Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>O1CCOCC1>[C:2]1([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cccc2ccccc12
Reactant: O=Cc1cccc(O)c1
Solvent: C1COCCO1
Product: O=Cc1cccc(Oc2cccc3ccccc23)c1
Temperature: 90 °C

Procedure:
1-iodonaphthalene (2.000 g) and 3-hydroxybenzaldehyde (1.442 g) were added to dioxane (25 mL). The solution was degassed and flushed with nitrogen three times. Cesium carbonate (5.13 g), N, N-dimethylglycine hydrochloride (82 mg), and copper (I) iodide (30 mg) were added, and the solution was heated at 90° C. overnight. The solution was cooled, added to 1M aqueous HCl, extracted with diethyl ether, dried with brine and anhydrous sodium sulfate. The solution was concentrated and purified by flash column chromatography on silica gel with 10% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-c2cnccn2)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Clc1ccc(C2CNCCN2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 2-(3,4-dichlorophenyl)pyrazine (10 g, 44.43 mmol) in dry THF (150 ml) was added slowly a solution of DIBAL-H (1M in THF, 444.3 ml) through a dropping funnel at 10° C. under N2. The color of solution turned into red wine at the end of addition. The solution was gradually warmed up to room temperature overnight. After completion (checked by TLC) the reaction was quenched slowly by the addition of saturated Na2 SO4 solution until no more H2 evolved. White precipitate was formed after stirring for 1.0 h. The precipitate was filtered off, rinsed with THF, dried over MgSO4 and evaporated to dryness. The crude material (10 g) was purified by flash chromatography on 300 g of flash grade silica gel in 7.5 % NH3 -MeOH/CH2Cl2 to give 4.11 g (17.77 mmol, 40%) of 2-(3,4-dichloro-phenyl)piperazine. m.p. 74°-76° C.; FAB mass [M+1]+35Cl 231.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[C:11]([CH2:28][CH2:29][CH3:30])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C)C=O>[CH2:35]([O:8][C:3]([C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]2)=[C:11]([CH2:28][CH2:29][CH3:30])[CH:10]=1)([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:31])[F:32])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
tert-Butyl 4-[6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4-propylpyridin-3-yl]piperazine-1-carboxylate (60 mg, 0.126 mmol) was dried with a vacuum pump, and dissolved in N,N-dimethylformamide (2.5 mL). Sodium hydride (7.3 mg, 0.152 mmol) and benzyl bromide (17 μL, 0.139 mmol) were added sequentially under ice-cold conditions, and the mixture was stirred at room temperature overnight. The reaction solution was added water under ice-cold conditions, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone), and the title compound (54 mg (yield 76%)) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>O1CCCC1.C(O)(C)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:33][CH3:34])=[O:19])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: Cc1ccc(-c2nc3cccnc3n2CC(=O)O)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(C)s2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A solution of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183 mole) in tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with a stream of nitrogen bubbling through it. A solution of dipropylamine (5.56 g, 0.055 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was stirred overnight at room temperature. The solvents were evaporated and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. The organic layer was dried over magnesium sulfate, treated with charcoal, filtered, and evaporated to give a solid which was dissolved in hot isopropyl alcohol and filtered while hot. Addition of water and cooling caused a solid to precipitate. The solid was dissolved again in hot isopropyl alcohol with charcoal, filtered while hot and brought to the cloud point by addition of water. Upon cooling, solid precipitated which was collected by filtration, rinsed with water, and dried under high vacuum at 50° C. overnight to give 2.28 g (35%) of title compound, mp 125°-127° C.
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][OH:14]>C(Cl)Cl>[OH:14][CH2:13][CH2:12][NH:11][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: COC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(NCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 11 %

Procedure:
Under an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), 2-aminoethanol (3.6 mmol), Zn4(OCOCF3)6O (0.15 mmol) and methylene chloride (2.5 mL) was stirred at room temperature for 3 days, and as a result, N-(2-hydroxyethyl)benzamide was obtained in 11% yield. The resulting compound was identified by comparison with physical property data of the known compound.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=[CH:9][N:4]2[N:3]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH3:1][C:2]1[CH:13]=[C:5]2[CH:6]=[C:7]([C:10]([O:12][CH2:19][CH3:20])=[O:11])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCO
Reactant: Cc1cc2cc(C(=O)O)ccn2n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccn2nc(C)cc2c1

Procedure:
2-Methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (723 mg) was dissolved in 10% sulfuric acid/ethanol (20 ml) and the mixture was refluxed under heating for 2.5 hr. The reaction mixture was neutralized under ice-cooling, extracted with ethyl acetate and dried over magnesium sulfate. The residue was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the objective compound (707 mg) as a pale-brown powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([CH3:18])[CH:20]=1)[CH2:13][CH3:14]
Reactant: CCCC1(C(=O)OCC)CCCC1O
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1(C(=O)OCC)CCCC1OC(=O)c1cccc(C)c1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-n-propyl-cyclopentane carboxylate (6.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.66 ml) was slowly added, then 3-methyl-benzoyl chloride (6.00 ml) was dropwise added, Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 10.05 g of yellow liquid. MS: m/e 319(M++1), 318(M+″), 273, 259, 244, 226, 199, 182, 119(base), 91, 77.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]#[CH:9].[C:11]1([CH3:18])[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[CH3:18][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[O:17][CH2:9][C:8]#[CH:7]
Reactant: C#CCCl
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccccc1C
Temperature: 25 °C

