Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[Se:16][CH:17]=[CH:18][CH:19]=2)=[C:11]([F:20])[C:10]=1[F:21])[CH3:7].[CH:22](N1CCOCC1)=[O:23]>C1COCC1.ClCCl.Cl>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[Se:16][C:17]([CH:22]=[O:23])=[CH:18][CH:19]=2)=[C:11]([F:20])[C:10]=1[F:21])[CH3:7]
Reactant: CCOc1ccc(-c2ccc[se]2)c(F)c1F
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(C=O)[se]2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
7.6 ml (44.4 mmol) of TMP are initially introduced at −20° C. in THF, and 26.7 ml (42.4 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 25 min at this temperature, a solution of 11.7 g (38.6 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)selenophene in 80 ml of THF is added. When the addition is complete, the batch is warmed to RT over the course of 45 min and left at this temperature for 20 min. The solution is cooled to −40° C., and N-formylmorpholine is added. The reaction mixture is warmed to RT and stirred for 4.5 h. The solution is diluted with a lot of dichloromethane, and 2 N hydrochloric acid is added. The mixture is briefly stirred vigorously, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with water. The solution is dried using sodium sulfate and concentrated to dryness. The residue is digested in cold ethanol, and the solid is filtered off with suction. Drying in vacuo gives 5-(4-ethoxy-2,3-difluorophenyl)selenophene-2-carbaldehyde as a violet solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[C:22]3[CH2:30][CH2:29][NH:28][CH2:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH:11]=1.Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C(O)C>[CH:33]1([CH2:32][N:28]2[CH2:29][CH2:30][C:22]3[C:21]([NH:20][C:12]4[CH:11]=[N:10][C:19]5[C:14]([CH:13]=4)=[CH:15][CH:16]=[CH:17][CH:18]=5)=[N:26][CH:25]=[N:24][C:23]=3[CH2:27]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: BrCC1CCCCC1
Reactant: c1ccc2ncc(Nc3ncnc4c3CCNC4)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1ccc2ncc(Nc3ncnc4c3CCN(CC3CCCCC3)C4)cc2c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 9.4 %

