Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[C:13]1(C)[C:14]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.O.[CH2:25]1COCC1>>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:19]([C:14]3[CH:13]=[CH:18][C:17]([CH3:25])=[CH:16][CH:15]=3)(=[O:20])=[O:21])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [10 g, 65.1 mmol] of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine in 250 mL of dry THF was cautiously added portionwise over 5 minutes time [2.86 g, 71.6 mmol] sodium hydride (60% oil dispersion). Reaction was then allowed to stir for 30 minutes at ambient temperature under a blanket of nitrogen gas. [12.96 g, 68.0 mmol] of solid toluene sulphonyl chloride was then added, in one portion and the reaction mixture was allowed to stir for one hour additional at ambient temperature. Ten mL of water was then cautiously added to the reaction (a quench for the excess hydride) and the solvent was removed under reduced pressure to ¼ the original volume. The residue was then suspended in 300 mL of water, stirred at ambient temperature for 30 minutes and isolated as a white solid via suction filtration. The material was washed with additional water and the damp cake was suspended in a minimum of acetonitrile and stirred overnight at ambient temperature. The precipitate was isolated via suction filtration and washed cautiously with cold acetonitrile and washed with hexanes; material air dried. Yield: 17.2 g of an off white solid (85%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([SH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Na+].C(O)(=O)C>CN(C)C=O>[CH2:10]([S:24][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCCCCCCCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCSc1ccc(C(=O)O)o1

Procedure:
A mixture of 20.1 g (0.011 mole) of 5-bromofuroic acid, 24.2 g (0.011 mole) of tetradecanethiol in 800 ml of dimethylformamide and 8.5 g (0.021 mole) of sodium hydride is heated on a steam bath overnight then refluxed for one-half hour. The mixture is then cooled, acidified with acetic acid and extracted with ether-water. The ether layer is washed with water and salt water, dried over sodium sulfate and filtered. The filtrate is evaporated to dryness, and the remaining solid is recrystallized from hexane and from methanol to give 5-tetradecylthio-2-furoic acid, M.P. 84°-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:38])[C:5]([CH3:37])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:33]C(=O)C)=[C:17]([CH:32]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:38])[C:5]([CH3:37])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:33])=[C:17]([CH:32]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(-n4ccnc4)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(-n4ccnc4)cc3)c2)=C(C)C1=O
Yield: 97.8 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-(imidazol-1-yl)aniline (0.070 g, 0.136 mmol) was dissolved in methanol (5 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.063 g, 0.133 mmol, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][C:15]1([OH:25])[CH2:24][CH2:23][C:18]2(OCC[O:19]2)[CH2:17][CH2:16]1>C1COCC1.O.CC(O)=O>[OH:25][C:15]1([CH2:14][CH2:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:24][CH2:23][C:18](=[O:19])[CH2:17][CH2:16]1
Reactant: COc1ccc2nccc(CCC3(O)CCC4(CC3)OCCO4)c2n1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2nccc(CCC3(O)CCC(=O)CC3)c2n1

Procedure:
A solution of 8-[2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]-1,4-dioxa-spiro[4.5]decan-8-ol (960 mg, 2.79 mmol) in THF/H2O/AcOH (2:2:3, 22 ml) was stirred overnight at 65° C. The reaction mixture was concentrated and purified by chromatography on silica gel (EtOAc).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)=[CH:21][CH:20]=1)#[N:2].[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(OCC)(=O)C.O>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[O:27])=[CH:21][CH:20]=1)#[N:2]
Reactant: Nc1ccccn1
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)cc3)c2cc1C#N
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccn4)cc3)c2cc1C#N
Temperature: 85 °C
Yield: 82.9 %

Procedure:
Phenyl N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (104 mg, 0.228 mmol) was dissolved in dimethylsulfoxide (1 ml), and then 2-aminopyridine (43 mg, 0.457 mmol) was added and the mixture was heated at 85° C. for 3 hours while stirring. After cooling, ethyl acetate and water were added for distribution, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent and concentrating under reduced pressure, ethyl acetate-hexane was added to the residue and the precipitated crystals were filtered out and dried under reduced pressure to obtain the title compound (86 mg, 0.189 mmol, 82.7%) as white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1F
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
Piperazine (6.0 g, 69 mmol) was dissolved in dimethylsulfoxide (50 ml), 2-fluorobenzonitrile (0.95 ml, 9 mmol) and potassium carbonate (2.2 g, 17 mmol) were added and the mixture was stirred at room temperature for 16 h. Water (100 ml) was added and the mixture was extracted with toluene (2×100 ml). The combined organic extracts were washed with 1N sodium hydroxide (3×75 ml), dried (MgSO4) and concentrated in vacuo to give 1.48 g (88%) 2-(1-piperazinyl)benzonitrile as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].CCN(C(C)C)C(C)C.[CH2:21]([O:23][C:24](=[O:30])[CH:25]=[CH:26][N:27]([CH3:29])C)[CH3:22].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36](CN)=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([C:25](=[CH:26][NH:27][CH2:29][C:36]1[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)[C:24]([O:23][CH2:21][CH3:22])=[O:30])=[O:8]
Reactant: CCOC(=O)C=CN(C)C
Reactant: COc1ccc(CN)cc1
Reactant: O=C(Cl)c1cc(Br)ccc1F
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=CNCc1ccc(OC)cc1)C(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 109.2 %

