Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[NH2:18][OH:19].[OH-].[K+].CO>C1COCC1>[OH:19][NH:18][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCSc1ccc(Cl)cc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCCCCSc1ccc(Cl)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 6-(4-chlorophenylsulfanyl)-hexanoic acid methyl ester (0.59 g, 2.2 mmol) in distilled THF (13 mL) containing 50% aqueous hydroxylamine (1.3 mL, 19.6 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 3.5 mL, 3.5 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (13 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×25 mL) and the combined extracts were washed with brine (20 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (0.54 g, 90%) as a white powder, mp 83-85° C.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:18]([NH2:20])=[O:19])[C:13]=3[C:14]([NH:16][CH3:17])=[O:15])[C:4]=2[CH:3]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C@:29]([OH:33])([C:31]#[CH:32])[CH3:30])[CH:25]=1>>[OH:33][C@:29]([C:26]1[CH:25]=[C:24]([CH3:23])[O:28][N:27]=1)([CH3:30])[C:31]#[C:32][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:18]([NH2:20])=[O:19])[C:13]=3[C:14]([NH:16][CH3:17])=[O:15])[C:4]=2[CH:3]=1
Reactant: CNC(=O)c1c(C(N)=O)nn2c1CCOc1ccc(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: CNC(=O)c1c(C(N)=O)nn2c1CCOc1ccc(C#C[C@@](C)(O)c3cc(C)on3)cc1-2
Yield: 26 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-N3-methyl-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2,3-dicarboxamide was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (37 mg, 26%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:52]=[CH:51][CH:50]=C[C:46]=1[C:47]#[N:48]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:51][CH:52]=[CH:45][C:46]=3[C:47]#[N:48])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccccc1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3C#N)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)benzonitrile and isolated as white solid (6.8 mg, 41%). MS(m/e): 398.3 (MH+).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl[CH2:22][C:23]([CH3:25])=[CH2:24]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]([CH2:24][C:23]([CH3:25])=[CH2:22])[C:2](=[O:3])[CH3:1])=[CH:6][CH:7]=1
Reactant: COc1ccc(NC(C)=O)cc1
Reactant: C=C(C)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(C)CN(C(C)=O)c1ccc(OC)cc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of p-acetanisidide (1.00 g, 6.05 mmol), potassium carbonate (0.92 g, 6.7 mmol), sodium hydroxide (0.27 g, 6.8 mmol) and tetra-n-butylammoniumbromide (0.39 g, 1.2 mmol) in 10 mL of toluene was added 3-chloro-2-methyl-1-propene (0.71 mL, 7.3 mmol) at room temperature. After the reaction mixture was stirred at 75° C. for 4 h, the reaction mixture was cooled to room temperature, and was diluted with ethyl acetate. The solution was washed with water, 3 M HCl, saturated NaHCO3 aqueous solution and brine, successively, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 60/40) to obtain the title compound (1.26 g, 95%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]([OH:21])=O)[CH:10]=2)[S:3]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH2:50])=[CH:47][CH:46]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH:50][C:19](=[O:21])[CH2:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:10]2)=[CH:47][CH:46]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)Cn1cc(C=C2SC(=O)NC2=O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Cn1cc(C=C2SC(=O)NC2=O)c2ccccc21)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indol-1-yl]acetic acid (example 300, 90.7 mg, 0.3 mmol) was dissolved in NMP (1 mL) and added to a mixture of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (86.4 mg, 0.45 mmol) and 1-hydroxybenzotriazol (68.8 mg, 0.45 mmol) in NMP (1 mL). The resulting mixture was shaken at RT for 2 h. 4-Chlorobenzylamine (51 mg, 0.36 mmol) and DIPEA (46.4 mg, 0.36 mmol) in NMP (1 mL) were added to the mixture resulting mixture shaken at RT for 2 days. Subsequently ethyl acetate (10 mL) was added and the resulting mixture washed with 2×10 mL water followed by saturated ammonium chloride (5 mL). The organic phase was evaporated to dryness giving 75 mg (57%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2>>[O:10]1[C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:16]3[C:15]4[C:19](=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=4)[NH:18][C:17]3=[O:22])=[CH:11][C:7]=2[CH2:8][CH2:9]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=Cc1ccc2c(c1)CCO2
Product: O=C1Nc2ccc(F)cc2C1=Cc1ccc2c(c1)CCO2