Procedure:
Diisopropylethyl amine(258 mg, 2 mmol) was added to the solution of 5,6,7,8-tetrahydro-N-(quinolin-3-yl)pyrido[3,4-d]pyrimidin-4-amine (55 mg, 0.2 mmol) and (bromomethyl)cyclohexane (177 mg, 1 mmol) in ethanol (2 ML) and stirred at 80° C. for 48 h. Solvent was removed in vacuo, and the residue was purified by column chromatography to yield the product as a light orange powder (7 mg, 9.5%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:10](Cl)([Cl:12])=[O:11]>O1CCCC1.C1(C)C=CC=CC=1>[N:1]1([C:10]([Cl:12])=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)n1nnc2ccccc21
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 1H-benzo[d][1,2,3]triazole (0.5 g, 4.20 mmol) in tetrahydrofuran (25 ml) was added dropwise to a stirred 20% solution of phosgene (5.30 ml, 10.1 mmol) in toluene at 0-5° C. The reaction mixture was allowed to stir at 20-25° C. for 2 h (reaction complete by TLC). Argon was bubbled through the solution for 15 min. Then the solvent was evaporated in vacuum to give 1H-benzo[d][1,2,3]triazole-1-carbonyl chloride (0.763 g, 4.20 mmol) as a clear oil. The product was used without further purification. Pyridine (0.357 ml, 4.41 mmol) was added dropwise to a stirred solution of the oil in Tetrahydrofuran (25 ml) at 0-5° C. This was followed by a dropwise addition of N-methylcyclohexanamine (0.499 g, 4.41 mmol) at 0-5° C. The reaction mixture was allowed to stir overnight at 20-25° C. Water and EtOAc were added and the organic layer was separated, washed with 1M HCl, water and brine. The organic layer was dried (MgSO4) and evaporated in vacuum to give a clear oil. The oil was recrystallised from 2-propanol/DCM, the solid was collected, dried in vacuum at 40-45° C. Yield 230 mg (21%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)C.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>O>[CH:13]1([NH:16][C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: N#Cc1cccnc1Cl
Reactant: NC1CC1
Solvent: CCO
Solvent: O
Product: N#Cc1cccnc1NC1CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A reaction flask equipped with a mechanical stirrer, temperature controller, condenser and addition funnel was charged with 2-chloro-3-pyridinecarbonitrile (69.25 g, 0.50 mol), 300 ml of ethanol and 200 ml of water. With agitation, cyclopropylamine ( 114g, 2.0 mol) was added dropwise over 30 minutes at a temperature<30° C. When the addition was completed, the stirred reaction mixture was heated to reflux temperature for 20 hours. The reaction mixture was cooled to 60° C. and then 350 ml of excess cyclopropylamine and ethanol were removed by vacuum distillation using water aspirator vacuum. The remaining aqueous solution was cooled to ambient temperature and allowed to stand overnight. The solid product was collected by filtration and the filter cake rinsed with water. The yield was 81.51 g (theoretical yield is 79.5 g).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:3]=1[O:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.C(=O)([O-])O.[Na+].[CH:26]1([C:32]2[C:33]3[S:48][C:47]([C:49]([O:51][CH3:52])=[O:50])=[CH:46][C:34]=3[NH:35][C:36]=2B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]1([C:32]2[C:33]3[S:48][C:47]([C:49]([O:51][CH3:52])=[O:50])=[CH:46][C:34]=3[NH:35][C:36]=2[C:2]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:3]=2[O:4][CH2:5][CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=[N+]([O-])c1cccc(Br)c1OCCOC1CCCCO1
Reactant: COC(=O)c1cc2[nH]c(B3OC(C)(C)C(C)(C)O3)c(C3CCCCC3)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc2[nH]c(-c3cccc([N+](=O)[O-])c3OCCOC3CCCCO3)c(C3CCCCC3)c2s1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
To a solution of 2-[2-(2-bromo-6-nitrophenoxy)ethoxy]tetrahydropyran (1.29 g, 3.72 mmol) in water (10 ml) and ethylene glycol dimethyl ether (20 ml) were added sodium hydrogen carbonate (1.23 g, 14.8 mmol) and tetrakis(triphenylphosphine)palladium (430 mg, 0.372 mmol). Methyl 6-cyclohexyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.60 g, 4.10 mmol) obtained in Step 1 was divided in 4 portions and added every 30 min while stirring at 90° C. with heating. After the completion of addition, the mixture was further stirred at 90° C. for 4 hr. The reaction mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1-3:1) to give methyl 6-cyclohexyl-5-{3-nitro-2-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-4H-thieno[3,2-b]pyrrole-2-carboxylate (863 mg, yield 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[OH:11].[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].C(Cl)(Cl)Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:10]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[O:11][C:26](=[O:27])[O:25]1
Reactant: OC(c1ccc(F)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1OC(c2ccc(F)cc2)C(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Yield: 78.7 %

Procedure:
A mixture of 500 mg of 2-(2,4-dichlorophenyl)-1-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol, 530 mg of 1,1'-carbonyldiimidazole and 10 ml of dry chloroform is heated under reflux for 1 hour. Water is added to the reaction mixture, and the chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated. The residue is chromatographed on a column of silica-gel and eluted with a mixture of methylene chloride and methanol (100:0-98:2 v/v). The eluate is concentrated, and the residue is crystallized from ethyl acetate-isopropyl ether to give 420 mg of 4-(2,4-dichlorophenyl)-5-(4-fluorophenyl)-2-oxo-4-(1H-1,2,4-triazol-1-yl)methyl-1,3-dioxolane as crystals. m.p. 191°-192° C. Yield: 78.7%
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:33]=[CH:32][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])OC(C)(C)C)[CH3:22])=[CH:15][C:14]=4[F:31])[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[N:34]1C=CC=C[CH:35]=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:33]=[CH:32][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24]([NH:34][CH3:35])=[O:30])[CH3:22])=[CH:15][C:14]=4[F:31])[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC4)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Reactant: c1ccncc1
Product: CNC(=O)N[C@@H](C)COc1cnc(-c2nc3ccc(OCC4CC4)cc3o2)c(F)c1

Procedure:
Using tert-butyl [(1S)-2-({6-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate, and in the same manner as in Example 16, step A (using pyridine instead of triethylamine), the title compound was obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13]>C(O)C>[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH:13][C:4](=[O:6])[CH2:3][C:1]#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: NCc1ccccc1Cl
Solvent: CCO
Product: N#CCC(=O)NCc1ccccc1Cl
Reaction time: 8 h
Yield: 38 %