Procedure:
On a larger scale, 5-bromo-2-fluorobenzoyl chloride (4318 g, 4205 g active, 17.71 mol) was charged to the vessel as a solution in toluene (7.5 L). DIPEA (3150 mL, 18.08 mol) was added with no observed exotherm. Ethyl-3-(dimethylamino)acrylate (2532 g, 17.71 mol) was added portion wise over 30 minutes maintaining a batch temperature <40° C. An exotherm from 21-24° C. was noted over the 30 minute addition with a further slow rise to 38° C. over 1 h. The reaction was stirred at 20-30° C. for 16.5 h, 4-Methoxybenzylamine (2439 g, 17.78 mol) was added portionwise over 30 mins maintaining a batch temperature <40° C. An exotherm of 25-30° C. was observed over the addition with cooling provided by a reduced jacket temperature of 15° C. The reaction was stirred for 4 h at 20-30° C. after which HPLC indicated 93.2% of desired material. The batch was split for workup with each half of the mixture diluted with DCM (28.6 L) and washed with water (3×7.8 L). The organics were dried over MgSO4 (˜550 g) and filtered, washing with DCM (4 L). The combined organics were then concentrated to give 8444 g of die desired material as an oil (8434 g, 106% yield, 94.7% parity by HPLC). Analytical data was consistent with that obtained from previous batches.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:17])OC(C)(C)C)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.CCN(CC)CC.[CH2:26]([N:28]1[C:32]2=[N:33][C:34]([CH2:57][CH3:58])=[C:35]([CH2:44][NH:45][C:46]([C:48]3[CH:49]=[C:50]([CH:54]=[CH:55][CH:56]=3)C(O)=O)=[O:47])[C:36]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:31]2[CH:30]=[N:29]1)[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:55]2[CH:54]=[CH:50][CH:49]=[C:48]([C:46]([NH:45][CH2:44][C:35]3[C:36]([NH:37][CH:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[C:31]4[CH:30]=[N:29][N:28]([CH2:26][CH3:27])[C:32]4=[N:33][C:34]=3[CH2:57][CH3:58])=[O:47])[CH:56]=2)=[O:17])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCc1cc(F)cc(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(F)cc(Br)c2)c1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
To a clear solution of 1,1-dimethylethyl [(3-bromo-5-fluorophenyl)methyl]carbamate (280 mg, 1.11 mmol) 207310-29 in DCM (1 mL) was added 4N HCl in dioxane (1 mL). Solid precipitated out from the solution after 30 min. but the mixture was stirred at RT for another hour. It was then concentrated under vacuum to get rid of solvent. Then the residue was re-dissolved in DCM. Et3N (0.5 mL, 3.07 mmol) was added followed by 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (300 mg, 0.62 mmol) and HBTU (311 mg, 3.07 mmol). The mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The organic layer was then washed with water followed by the brine wash. The organic layer was then concentrated under vacuum to give a crude residue. It was purified with CombiFlash chromatography, eluting with 0 to 10% methanol in DCM to obtain N-[(3-bromo-5-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide as a solid (307 mg, 78%). LC-MS m/z 637 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]([F:14])([F:13])[F:12])[CH2:9][N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7]1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.O.C(Cl)Cl>[C:18]([O:17][C:15]([N:8]1[CH2:9][CH:10]([C:11]([F:14])([F:12])[F:13])[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)C(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
107.2 (3RS,4SR)-4-Trifluoromethyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (9.76 g) was dissolved in THF/water (1:1 10 ml) and LiOH (0.826 g) was added to the emulsion. The mixture was stirred for 18 h at 25° C. The reaction mixture was then diluted with CH2Cl2 (50 ml) and treated with HCl (1N, 20 ml). The aqueous phase was extracted twice with CH2Cl2 (20 ml) and the combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to yield (3RS,4SR)-4-trifluoromethyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (5.8 g) as light yellow solid. MS 284.3 ([M+H]+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[Br:26][C:27]1[CH:28]=[C:29]([CH:35]=[C:36](I)[CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>C1COCC1.C(O)(C(F)(F)F)=O.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:26][C:27]1[CH:37]=[C:36]([C:25]#[C:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]2[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[C:7]([CH:15]=[CH:16][CH:17]=2)[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:35]=[C:29]([C:30](=[O:31])[N:32]([CH3:33])[CH3:34])[CH:28]=1
Reactant: C#CCCCCCc1cccc(OCCCC(=O)O)c1CCC(=O)O
Reactant: CN(C)C(=O)c1cc(Br)cc(I)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Temperature: 70 °C
Yield: 65.8 %