Procedure:
2,3-Dihydro-5-formylbenzofuran (commercially available) was condensed with 5-fluoro-2-oxindole to give 0.25 g of 3-(2,3-dihydrobenzofuran-5-ylmethylene)-5-fluoro-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9]Br>C(O)C>[NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1ncccc1O
Solvent: CCO
Product: Nc1ncc(Br)cc1O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
The 2-amino-5-bromo-3-pyridinol is prepared by dissolving 110.0 g of 2-amino-3-pyridinol in 250 ml of 95% ethanol. The solution is cooled to about 5° C. and at that temperature is treated with 160 g of liquid bromine during 2 hours. The mixture is stirred for 1 hour after the addition is completed and then concentrated to give 170.6 g of 2-amino-5-bromo-3-pyridinol.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[NH4+].[Cl-].[NH4+].[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=O)=[CH:14][CH:13]=1>C(O)C>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])=[CH:14][CH:13]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccnc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: O=C1NC(=S)SC1=Cc1ccnc2ccccc12
Temperature: 5 °C
Yield: 89 %

Procedure:
Rhodanine (2.2 g; 16.5 mmol), 1.3 ml of concentrated ammonium hydroxide and 1 g of ammonium chloride in 20 ml of ethanol were heated on a steam bath for 15 minutes. 4-Quinoline carboxaldehyde (2.6 g; 16.5 mmol) was added and the resulting mixture was heated on the steam bath for another hour. Upon cooling to 5° C. a precipitate formed. This precipitate was recovered by filtration and then washed with water to provide 4 g of title compound, m.p. 325°-328° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S-:20].[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:20][CH3:19])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 71.4 %

Procedure:
A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.015 g), sodium thiomethoxide (635 mg) was heated to 80° C. in dimethylformamide (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-methylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (600 mg). To a solution of 4-methylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (600 mg) in chloroform (15 mL) was added mCPBA (1.46 g). After stirring for 2 days, the reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo to yield 4-methanesulfonyl-piperidine-1-carboxylic acid tert-butyl ester (505 mg) as a white solid. Treatment of this compound with HCl in dichloromethane/methanol yielded 4-(methylsulfonyl)piperidine, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.FC(F)(F)C([N:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=O.[OH-].[Na+]>ClCCl.O1CCOCC1.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:21]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[NH:12][CH2:13][CH2:14]3)(=[O:22])=[O:23])[CH2:4][CH2:3]1
Reactant: O=C(N1CCc2cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCN(S(=O)(=O)c2ccc3c(c2)CCN3)CC1
Reaction time: 0.75 h

Procedure:
N-Methylpiperazine (4.41 mL, 39.7 mmol, 2.00 equiv) was added to a solution of 1-(trifluoroacetyl)indoline-5-sulfonyl chloride (1-6, 6.23 g, 19.9 mmol, 1 equiv) in dichloromethane (50 mL) at 23° C., and the resulting mixture was stirred for 45 minutes. The brown-colored reaction mixture was concentrated and the residue dried in vacuo to give a tan solid. A suspension of the solid in a mixture of 1,4-dioxane (130 mL) and methanol (35 mL) was then treated with aqueous 1N NaOH solution (81.6 mL, 81.6 mmol, 3.00 equiv) and stirred for 1 hour. The mixture was concentrated, and the resulting solids were suspended in diethyl ether (175 mL), filtered, and dried in vacuo. The resulting solid was then partitioned between saturated sodium chloride solution (200 mL) and ethyl acetate (4×100 mL). The organic layer was dried over sodium sulfate and concentrated to provide the 5-[(4-methylpiperazin-1-yl)sulfonyl]indoline (1-7) as a tan solid. 1H NMR (500 MHz, DMSO-d6) δ 7.26 (s, 1H), 7.25 (d, 1H, J=7.8 Hz), 6.52 (d, 1H, 8.1 Hz), 6.48 (s, 1H), 3.55 (t, 2H, J=8.8 Hz), 3.00 (t, 2H, J=8.54 Hz), 2.79 (br s,4H), 2.34 (br s, 4H), 2.13 (s, 3H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][C:15]([C:17]1[N:18]=[C:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:21]=1)=[O:16])(=O)C.[BH4-].[Na+].CC(C)=O>C1COCC1.O>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:19]1[N:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:21]=[C:17]([C:15]([NH:14][C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:8]2[O:7][CH2:6][CH2:5][OH:4])=[O:16])[N:18]=1
Reactant: CC(=O)OCCO[C@@H]1CCCC[C@H]1NC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCCC[C@@H]1OCCO)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a solution of 2-{[trans-2-({[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}amino)cyclohexyl]oxy}-ethyl acetate (Table entry 286) (31 mg, 0.06 mmol) in THF (7 mL) and water (0.7 mL) was added NaBH4 (5 mg, 0.13 mmol) portionwise over 1 h with the temperature kept below 20° C. The mixture was stirred at rt overnight, cooled to 5° C., treated with acetone (1 mL), and then concentrated. The residue was dissolved in CH2Cl2 and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (2.5% methanol in EtOAc) to give the product 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[(1R, 2S)-2-(2-hydroxyethoxy)cyclohexyl]-1H-imidazole-4-carboxamide (7.5 mg, 26% yield): LC-MS m/z (474.8 MH+), retention time 2.91 min (method 1); Rf=0.17 (EtOAc).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:22]([O:24][C:25](=[O:30])[CH:26]=[C:27](Cl)[CH3:28])[CH3:23]>O1CCCC1>[CH2:22]([O:24][C:25](=[O:30])/[CH:26]=[C:27](/[O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)\[CH3:28])[CH3:23]
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1OCc1ccccc1
Temperature: 23 °C
Yield: 73 %

