Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8](Cl)[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[N:5]=1)[CH3:2].C(N(CC)CC)C.[NH2:25][CH:26]([CH2:28][CH3:29])[CH3:27]>C(O)C>[CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([NH:25][CH:26]([CH2:28][CH3:29])[CH3:27])[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[N:5]=1)[CH3:2]
Reactant: CCC(C)N
Reactant: CCNc1nc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCNc1nc(C(F)(F)F)nc(NC(C)CC)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 73.2 %

Procedure:
5.4 g (0.02 mol) of 4-ethylamino-6-chloro-5-nitro-2-trifluoromethyl-pyrimidine are dissolved in 100 ml of abs. ethanol. The solution is treated with 2.3 g of triethylamine (0.023 mol) and 1.7 g (0.023 mol) of 2-amino-butane and the mixture is stirred overnight. After the mixture has been evaporated, the product is taken up in water and extracted with ether to yield 4.5 g of 4-ethylamino-5-nitro-6-(2-butylamino)-2-trifluoromethyl-pyrimidine; nD20 = 1.5209.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([OH:13])(=O)=[O:11])=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([Cl:16])(=[O:13])=[O:11])=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)c1sccc1S(=O)(=O)Cl

Procedure:
7.4 G of crude 3-sulfothiophene-2-carboxylic acid methyl ester are dissolved in 50 ml. of thionyl chloride and boiled to reflux for 16 hours. The mixture is then evaporated to dryness in vacuo and the remaining bright-yellow oil is brought to crystallization with petroleum ether. There is obtained 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=1[Br:24])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:11].[C:25]([O-])(O)=O.[Na+]>CO>[Br:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=1[Br:24])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:25])=[O:19])=[O:11]
Reactant: O=C([O-])O
Reactant: O=C(O)CCCCCNC(=O)c1ccc(Br)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCNC(=O)c1ccc(Br)c(Br)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
Added conc. H2SO4 (0.2 mL) to a solution of N-(3,4-dibromobenzoyl)-6-aminohexanoic acid (1.73 g, 4.4 mmol) in methanol (50 mL). Heated under reflux for 2 hours until reaction complete (as determined by TLC). Allowed solution to cool to room temperature and neutralized by adding NaHCO3 solution. Removed solvent in vacuo and extracted residue with ether (2×50 mL). Washed extract with brine (2×30 mL) and dried over anhydrous MgSO4. Filtered extract and dried filtrate under high vacuum to afford a white solid. Obtained 1.72 g (96% yield) of methyl N-(3,4-dibromobenzoyl)-6-aminohexanoate. 1H NMR (300 MHz, DMSO-d6): δ8.59 (triplet, J=5.7 Hz, 1H), 8.16 (doublet, J=1.8 Hz, 1H), 7.84 (doublet, J=8.1 Hz, 1H), 7.73 (doublet of doublets, J=8.1, 1.8 Hz, 1H), 3.55 (singlet, 3H), 3.21 (doublet of triplets, J=6.0, 6.6 Hz, 2H), 2.28 (triplet J=7.3 Hz, 2H), 1.51 (multiplet, 4H), 1.28 (multiplet, 2H). 13C NMR (300 MHz, DMSO-d6): δ173.55, 164.05, 135.67, 133.96, 132.31, 128.20, 127.09, 124.13, 51.19, 39.20, 33.21, 28.56, 25.89, 24.15.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCNCC3)cnc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCN(S(C)(=O)=O)CC3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Piperidin-4-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.073 g, 0.158 mmol) was suspended in DCM (1 mL) and N,N-diisopropylethylamine (0.1 mL, 0.55 mmol) was added. Methanesulfonyl chloride (0.015 mL, 0.19 mmol) was added and the resulting solution stirred at RT overnight. The solvent was evaporated. The remaining semi-solid was purified by SiO2 chromatography (12 g SiO2, DCM/MeOH 0-4% MeOH). Obtained 0.065 g of 1-(1-methanesulfonyl-piperidin-4-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as an off-white solid (88% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+:30]>[OH-].[NH4+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([NH2:30])=[O:25])=[CH:27][CH:28]=4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)cc1
Agent: [Cl-]
Agent: [OH-]
Product: NC(=O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)cc1
Yield: 357.2 %