Procedure:
To a solution of 4-[2-(2-carboxy-ethyl)-3-hept-6-ynyl-phenoxy]-butyric acid (900 mg, 2.6 mmol), 3-bromo-5-iodo-N,N-dimethyl-benzamide (1.0 g, 2.8 mmol), CuI (20 mg, 0.11 mmol) in THF (10 mL) and TEA (10 mL) was added bis(triphenylphosphine) palladium(II) dichloride (75 mg, 0.11 mmol). The reaction mixture was heated at 70° C. for 5 h. Then the reaction mixture was cooled to room temperature, a few drops of TFA were added and the resulting mixture was concentrated under reduced pressure. The crude material was purified by column chromatography (Isco™ 120 g) using ethyl acetate as eluting solvent to give the title compound (980 mg, 65%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH:10]1N=CN(C(N2C=NC=C2)=O)C=1.CN(C=O)C.[CH2:27]1[CH2:37][CH2:36]N2C(=NCCC2)CC1>CC(O)(C)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][C:37]([CH3:27])([CH3:10])[CH3:36])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)o1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)OC(C)(C)C)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
A mixture of 5.05 g of 5-methyl-2-furanecarboxylic acid, 7.14 g of CDI, and 40 mL of DMF was stirred at 50° C. for 2 hours. To the reaction solution were added 6.71 g of DBU and 6.53 g of 2-methyl-2-propanol at room temperature, followed by stirring at 50° C. for 48 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with diethyl ether and washed with a 5% aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and then a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 2.82 g of tert-butyl 5-methyl-2-furanecarboxylate as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[C:14](OCC)(OCC)(OCC)[CH3:15].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:14][C:15]1[O:13][C:3]2[C:4]([C:5]#[N:6])=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=2[N:1]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1O
Reactant: CCOC(C)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: Cc1nc2c([N+](=O)[O-])ccc(C#N)c2o1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
To a solution of 11A (0.2 g, 1.12 mmol) in xylene (6 mL) was added triethyl orthoacetate (0.62 mL, 3.35 mmol) and pyridinium p-toluenesulfonate (0.04 g, 1.12 mmol). The mixture was refluxed for 3 h, then allowed to cool to rt and partitioned between H2O and EtOAc. The separated EtOAc layer was concentrated under reduced pressure and the residue was chromatographed eluting with 20% EtOAc in hexane to afford compound 11B (0.16 g) as a solid.
Reaction SMILES: [Cl-].[CH3:2][NH2+:3][CH3:4].[N:5]1[C:14]2[CH:13]=[CH:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>>[CH3:2][N:3]([CH3:4])[CH:12]1[CH2:13][C:14]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:10][CH2:11]1
Reactant: C1=Cc2ncccc2CC1
Reactant: C[NH2+]C
Agent: [Cl-]
Product: CN(C)C1CCc2cccnc2C1

Procedure:
This compound was prepared from dimethylammonium chloride (1.63 g, 20 mmol) and 5,6-dihydroquinoline (1.31 g, 10 mmol) using the experimental and purification method describes in Example 48. The product (0.72 g) was an oil which was identical to the compound isolated in Example 3.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1cccc(OCCCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(OCCCCCN2CCN(c3ccc(F)cc3)CC2)c1
Yield: 94.7 %

Procedure:
To a stirred solution of 1-(5-bromo-pentyloxy)-3-nitro-benzene (432 mg, 1.5 mmol) and 1-(4-fluoro-phenyl)-piperazine (297 mg, 1.65 mmol) in acetonitrile (5 mL) was added potassium carbonate (414 mg, 3.0 mmol). After refluxed for 6 hours, the reaction mixture was quenched with water (10 mL) followed by extraction with ethyl acetate (10 mL×3). The combined organic layers were washed with brine and then concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give 1-(4-fluoro-phenyl)-4-[5-(3-nitro-phenoxy)-pentyl]-piperazine (549 mg, 1.42 mmol, 94%) as a yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][CH2:34]O)=[CH:29][NH:30]2)=[CH:26][CH:25]=1>C(#N)C.C(OCC)C>[CH3:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][CH2:34][Br:20])=[CH:29][NH:30]2)=[CH:26][CH:25]=1
Reactant: BrBr
Reactant: COc1ccc2c(CCO)c[nH]c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc2c(CCBr)c[nH]c2c1
Reaction time: 0.33 h