Procedure:
Potassium t-butoxide (5.60 g, 0.05 mol) was added to a stirred solution of 2-benzyloxy-phenol (5.00 g, 0.025 mol) in tetrahydrofuran (50 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 3.70 g, 0.025 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2-benzyloxy-phenoxy)-but-2-enoic acid ethyl ester (5.70 g, 73%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:18]([O-])=O)=[C:12]([CH2:14][C:15]([NH2:17])=[O:16])[CH:13]=2)[CH2:4][CH2:3]1>CO.[Pd]>[NH2:18][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][C:12]=1[CH2:14][C:15]([NH2:17])=[O:16]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(CC(N)=O)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(N)c(CC(N)=O)c2)CC1
Reaction time: 18 h

Procedure:
To a solution of 2-[5-(4-methyl-piperazin-1-yl)-2-nitro-phenyl]-acetamide (468 mg, 1.68 mmol) in MeOH (8.0 mL) is added 10% Pd on charcoal (59 mg). The reaction mixture is stirred for 18 h under a hydrogen atmosphere (1 atm.), filtered through a microfilter (0.45 μM), and the filtrate concentrated at reduced pressure. The remaining brown oil is dissolved in MeOH (1 mL), MTBE (5 mL) is added, and the solvent is carefully removed at reduced pressure to afford the title compound as a beige powder. ES+-MS: 249 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=[C:5]([Sn](CCCC)(CCCC)CCCC)[N:6]=1.Cl[C:40]1[S:41][CH:42]=[CH:43][C:44]=1[N+:45]([O-:47])=[O:46]>>[CH3:1][C:2]1[N:3]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:4]=[C:5]([C:40]2[S:41][CH:42]=[CH:43][C:44]=2[N+:45]([O-:47])=[O:46])[N:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Reactant: O=[N+]([O-])c1ccsc1Cl
Product: Cc1nc(-c2sccc2[N+](=O)[O-])cn1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from 2-methyl-4-(tributylstannyl)-1-trityl-1H-imidazole and 2-chloro-3-nitrothiophene using protocol E (3.43 g, 76% over 2 steps). Method [7] Retention time 8.87 min by HPLC (M+Na=474).
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.C([O:18][C:19](=[O:25])[C:20](OCC)=[O:21])C>O>[N+:13]([C:8]1[CH:7]=[C:6]([Cl:5])[CH:11]=[CH:10][C:9]=1[CH2:12][C:20](=[O:21])[C:19]([OH:25])=[O:18])([O-:15])=[O:14]
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
To a cooled mixture prepared by adding 13.6 g. of sodium to 300 ml. of ethanol is added a solution of 100 g. of 4-chloro-2-nitrotoluene and 84 g. of diethyloxalate in 150 ml. of ethanol while maintaining the temperature below 20° C. The resulting mixture is refluxed for one hour, cooled, 400 ml. of water added and the resulting mixture refluxed for 90 minutes. The ethanol is then evaporated to a small volume and the resulting precipitate contains tan and black material and the black material is mechanically separated and discarded and the remainder (filtrate plus tan precipitate) used in the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.6 g, 2 mmol) stirring at room temperature under argon in DMF (150 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (0.356 g, 2 mmol), followed by PyBOP (1.14 g, 2.2 mmol), and N,N-diisopropylethylamine (1.38 mL, 8 mmol). The mixture was stirred at room temperature for 17 h. The solvent was pumped off, and the residue taken up in CH2Cl2 (300 mL), and washed with water (300 mL). The organic phase dried over anhydrous Na2SO4, filtered and concentrated. This was then CombiFlashed on a 40 gram silica column eluted with 20-100% EtOAc to afford the title compound. LC-MS m/z 465.8 (M+H)+, 1.49 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl.[Sn].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(C=Cc2ccc(F)cc2)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
A solution of 7.3 g (30 mmol) of 4-[2-(4-fluoro-phenyl)-vinyl]-1-nitro-benzene in 250 ml of ethanol is treated with 80 ml of aqueous 25% hydrochloric acid. The mixture is heated at 110° C. and 5 g (42 mmol) of tin is added portionwise. After stirring for 3 h at 110° C. the suspension is cooled to room temperature, neutralised by additon of aqueous sodium hydroxide and extracted 3 times with dichloromethane. Drying over magnesium sulfate and evaporations yields 5.46 g (85%) of a colorless solid. MS: m/e=214.2 (M++H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH:16]=[C:17]([CH2:19][CH3:20])[O:18][C:14]=3[CH:13]=[C:12]([C:21](O)=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][C:61]1[CH:62]=[CH:63][C:64]([NH2:67])=[N:65][CH:66]=1>CN(C=O)C.O>[CH3:1][N:2]([CH3:26])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:15]3[CH:16]=[C:17]([CH2:19][CH3:20])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([NH:67][C:64]3[CH:63]=[CH:62][C:61]([CH3:60])=[CH:66][N:65]=3)=[O:22])[CH:11]=2)=[CH:24][CH:25]=1)=[O:4]
Reactant: CCc1cc2c(Oc3ccc(C(=O)N(C)C)cc3)cc(C(=O)O)cc2o1
Reactant: Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(Oc3ccc(C(=O)N(C)C)cc3)cc(C(=O)Nc3ccc(C)cn3)cc2o1
Reaction time: 8 h
Yield: 26.7 %