Procedure:
The product of example 45 (195 mg, 0.500 mmol) in concentrated ammonium hydroxide (5 mL) and ammonium chloride (1.00 mg) was heated in a sealed tube at 100° C. for 4 hours. The resulting precipitate was filtered, dried and purified by chromatography (SiO2, 80% ethyl acetate/hexanes) to provide the title compound (25 mg, 13% yield). 1H NMR (DMSO-d6) δ 13.24 (br s, 1H), 10.42 (s, 1H), 8.53 (s, 1H), 8.12 (s, 1H), 7.97 (m, 6H), 7.74 (d, 1H), 7.55 (m, 2H), 7.37 (t, 2H); ES-MS (m/z) 375 [M+1]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3](=[N:6][NH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]1.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>O>[O:1]1[CH2:5][CH2:4][CH:3]([NH:6][NH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]1
Reactant: O=C(NN=C1CCOC1)OCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(NNC1CCOC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Benzyl 2-[dihydrofuran-3(2H)-ylidene]hydrazinecarboxylate (14.8 g) was suspended in water (96 mL). Acetic acid (42.1 mL) was added to the suspension at room temperature. The mixture was stirred at room temperature for one hour. The suspension turned into a solution. Sodium cyanoborohydride (4.0 g) was added to the solution in small portions. The mixed solution was stirred at room temperature for two hours. The reaction mixture was cooled to 0° C. The reaction mixture was neutralized by adding a 5 N aqueous sodium hydroxide solution. The mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate, 5%). The title compound (13.9 g) was obtained.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].C(N(CC)CC)C.[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>C1C=CC=CC=1>[Cl:6][CH2:5][C:4]([O:7][C:17](=[O:18])[N:16]([CH3:20])[CH3:15])=[N:3][O:2][CH3:1]
Reactant: CONC(=O)CCl
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CON=C(CCl)OC(=O)N(C)C
Temperature: 25 °C

Procedure:
N-Methoxychloroacetamide (12.3 grams; 0.1 mole), benzene (75 ml) and triethylamine (12 grams; 1.2 mole) are charged into a glass reaction flask equipped with a mechanical stirrer, therometer and reflux condenser. N,N-Dimethylcarbamoyl chloride (11 grams; 0.1 mole) dissolved in benzene (25 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 3 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N,N-dimethylcarbamoyloxy)-2-methoxyiminoethane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[C:27]([OH:29])=[O:28])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:31]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:31][O:28][C:27]([C@H:19]1[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]1[S:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:16])=[O:17])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)[C@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 335.8 %

Procedure:
A solution of the title A compound, (R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylic acid (5.55 g, 13.6 mmol) and p-toluenesulfonic acid monohydrate (0.52 g, 2.7 mmol) in methanol (260 mL) is heated under nitrogen at reflux for 4 hours. The solution is allowed to stand overnight at room temperature which results in the formation of a crystalline solid. The crystals are collected by vacuum filtration and dried at high vacuum. A second crop of crystals is obtained from the mother liquor that is isolated and dried at high vacuum. A combined yield of 3.84 g of (R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylic acid methyl ester is obtained as a pure crystalline product: [M+1]+=424.27.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[CH:23]1([CH:26]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([OH:39])[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH:23]1([CH:26]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([O:39][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=4[F:22])=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=3)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1
Reactant: CCOC(=O)CC(c1ccnc(O)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(CBr)nc2CC(C)(C)C)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1ccnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 6-(bromomethyl)-3-(2-fluoro-5-methoxyphenyl)-2-neopentylpyridine (200 mg) in toluene (3.0 mL) were added ethyl 3-cyclopropyl-3-(2-hydroxypyridin-4-yl)propanoate (141 mg) and silver carbonate (166 mg), and the mixture was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature, and filtered. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (218 mg) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:18])(=O)=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1ccc(C(=O)O)cc1C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Nc1c(Cl)cc(C(=O)O)cc1C(F)(F)F

Procedure:
7.8 g (40 mmol) of 4-amino-5-trifluoromethylbenzoic acid in 80 ml of chloroform are placed in a 500 ml round-bottomed flask in the presence of 9.97 ml (50 mmol) of sulphuryl chloride, and the mixture is stirred under reflux overnight.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:23]=[O:24].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([O:28][C:27]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[CH2:19][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)COc1ccc(C=O)cc1CCl
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(C=O)cc1Cn1c(-c2ccccc2)cc2ccccc21
Temperature: 0 °C
Yield: 35.5 %