Procedure:
To a mechanically stirred mixture of 18.3 g (69.7 mmol) triphenylphosphine and 200 ml acetonitrile, 11.15 g (69.7 mmol) bromine is added dropwise over 20 minutes. The mixture is stirred 20 minutes at 0° and the ice bath is removed. A solution of 12.1 g (63.4 mmol) 6-methoxy-3-(2-hydroxyethyl)indole in 60 ml acetonitrile is added over 30 minutes. After stirring 2 hours at room temperature the mixture is diluted with 250 ml diethyl ether. The liquid is decanted from precipitated tar. The residue is washed with an additional 250 ml diethyl ether. The volume of the ethereal extracts is reduced to about 60 ml and the solution is filtered through 75 g silica gel with diethyl ether. The solvent is removed to yield 6-methoxy-3-(2-bromoethyl)indole, 4.1 g, yellow waxy solid, mp 98°-101°, which turns green on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[C:23]([F:24])=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:13]([F:25])[CH:12]=2)[CH:5]=[N:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[C:23]([F:24])=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:25])[CH:12]=2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)c1cc(F)c(OCc2cnc(Cl)c(Cl)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(F)c(OCc2cnc(Cl)c(Cl)c2)cc1F
Yield: 49.5 %

Procedure:
To a solution of tert-butyl 4-((5,6-dichloropyridin-3-yl)methoxy)-2,5-difluorobenzoate (Preparation 13, 490 mg, 1.27 mmol) in DCM (5 mL) was added TFA (5 mL). After 30 minutes the reaction mixture was concentrated in vacuo and the resulting residue was purified by reverse phase chromatography eluting with H2O/MeCN/HCOOH (95/5/0.1 to 5/95/0.1, Biotage™ 40 g C18-silica gel) to yield the title compound (210 mg, 50%).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[C:8]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[C:7]([CH3:24])=[C:6]([Cl:25])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[NH2:32][CH:1]([C:4]1[C:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[C:8]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[C:7]([CH3:24])=[C:6]([Cl:25])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(N2CCCC2=O)c1-c1cc(F)cc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)N)c(-c2cc(F)cc(F)c2)c1N1CCCC1=O
Temperature: 25 °C

Procedure:
A mixture of 1-(6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-yl)pyrrolidin-2-one (0.015 g, 0.041 mmol), ammonium acetate (0.032 g, 0.41 mmol), 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.10 mL, 0.10 mmol) in methanol (0.1 mL) and acetonitrile (0.1 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C19H17ClF2NO (M−NH2)+: m/z=348.1. found: 348.0.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.P(=O)(O)(O)O.[N+]([O-])(O)=O.N([O-])=O.[Na+].[BrH:26]>O>[Br:26][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: Br
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCOC(=O)c1sc(Br)nc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Ethyl 2-amino-4-methylthiazole-5-carboxylate (1.20 g, 6.44 mmoles) was added to a solution of 85% phosphoric acid (18 mL) and 70% nitric acid (9 mL) at 0° C. Aqueous sodium nitrite(1.38 g (20 mmol) in water (9 mL) was immediately added dropwise over 20 minutes. After stirring at 0° C. for 15 minutes, cuprous bromide (930 mg, 6.44 mmoles) in hydrobromic acid (9 mL) was added. After stirring for 10 minutes, water (30 mL) was added. The mixture was filtered and the crude solid purified via silica gel chromatography (10% ethyl acetate/hexane) to afford 1.15 g (4.6 mmoles) of the product as a yellow solid (71%). H1 NMR (CDCl3) δ 4.35 (2H, q, J=7.1 Hz), 2.73 (3H, s), 1.38 (3H, t, J=7.1 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:15][NH2:16])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>C1COCC1>[Br:1][C:2]1[C:3]2[N:4]([C:17](=[O:18])[NH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: NNc1nccc(-c2ccc(Cl)cc2)c1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Temperature: 0 °C
Reaction time: 10 h
Yield: 84.4 %

Procedure:
Crude 3-bromo-4-(4-chlorophenyl)-2-hydrazinylpyridine (7 g, 23 mmol) was dissolved in dry THF (100 mL), and the resulting solution was cooled to 0° C. To this was added 1,1′carbonyldiimidazole (18 g, 111 mmol). The reaction mixture was stirred at room temperature for 10 h. The solvent was evaporated under vacuum, and water (10 mL) was added, which caused solid desired product to precipitate. This was filtered, washed with water (2×25 mL), and dried to obtain the title compound as a yellow solid (6.3 g), which was used without further purification.