:4].Cl[C:44]1[N:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][N:45]=1>CN(C)C=O>[C:3]([C:5]1[CH:6]=[C:7]([CH:40]([CH3:42])[CH3:41])[C:8]2[O:12][C:11]([C:13]3[CH:38]=[CH:37][C:16]([C:17]([NH:19][CH2:20][C:21]4([CH3:36])[O:25][C:24](=[O:26])[N:23]([C:44]5[N:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][N:45]=5)[CH2:22]4)=[O:18])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH:39]=1)#[N:4]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: COc1ccc(CN2CC(C)(CNC(=O)c3ccc(-c4nc5cc(C#N)cc(C(C)C)c5o4)cc3)OC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5nccc(C(F)(F)F)n5)C(=O)O4)cc3)oc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a mixture was sodium hydride (9 mg, 60% dispersion) in 5 ml of dimethylformamide was added 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-[(5-methyl-2-oxo-1,3-oxazolidin-5-yl)methyl]benzamide (31 mg, EXAMPLE 65) followed by 2-chloro-4-trifluoromethylpyrimidine (14 mg). The mixture was stirred at 70° C. for 1 h. Excess sodium hydride was quenched by addition of 1 ml of methanol. The sample was then purified via mass-directed HPLC on a Kromasil C18 column eluting with a gradient of 10% acetonitrile in water (0.01% TFA) to 60% acetonitrile in water (0.01% TFA) providing the title compound (25 mg, 59%). Mass spectrum (ESI) 565.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.94 (d, J=3.9 Hz, 1H), 8.33 (d, J=7.8 Hz, 2H), 7.95 (s, 1H), 7.94 (d, J=7.3 Hz, 2H), 7.52 (s, 1H), 7.36 (d, J=4.1 Hz, 1H), 6.69 (bs, 1H), 4.26 (d, J=11.2 Hz, 1H), 4.12 (d, J=10.7 Hz, 1H), 3.99 (dd, J=14.6, 6.2 Hz, 1H), 3.55 (dd, J=14.8, 6.1 Hz, 1H), 3.48 (sept, J=6.5 Hz, 1H), 1.66 (s, 3H), 1.46 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:5]=2[CH:6]=1.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[O:13][N:23]=[C:16]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[N:15]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: NC(=NO)c1cccnc1
Reactant: Cc1cc2cc(C(=O)O)ccc2o1
Agent: N
Product: Cc1cc2cc(-c3nc(-c4cccnc4)no3)ccc2o1

Procedure:
The title compound was prepared according to Method C using 2-methylbenzofuran-5-carboxylic acid (Chembridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 3.33 (s, 3 H), 6.58-6.97 (m, 1 H), 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 7.78 (d, J=8.5 Hz, 1 H), 8.40-8.55 (m, 2 H), 8.82 (dd, J=4.7, 1.7 Hz, 1 H), 9.27 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O.C(N(CC)C(C)C)(C)C.Cl.Cl.[CH2:32]([O:39][C:40](=[O:48])[CH2:41][C@@H:42]([NH2:47])[CH2:43][N:44]([CH3:46])[CH3:45])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH2:32]([O:39][C:40](=[O:48])[CH2:41][C@@H:42]([NH:47][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]1[CH:17]=[CH:18][C:19]([F:20])=[C:2]([F:1])[CH:3]=1)[CH2:43][N:44]([CH3:45])[CH3:46])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)CCCCCCCOCc1ccc(F)c(F)c1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
A solution of 8-(3,4-difluoro-benzyloxy)-octanoic acid (153 mg, 0.53 mmol), N,N-diisopropylethylamine (414 mg, 3.21 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexaflurophophate (244 mg, 0.64 mmol) in N,N-dimethylformamide was stirred for 1 h at room temperature, then a solution of (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride (198 mg, 0.64 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred for 16 h at room temperature, then evaporated. Chromatography (SiO2, dichloromethane-[dichloromethane/methanol/25% aq. ammonia solution 110:10:1] gradient) produced (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester (136 mg, 50%). Light yellow oil, m/e=505.4 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13]CC(C)=C)[C:6]([O:8][CH3:9])=[O:7]>CN1C(=O)CCC1>[OH:13][C:12]1[C:11]([CH2:6][C:5]([CH3:10])=[CH2:4])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: C=C(C)COc1ccc(C(=O)OC)cc1OC
Solvent: CN1CCCC1=O
Product: C=C(C)Cc1cc(C(=O)OC)cc(OC)c1O
Yield: 230.9 %