Procedure:
A solution of 80.5 g. (0.71 mole) of ethyl cyanoacetate and 100 g. (0.71 mole) of 2-chlorobenzylamine in 200 ml. of absolute ethanol heated at reflux for 2 hours and then allowed to stand at ambient temperature overnight. The solvent is removed in vacuo and the residue is recrystallized from ether/pentane to give 56 g. (38% yield) of the desired product as a near white solid, m.p. 102°-4° C.; ν3300 (NH), 2270 (CN), and 1650 cm.-1 (C= O); δ 8.7 (broad, 1H, NH), 7.35 (broad s, 4H, aromatic protons), 4.40 (d, 2H, benzyl methylene) and 3.7 (broad s, 2H, CH2CO).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)#[CH:2].[N:15]([CH2:18][CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])=[N+:16]=[N-:17]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:10]1[N:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[CH:5][CH:4]=[C:3]2[C:1]1[N:17]=[N:16][N:15]([CH2:18][CH2:19][CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])[CH:2]=1
Reactant: C#Cc1ccnc2ccc(OC)nc12
Reactant: [N-]=[N+]=NCCCN1C(=O)c2ccccc2C1=O
Solvent: Cc1ccccc1
Product: COc1ccc2nccc(-c3cn(CCCN4C(=O)c5ccccc5C4=O)nn3)c2n1
Yield: 45.9 %

Procedure:
A mixture of 8-ethynyl-2-methoxy-[1,5]naphthyridine (184 mg, 1.0 mmlole) and 2-(3-azido-propyl)-isoindole-1,3-dione (230 mg, 1.0 mmole) were refluxed in toluene (5 mL) for 12 hours. Upon cooling the product precipitated. The mixture was diluted with ether (5 mL) filtered, and the solid product was washed with ether and dried to give 190 mg (46%) of 2-{3-[4-(6-Methoxy-[1,5]naphthyridin-4-yl)-[1,2,3]triazol-1-yl]-propyl}-isoindole-1,3-dione as a grey solid as single regioisomer.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>CS(C)=O>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:4][C:3]2[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=2[F:9])[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(F)cccc1F
Reactant: Nc1c(F)cccc1F
Solvent: CS(C)=O
Product: N#Cc1c(F)cccc1Nc1c(F)cccc1F
Temperature: 25 °C

Procedure:
2,6-Difluoroaniline (1.29 g, 10 mmol) was dissolved in dimethyl sulfoxide (10 mL) and stirred under argon at room temperature. Sodium hydride, dry, 95%, (0.24 g, 10 mmol) was added in portions and the mixture was stirred at room temperature for 1 hour. 2,6-Difluorobenzonitrile (0.463 g, 3.3 mmol) dissolved in dimethyl sulfoxide (5 mL) was added and the mixture stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic phase was washed with water (5×), brine (1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0–25% CH2Cl2 in hexane to give the title compound as a white amorphous solid. mp 145–146° C.
Reaction SMILES: C(O[C:6]1[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:7]=1)CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]=[CH:23][C:22]1=[O:27].O>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:20][N:21]1[CH2:26][CH2:25][C:24]2[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:7]=[C:6]([OH:10])[C:23]=2[C:22]1=[O:27]
Reactant: O=C1C=CCCN1Cc1ccc(F)c(Cl)c1
Reactant: CCCCOc1cnc(C(=O)OCC)o1
Solvent: O
Product: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 130 °C
Reaction time: 72 h

Procedure:
A mixture of ethyl 5-butoxy-1,3-oxazole-2-carboxylate (44.5 g, 208.6 mmol), 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (25 g, 104.3 mmol), and water (2.82 mL, 156.7 mmol) was heated in a sealed heavy walled vessel at 130° C. with stirring for 72 hours. Upon cooling, the product mixture solidified. The solid was triturated with diethyl ether and collected by filtration. The product was further purified by crystallization from boiling ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[C:11]1([N:20]2[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]2)[C:12]2[N:13]([CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:15][N:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([NH:25][C@H:22]2[CH2:23][CH2:24][N:20]([C:11]3[C:12]4[N:13]([CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:15][N:16]=3)[CH2:21]2)=[O:10])=[N:4][CH:3]=1
Reactant: N[C@H]1CCN(c2nccn3cccc23)C1
Reactant: Cc1cnc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cnc(C(=O)N[C@H]2CCN(c3nccn4cccc34)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a solution of 5-methylpyrimidine-2-carboxylic acid (0.03 g, 0.22 mmol, 1 eq) and (S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine (0.060 g, 0.22 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.12 mL, 0.86 mmol, 4 eq) and HATU (0.09 g, 0.24 mmol, 1.1 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)-5-methyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.029 g, 0.09 mmol, 41%). 1H NMR (400 MHz, CD3OD) δ 8.75 (s, 2 H), 7.76 (s, 1 H), 7.71 (d, J=5.5 Hz, 1 H), 7.54 (s, 1 H), 6.91 (s, 1 H), 6.85 (d, J=5.8 Hz, 1 H), 5.00-3.60 (br, 5 H), 2.65-2.30 (br, 2 H), 2.40 (s, 3 H); MS: (ES) m/z calculated for C17H18N6O [M+H]+ 323.2, found 323.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1)[C:5]([NH2:7])=[O:6].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][NH:27][CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:17]=1)[C:5]([NH2:7])=[O:6]
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)c(Cl)c1
Reactant: NCCc1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccs3)cc2)c(Cl)c1
Yield: 96.9 %