Procedure:
To a solution of 2-phenyl-1H-indole (0.94 g, 4.85 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.19 g, 4.85 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 5 min. 3-(Chloromethyl)-4-isobutoxybenzaldehyde (1.0 g, 4.41 mmol) and sodium iodide (0.73 g, 4.85 mmol) were added to the obtained mixture and the mixture was stirred at the same temperature for 2 hr. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the mixture was washed with 5% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give the title compound (0.60 g, yield 36%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][Br:20])=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccc(OCc2ccccc2)c(F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1cc(CCBr)ccc1OCc1ccccc1
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 2-(4-benzyloxy-3-fluoro-phenyl)-ethanol (1.0 g, 4.0 mmol) and CBr4 (1.5 g, 4.5 mmol) in CH2Cl2 (10 mL), was PPh3 (1.2 g, 4.5 mmol) added portionwise at 0° C. The reaction mixture stirred for 2 hours at the same temperature. The reaction was concentrated under vacuum and the residue was stirred in ether (10 mmol). The solid, mainly triphenylphosphine oxide, was filtrated off and the filtrate was concentrated under vacuum. The residue was purified over SiO2 to afford the desired compound (1.15 g, 93.5%) as a white crystal. 1H NMR (400 MHz, DMSO-d6) δ 7.36-7.49 (m, 5H), 7.17-7.23 (m, 2H), 7.03-7.05 (m, 1H), 5.18 (s, 2H), 3.72 (t, 2H), 3.08 (t, 2H). LCMS 273.4 [MH+].
Reaction SMILES: C([N:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:6]1(=[O:21])=[O:20])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:7]2[CH2:8][CH2:9][NH:5][S:6]2(=[O:21])=[O:20])=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: CC(C)(C)N1CCN(Cc2ccc([N+](=O)[O-])cc2)S1(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(CN2CCNS2(=O)=O)cc1
Reaction time: 48 h
Yield: 78.4 %

Procedure:
A solution of the product from Step 1 (1.5 g) in anhydrous dichloromethane (10 ml) and trifluoroacetic acid (10 ml) was allowed to stand at room temperature for 48 hours. Solvents were removed under vacuum and the remaining residue was azeotroped with methanol (1×25 ml) and crystallised from ethyl acetate-hexane to give 966 mg (78%) of the title compound as a pale yellow solid; mp 115°-117° C.; δH (250 MHz, CDCl3) 8.23 (2H, d, J=8.8 Hz, Ar--H), 7.57 (2H, d, J=8.8 Hz, Ar--H), 4.38 (1H, br t, --NH--), 4.29 (2H, s, Ar--CH2 --), 3.54 (2H, q, J=6.6 Hz, --CH2 --NH--), 3.34 (2H, t, J=6.6 Hz, --CH2 --).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)[CH3:2].[N:15]([O-:17])=[O:16].[Na+]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[N+:15]([O-:17])=[O:16])[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)[CH3:2]
Reactant: O=N[O-]
Reactant: CCOc1ccc2c(c1)CCC(=O)N2
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
To the solution of 6-ethoxy-3,4-dihydroquinolin-2(1H)-one (72.3 g, 0.38 mol, 1 equiv) in TFA (800 mL) was added NaNO2 (33.7 g, 0.496 mol, 1.3 equiv) at 0° C. The solution was allowed to warm to room temperature and stirring was continued for 4 hours. The mixture was poured into ice and the yellow precipitate was isolated via filtration and dried under high vacuum at 50° C. The crude product was recrystallized from ethyl acetate to afford 6-(ethyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (69.2 g, 77% yield). 1H NMR (400 MHz, DMSO) δ 1.31 (t, J=6.8 Hz, 3H), 2.45-2.49 (m, 2 H), 2.95 (t, 2 H, J=6.4 Hz), 4.13-4.15 (m, 2 H), 7.25 (s, 1 H), 7.34 (s, 1 H), 10.16 (bs, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>ClCCl>[N+:14]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[CH:6]=[CH:7]2)([O-:16])=[O:15]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc2c(ccn2CCCCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(ccn2CCCN2CCOCC2)c1
Temperature: 81 °C
Reaction time: 68 h
Yield: 101.2 %