Procedure:
A solution of methyl 3-methoxy-4-(2-methylallyloxy)benzoate (130 g, 0.55 mol) in NMP (500 mL) was heated to reflux for 6 h. TLC (EtOAc/petroleum ether=1/5) showed the reaction was complete. The mixture was washed with 1 N aq. HCl and extracted with EtOAc (250 mL×3). The combined organic phases were washed with brine (400 mL), dried over Na2SO4 and concentrated to give the product (150 g, 100%) as a brown oil. The oil was used directly to the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=O)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[I:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[O:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1O)c1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Ic1ccc(-c2nc3ccccc3o2)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
In a 300 mL three-neck flask were put 15 g (44 mmol) of 4-iodo-N-(2-hydroxyphenyl)benzamide and 24 g (0.14 mol) of para-toluenesulfonic acid monohydrate. The atmosphere in the flask was replaced with nitrogen. To this mixture was added 300 mL of toluene. The resulting mixture was stirred under a nitrogen stream at 110° C. for 4 hours. After that, this reaction mixture was added to about 300 mL of water, followed by extraction with ethyl acetate. Then, the organic layer and the extract were combined and washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order. After that, magnesium sulfate was added to the organic layer to dry it. Next, this mixture was suction filtered through Celite. The resulting filtrate was concentrated to give a solid. This solid was recrystallized with a mixed solvent of ethyl acetate and hexane to give 11 g of a white solid in a yield of 75%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH3:14][CH:15]([NH:17][C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:16].C(N=C=NCCCN(C)C)C>>[CH3:13][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([CH3:1])[C:10]=1[O:11][CH3:12])[C:5]([N:27]1[CH2:28][CH2:29][N:24]([C:19]2[C:18]([NH:17][CH:15]([CH3:16])[CH3:14])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:25][CH2:26]1)=[O:7]
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Reactant: COc1c(C)cc(C(=O)O)cc1C
Agent: CCN=C=NCCCN(C)C
Product: COc1c(C)cc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1C

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 3,5-dimethyl-4-methoxybenzoic acid (0.075 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.101 g) and 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.096 g), the title compound is obtained, mp 89°-93°.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[CH:6]=[C:5]([CH3:11])[N:4]=1.I[CH3:13]>>[CH3:13][N:4]1[C:5]([CH3:11])=[CH:6][C:7](=[O:9])[NH:8][C:3]1=[O:2]
Reactant: CI
Reactant: COc1cc(C)nc(OC)n1
Product: Cc1cc(=O)[nH]c(=O)n1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
14.2 g (92 mmol) 2,4-dimethoxy-6-methylpyrimidine was dissolved in 210 mL iodomethane and the reaction allowed to continue for 2 days at room temperature. After 2 days, the excess of iodomethane was evaporated off under reduced pressure, the residue treated with 675 mL 1 N HCl and the resulting mixture refluxed for one and a half hours. After cooling to room temperature and neutralization with a concentrated sodium hydroxide solution, the water was removed under reduced pressure and the residue extracted with chloroform using a Soxhlet extractor. The chloroform was evaporated under reduced pressure and the crude compound recrystallized first from ethanol and then from water yielding 4.03 g (31%) of 1,6-dimethyluracil (m.p. 221–223° C.).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:27])[C:7]([CH2:16][C:17]1[C:25]2[C:20](=[C:21]([Cl:26])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)([NH:13][CH:14]=[O:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[CH3:28]I>CS(C)=O>[CH2:11]([O:10][C:8](=[O:9])[C:7]([CH2:16][C:17]1[C:25]2[C:20](=[C:21]([Cl:26])[CH:22]=[CH:23][CH:24]=2)[N:19]([CH3:28])[CH:18]=1)([NH:13][CH:14]=[O:15])[C:6]([O:5][CH2:3][CH3:4])=[O:27])[CH3:12]
Reactant: CCOC(=O)C(Cc1c[nH]c2c(Cl)cccc12)(NC=O)C(=O)OCC
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)C(Cc1cn(C)c2c(Cl)cccc12)(NC=O)C(=O)OCC
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a suspension of DMSO (5 mL) and KOH (229 mg, 4.1 mmol) was added 2-(7-Chloro-1H-indol-3-ylmethyl)-2-formylamino-malonic acid diethyl ester (500 mg, 1.4 mmol), followed by MeI (0.127 mL, 2 mmol) at 0° C. The reaction mixture was stirred for 4 hr. After the usual workup the product was purified by column chromatography on silica gel using 30% ethyl acetate-hexane to give 2-(7-Chloro-1-methyl-1H-indol-3-ylmethyl)-2-formylamino-malonic acid diethyl ester (402 mg, 77%): mp 83-87° C., 1H NMR (500 MHz, CDCl3): 1.28 (t, J=7.5 Hz, 6H), 3.81 (s, 2H), 4.08 (s, 3H), 4.17-4.31 (m, 4H), 6.71 (s, 1H), 6.93 (dd, J=7.5 and 7.5 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 8.18 (d, J=1.0 Hz, 1H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[C:19](O)([CH3:28])[CH2:20][NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23]>C(Cl)Cl>[F:7][C:19]([C:12]1[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=1[F:10])([CH3:28])[CH2:20][NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(C(C)(O)CNS(=O)(=O)C(C)C)c(F)c1
Solvent: ClCCl
Product: COc1ccc(C(C)(F)CNS(=O)(=O)C(C)C)c(F)c1
Yield: 64.1 %