Procedure:
Use 3-chloro-4-(4-formyl-phenoxy)-benzamide (0.20 g, 0.71 mmol), 2-thiophen-2-yl-ethylamine (0.075 mL, 0.64 mmol), sodium borohydride (0.049 g, 1.29 mmol) and methanol (8 mL) in a procedure and purification similar to that of Example 1, to obtain the product (0.24 g, 94%), 2137632. Mass spectrum (ion spray): m/z=387.1 (M+1); 1H NMR (CDCl3) 7.93 (d, J=2.1 Hz, 1H), 7.62 (dd, J=2.1 Hz, 8.7 Hz, 1H), 7.31 (d, J=8.5 Hz, 2H), 7.14 (d, J=5.2 Hz, 1H), 6.97 (d, J=8.3 Hz, 2H), 6.93 (dd, J=3.4 Hz, 5.1 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.84 (d, J=3.1 Hz, 1H), 6.11 (bs, 2H), 3.81 (s, 2H), 3.05 (t, J=6.7 Hz, 2H), 2.95 (t, J=6.7 Hz, 2H).
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:11][C:12]1[CH:24]=[CH:23][C:15]2[N+:16]([O-])=[C:17](N)[N:18]=[N+:19]([O-])[C:14]=2[CH:13]=1)[CH:9]=[CH2:10]>CN(C=O)C>[CH2:8]([O:11][C:12]1[CH:24]=[CH:23][C:15]2[N:16]=[CH:17][N:18]=[N:19][C:14]=2[CH:13]=1)[CH:9]=[CH2:10]
Reactant: C=CCOc1ccc2c(c1)[n+]([O-])nc(N)[n+]2[O-]
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2ncnnc2c1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a stirred solution of t-butyl nitrite (271 mg, 0.312 ml, 2.63 mmol) in DMF (15 ml) at 60°-65° C. was added 7-allyloxy-3-amino-1,2,4-benzotriazine-1,4-dioxide 23 (205 mg, 0.875 mmol) in small portions over 5 min. After 30 min additional t-butyl nitrite (271 mg, 0.312 ml, 2.63 mmol) was added, and shortly thereafter the deep red solution effervesced and lightened appreciably in color over a period of a few minutes. After an additional 30 min the resultant orange solution was reduced under vacuum to a brown solid which was sequentially flash chromatographed (10% EtOAc/CH2CL2) and crystallized (CH2Cl2/petroleum ether) to give 72 mg (38% yield) of the product 24 as light orange crystals, m.p 147°-148° C. NMR: δ(400 MHz, d6-acetone) 4.89 (2H, ddd, H-1′,J1′2′=5.5, J1′.3′cis=J1′.3′trans=1.5 Hz), 5.36(1 H, ddd, H-3′, J3′.2′cis=10.5, J3′.3′=1.5 Hz), 5.52 (1 H, ddd, H-3′, J3′.2′trans=17.5, J3′.3′=3, J3′1′=1.5 Hz), 6.14 (1 H, ddd, H-2′, J2′,3′cis=10.5, J2′.1′-5.5 Hz), 7.70 (1 H, d, H-8, J8.6=2.5 Hz), 7.7.4 (1 H, dd, H-6, J6.5=9.5, J6.8-2.5 Hz), 8.33 (1 H, d, H-5, J5.6=9.5 Hz), 8.93 (1 H,s H-3). UV: λmax 425, 410, 365, 355, 320, 245, 200. MS m/z (relative intensity) 220(4), 219(34 M+), 103(4), 77(4), 75(4), 63(13), 62(4), 42(3), 41(100), 39(16). Anal. Calc'd. for C10H9N3O3: C, 54.79; H, 4.14; N, 19.17. Found: C, 54.73; H, 4.16; N, 19.15.
Reaction SMILES: C(OC(N[C@H:9]([C:13]([CH2:17]C)([CH3:16])[CH2:14][CH3:15])[C:10](O)=O)=O)(C)(C)C.[O-]S([O-])(=O)=O.[Na+].[Na+].[NH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:9]([C:13]([CH3:17])([CH2:14][CH3:15])/[CH:16]=[N:26]/[CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:10]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CCC(C)(CC)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(C)(/C=N/C(c1ccccc1)c1ccccc1)CC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 100-mL round-bottomed flask containing crude 2-ethyl-2-methylbutanal (15) was charged with CH2Cl2 (20 mL) and Na2SO4 (10 g). Aminodiphenylmethane (9) (8.83 mL, 80 mmol, 0.80 equiv) was added via syringe. The flask was capped with a plastic stopper, and the mixture was stirred at room temperature for 14 h. The reaction mixture was filtered through a medium porosity fritted disk funnel and rinsed with CH2Cl2 (4×10 mL). The filtrate was concentrated under reduced pressure and maintained at 1 torr with stirring for 1 h to provide a slightly cloudy, colorless oil. A 5-cm diameter fritted disk funnel was filled with a 3-cm high layer of silica gel. The funnel was rinsed with a solution of 20:1:0.5 hexanes/Et2O/triethylamine (50 mL) under reduced pressure, followed by a solution of 20:1 hexanes/Et2O (50 mL). The oil prepared above was dissolved in 20:1 hexanes/Et2O (25 mL) and rinsed through the frit into a 250-mL round-bottomed flask under reduced pressure, rinsing with 20:1 hexanes/Et2O (4×25 mL). The mixture was concentrated under reduced pressure (30 torr→1 torr) to provide a clear, colorless oil that was slightly cloudy. The oil was maintained at 1 torr for 1 h while stirring to provide (E)-N-(2-ethyl-2-methylbutylidene)diphenylmethanamine (2b) in 95% 1H-NMR purity. Yield: 18.7 g (67 mmol, 84% from aminodiphenylmethane, 67% from 2-ethyl-2-butanal).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(C(=O)OCc2ccccc2)c1
Reaction time: 0.17 h
Yield: 8.4 %