Procedure:
To a small reaction vial containing a magnetic stirbar was added compound 38 (155 mg, 0.649 mmol), potassium iodide (1.078 g, 6.49 mmol) and potassium carbonate (898.0 mg, 6.49 mmol). The vial was sealed and purged with argon. Anhydrous acetonitrile (4 mL) was added through the septum, followed by morpholine (0.57 mL, 6.54 mmol). The vial was placed in the heating block and stirred at 81° C. for 68 hours. The reaction was cooled to room temperature. The non-homogenous reaction was diluted with dichloromethane (5 mL) and filtered through celite. Additional dichloromethane (10 mL) followed by methanol (5 mL) was used to wash the celite plug. The filtrate was concentrated on the rotary evaporator and dried further under high vacuum. The product was purified using silica gel column chromatography (2M NH3 in methanol:CH2Cl2, 5:95) to obtain compound 39 (190 mg, 100%) as a yellow oil. 1H NMR (CDCl3) δ 8.59 (d, J=2.1 Hz, 1H), 8.11 (dd, J=2.7, 9.0 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 7.28 (d, J=3.3 Hz, 1H), 6.69 (d, J=3.0 Hz, 1H), 4.30 (t, J=6.3 Hz, 2H), 3.75 (brs, 4H), 2.41 (brs, 4H), 2.27 (brs, 2H), 2.04 (brs, 2H); ESI-MS (m/z, %): 290 (M+1, 100).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=2[CH:18]=O)[C:13]#[N:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:34]>>[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[C:26]([CH2:18][C:17]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])=[C:25]1[CH3:34]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: N#Cc1ccc(C=O)c(S(=O)(=O)c2ccccc2)c1
Product: COC(=O)Cn1c(C)c(Cc2ccc(C#N)cc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 3-benzenesulfonyl-4-formylbenzonitrile and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1ccc2c(c1)CCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1nccc(N2CCc3ccccc32)n1
Yield: 49.6 %

Procedure:
A solution of 2,4-dichloropyrimidine (596 mg, 4.0 mmol), indoline (0.45 ml, 4.0 mmol) and N,N-diisopropylethylamine (0.69 ml, 4.0 mmol) in n-butanol (20 ml) was heated at 100° C. for 18 hours. Silica (3 g) was added and volatile material was removed by evaporation. The residue was purified by column chromatography, eluting with 0-40% ethyl acetate/isohexane, to give the product as a colourless solid (460 mg, 50%). NMR (CDCl3): 3.2 (t, 2H), 4.0-4.1 (t, 2H), 6.5 (d, 1H), 7.0-7.1 (m, 1H) 7.2-7.3 (m, 2H), 8.2 (m, 1H), 8.3-8.4 (m, 1H); MS (MH+): 232.7.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[C:9]1([CH2:15][CH:16]=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][CH:16]=[CH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNc1ccccn1
Reactant: O=CCc1ccccc1
Product: C(=Cc1ccccc1)NNc1ccccn1
Yield: 100 %

Procedure:
React Pyridin-2-yl-hydrazine and Phenyl-acetaldehyde under literature conditions (Azaindoles. I. Preparation of 7-azaindoles by thermal indolization of 2-pyridylhydrazones. Canadian Journal of Chemistry (1966), 44(21), 2455-9) to give N-Pyridin-2-yl-N′-styryl-hydrazine (10 g, 100% yield crude material) Mass Spectrum (m/e): 211.96 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:24]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:32]2[CH2:33][CH2:34][CH:29]([C:25]3[N:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)=[CH:8][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)n1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(F)c(F)c4)cc3)CC2)n1

Procedure:
Prepared by Procedure AA and Scheme AJ using 4-(3,4-difluorophenoxy)benzaldehyde and 2-methyl-N-[6-(4-piperidinyl)-2-pyridinyl]propanamide: ESMS m/e: 466.0 (M+H)+.
Reaction SMILES: [CH:1]1([CH:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][CH:8]=[C:9]([F:11])[F:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH:1]1([CH:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][CH:8]=[C:9]([F:10])[F:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=C(F)F)C4CCCC4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)=CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 4-[1-(1-cyclopentyl-4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(tri-methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (41 mg, 0.086 mmol) in DCM (3 mL) and TFA (1.5 mL) was stirred for two hours at room temperature. The solution was then concentrated in vacuo. The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL) was added. After stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the desired product (39 mg, 98%).