Procedure:
A solution of 4-{4-[(dimethylamino)carbonyl]phenoxy}-2-ethyl-1-benzofuran-6-carboxylic acid (400 mg, 1.13 mmol), HATU (671 mg, 1.70 mmol) and DIPEA (226 mg, 1.70 mmol) in DMF (20 mL) was stirred for 1 h. Then 5-methylpyridin-2-amine (146 mg, 2.26 mmol) was added. The resulting solution was stirred overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 1:1). The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via preparative HPLC to afford the desired compound (133.7 mg, 27%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.92 (bs, 1H), 8.25 (d, 1H), 8.03 (s, 1H), 7.82 (s, 1H), 7.55 (d, 2H), 7.44-7.37 (m, 3H), 6.96 (d, 2H), 6.22 (s, 1H), 3.10-2.93 (d, 6H), 2.74 (q, 2H), 2.26 (s, 3H), 1.26 (t, 3H). LCMS m/z 444.40 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][NH2:4])=[O:2].[Cl:5][C:6]1[C:11]([O:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][C:9]([N:23]=[C:24]=[S:25])=[C:8]([F:26])[CH:7]=1>O1CCCC1>[Cl:5][C:6]1[C:11]([O:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][C:9]([NH:23][C:24]([N:3]([CH:1]=[O:2])[NH2:4])=[S:25])=[C:8]([F:26])[CH:7]=1
Reactant: Fc1cc(Cl)c(Oc2ncccc2C(F)(F)F)cc1N=C=S
Reactant: NNC=O
Solvent: C1CCOC1
Product: NN(C=O)C(=S)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Formic hydrazide (0.6 g) was added to a mixture of 4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl isothiocyanate (3.4 g) in tetrahydrofuran (20 ml) and the mixture was stirred for 3 hours at room temperature. The solvent was removed under reduced pressure and the residue processed. The resulting oil was dissolved in ethanol (30 ml), and hexane added to induce crystallization. The crystals were filtered and dried to give the product, (3.5 g, 69%).
Reaction SMILES: [I:1][C:2]1[O:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:9]1[C:4]2[C:3]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([I:1])[O:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=c1[nH]cnc2oc(I)c(-c3ccccc3)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2oc(I)c(-c3ccccc3)c12
Yield: 68 %

Procedure:
163 (0.8 g, 2.35 mmol) was refluxed in phosphorous oxychloride (12 mL) for 90 minutes. The reaction mixture was concentrated and diluted with ice-cold water, extracted with dichloromethane. The organic layer was washed with water and dried over MgSO4. The organic solvent upon concentration provided a pale solid which on trituration with MeOH provided 164 as a pale solid (0.57 g, 68%).