Procedure:
To a solution of 3-acetylbenzoic acid (6.00 g, 0.36 mol) in DMF (36 mL) was added Na2CO3 (4.26 g, 0.40 mol) at 0° C. and the reaction stirred for 10 min. After 10 min, benzyl bromide (4.80 mL, 0.40 mol) was added and the reaction stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by combiflash chromatography (silica gel, 40 g, 2-5% ethyl acetate/hexanes) to afford the title compound (7.73 g, 84%) as a white solid.
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[N:16]1([C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[C:31]([F:34])([F:33])[F:32])[CH2:17][CH2:18]2)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Product: CCCCCNC(=O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid pentylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(5-fluoro-2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (31% yield). m.p. 162-164° C. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.87, 7.24, 7.07, 6.99, 4.08-3.99, 3.90-3.66, 3.45, 3.35, 1.65-1.55, 1.37-1.30. 13C NMR (75 MHz, CDCl3) δ 166.1, 162.9, 160.0, 145.7, 129.7, 127.2, 116.9, 116.6, 115.0, 114.7, 112.6, 77.2, 46.4, 44.6, 44.4, 41.3, 39.4, 29.3, 29.1, 22.4, 14.0.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([F:18])[CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O=P(Cl)(Cl)Cl>>[F:18][C:10]1[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=[C:8]2[C:9]=1[C:4](=[O:3])[NH:5][CH2:6][CH2:7]2
Reactant: CCOC(=O)NCCc1ccc(C(F)(F)F)c(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2ccc(C(F)(F)F)c(F)c21
Temperature: 110 °C
Yield: 27.9 %

Procedure:
[2-(3-Fluoro-4-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester (I-47c: 1.5 g, 5.376 mmol) was reacted with P2O5 (1.52 g, 10.75 mmol) and POCl3 (15 mL). The resulting mixture was refluxed for 1 hour at 110° C. to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 350 mg of the product (27.97% yield).