Procedure:
A dry CH2Cl2 solution (10 mL) of (diethylamino)sulfur trifluoride (DAST) (0.419 mL, 3.17 mmol) was cooled to −78° C. while stirring under N2. A CH2Cl2 solution (5 mL) of propane-2-sulfonic acid [2-(2-fluoro-4-methoxyphenyl)-2-hydroxy-propyl]-amide (0.79 g, 2.64 mmol) was added dropwise via syringe and the reaction was immediately brought to 0° C. The reaction was quenched with water and diluted with diethyl ether. The organic layer was separated and washed with water and saturated NaCl solution, dried (MgSO4), filtered, and concentrated to a yellow oil. The crude residue was purified by silica gel chromatography, eluting with 30% ethyl acetate/hexanes, to provide the final title compound, propane-2-sulfonic acid [2-fluoro-2-(2-fluoro-4-methoxy-phenyl)-propyl]-amide, (0.52 g, 64%) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2)[C:4]([OH:6])=O.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:33][NH:34][O:35][CH3:36]>C(Cl)Cl>[CH3:36][O:35][N:34]([CH3:33])[C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: CNOC
Reactant: COC(C(=O)O)c1cccc2ncccc12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(C(=O)N(C)OC)c1cccc2ncccc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60 %

Procedure:
To an ice-cold solution of 2-methoxy-2-(quinolin-5-yl)acetic acid (2.8 g, 12.9 mmol) in anhydrous CH2Cl2 (50 mL) and NMM (3.1 mL, 29 mmol) under argon was added isobutyl chloroformate (1.9 mL, 14 mmol) dropwise. After stirring over an ice bath for 40 min, N,O-dimethylhydroxylamine hydrochloride (1.63 g, 16.8 mmol) was added in three aliquots over a period of 15 min. The mixture was stirred for 15 min then the ice bath was removed. After 24 hrs, saturated aqueous NaHCO3 was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaHCO3, H2O and brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-100% EtOAc-hexanes) gave N,2-dimethoxy-N-methyl-2-(quinolin-5-yl)acetamide as an oil which became crystalline upon standing (1.8 g, 60% yield).
Reaction SMILES: O[C:2]1[C:11]([CH:12]([CH:15]=[CH2:16])[CH2:13][OH:14])=[CH:10][C:9]([CH3:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:18])[NH:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.Cl>N1C=CC=CC=1.CO>[CH3:17][C:9]1[CH:10]=[C:11]2[CH:12]([CH:15]=[CH2:16])[CH2:13][O:14][C:2]2=[C:3]2[C:8]=1[NH:7][C:6](=[O:18])[CH:5]=[CH:4]2
Reactant: C=CC(CO)c1cc(C)c2[nH]c(=O)ccc2c1O
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: C=CC1COc2c1cc(C)c1[nH]c(=O)ccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
5-Hydroxy-6-(2-hydroxy-1-vinylethyl)-8methylcarbostyril (7.2 g) was dissolved in pyridine (50 ml), to which triphenylphosphine (25.0 g) and carbon tetrachloride (15 ml) were added in this order, followed by stirring at 60° C. for 3 hours. Methanol (50 ml) was added thereto and stirred for 1 hour. The reaction mixture was filtered. The filtrate was condensed under reduced pressure, to which 1N-HCl was added. Extraction was performed with chloroform. The chloroform phase was dried, and the solvent was evaporated. The residue was recrystallized from a solvent mixture of chloroform-ethyl acetate-ether to obtain 6.4 g of 5-methyl-2,3,6,7-tetrahydro-3-vinylfuro[2,3-f]quinoline-7-one as colorless powdery crystals (95.9%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]([O:9]C)=O.O.[NH2:12][NH2:13]>CCO>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[C:7]([NH:12][NH2:13])=[O:9]
Reactant: NN
Reactant: COC(=O)c1ncccn1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ncccn1
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
To a slurry of methyl pyrimidine-2-carboxylate (1.0 g, 7.2 mmol) in EtOH (5.6 mL) was added hydrazine monohydrate (0.72 mL, 14 mmol). The reaction mixture became homogeneous and after 5 min a precipitate formed. Stirring was continued for 1 h. The mixture was filtered, and the collected solid was washed with additional EtOH to provide the desired product as a beige solid (720 mg, 72%). MS (ESI): mass calcd. for C5H6N4O, 138.1; m/z found, 139.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.92 (d, J=4.9 Hz, 2H), 7.64 (t, J=4.9 Hz, 1H), 4.64 (s, 2H).