Procedure:
245 g of potassium carbonate and 75 ml of propargyl chloride are added to a solutions of 96 g of o-cresol in 1500 ml of acetonitrile. The mixture is now heated for 14 hours at 65°, cooled to room temperature, and filtered with suction, and the filtrate is evaporated. The residue is taken up in 150 ml of ethyl acetate, the mixture is filtered with suction and the filtrate is evaporated. This gives 134 g of the total compound as a pale brown oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: COc1ccc(N(Cc2cnn(Cc3ccccc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.94 g) and benzyl bromide (0.285 mL) as starting materials, 5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-[(1-benzylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.087 g) was obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[O:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[O:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: COCCOCOc1c(CCl)ccc2ccccc12
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2OCOCCOC)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 86(b)] with 2-chloromethyl-1-(2-methoxy-ethoxymethoxy)-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-[1-(2-methoxy-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate, from which by cleavage of the allyl group by means of bis-(triphenylphosphine)-palladium(II) diacetate analogously to Example 152(e) there was obtained tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-[1-(2-methoxy-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate. Subsequent alkylation with 5-bromomethyl-3-thiophen-2-yl-[1,2,4]oxadiazole analogously to Example 44(e) gave tert-butyl (3RS,4RS)-3-[1-(2-methoxy-ethoxymethoxy)-naphthalen-2-ylmethoxy]-4-[4-(3-thiophen-2-yl-[1,2,4]oxadiazol-5-ylmethoxy)-phenyl]-piperidine-1-carboxylate as a colourless, viscous oil; MS: 702 (M+H)+.
Reaction SMILES: [CH3:1][Mg]Br.[NH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13](=[O:15])[CH3:14])=[C:7]([O:16][CH3:17])[CH:6]=1.[Cl-].[NH4+]>O1CCCC1.O>[NH2:4][C:5]1[CH:6]=[C:7]([O:16][CH3:17])[C:8]([C:13]([OH:15])([CH3:1])[CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(N)cc(OC)c1C(C)=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N)cc(OC)c1C(C)(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
To a solution of methyl magnesium bromide (3M in ether, 16.8 mL, 50.5 mmol) in anhydrous tetrahydrofuran (20 mL), cooled in an ice bath, was added 1-(4-amino-2,6-dimethoxy-phenyl)-ethanone (2.19 g, 11.2 mmol-dissolved in 65 mL anhydrous tetrahydrofuran), maintaining the reaction temperature below 10° C. After stirring 4 hours at room temperature, 10% ammonium chloride (20 mL) was added, maintaining the temperature of the reaction below 20° C. (with the use of an ice bath) during the addition. The mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried using anhydrous sodium sulfate, filtered and concentrated to yield 2-(4-Amino-2,6-dimethoxy-phenyl)-propan-2-ol (2.23 g, 94%) as a pale yellow solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:13][C:12](=[O:14])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[O:14]=[C:12]1[NH:13][C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=[CH:11]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2cccc(=O)[nH]2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3cccc(=O)[nH]3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 6-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH2:10][CH2:11][C@H:12]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:13](=[O:24])[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:35][OH:36].CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([O:8][C:9](=[O:33])[CH2:10][CH2:11][C@H:12]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:13](=[O:24])[NH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22](=[NH:23])[NH:35][OH:36])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)NCc1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)NCc1ccc(C(=N)NO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 152.7 %

Procedure:
A solution of compound Q (9.65 g, 20.0 mmol), hydroxylamine hydrochloride (2.10 g, 30.0 mmol) and DIEA (5.22 ml, 30.0 mmol) in ethanol (abs., 150 ml) was refluxed for 6 h. The reaction mixture was allowed to cool to room temperature and stirred for additional 16 h, then the solvents were evaporated in vacuo. The resultant residue was dried in vacuo to provide compound R (14.8 g, yield exceeded quantitative) as yellowish oil. LC-MS [M+H] 485.5 (C25H32N4O6+H, calc: 485.8). Compound R was used without further purification.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH:14]=[C:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8])[CH3:13]
Reactant: COC(OC)N(C)C
Reactant: O=C1CCCC(=O)C1
Product: CN(C)C=C1C(=O)CCCC1=O

Procedure:
A mixture was prepared from 90 grams of 1,3-cyclohexanedione and 225 ml of N,N-dimethylformamide dimethyl acetal and heated at reflux for 90 minutes. Excess solvent was removed under reduced pressure and the residue was triturated in hot ethyl acetate to give 2-dimethylaminomethylene-1,3-cyclohexanedione as rust colored crystals melting at about 114.5°-116° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[C:24]([Cl:30])[CH:23]=1>C1COCC1>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:9]2[CH2:10][CH2:11][N:7]([CH:1]3[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]3)[C:8]2=[O:12])=[C:24]([Cl:30])[CH:23]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: O=C1CCCN1C1CC=CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CC=CCC1
Temperature: -78 °C
Yield: 55.1 %

Procedure:
Dissolve 1-cyclohex-3-enyl-pyrrolidin-2-one (Preparation 66) (300 mg, 1.82 mmol) in anhydrous THF (8 mL), cool to −78° C. and add LDA (2M in THF, 1.36 mL, 2.72 mmol) dropwise. After 10 minutes add 4-bromo-1-bromomethyl-2-chloro-benzene (512 mg, 1.82 mmol) and allow the mixture to warm to room temperature over 16 h. Quench with saturated aqueous ammonium chloride, extract with dichloromethane, dry the organic layer over sodium sulfate and evaporate. Purify the residue by chromatography on silica gel (eluting 0 to 50% ethyl acetate in hexane) to give the title compound as a clear oil (370 mg, 56%): MS (EI) m/z=367,369 (M+).
Reaction SMILES: [C:1]1(=[O:14])[C:6]2=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:5]2[CH2:4][CH2:3][NH:2]1.[Br:15]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:15][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[N:5]2[CH2:4][CH2:3][NH:2][C:1](=[O:14])[C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1NCCn2c1cc1c2CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCn2c3c(c(Br)c21)CCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed a solution of 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-1-one 104j (9.5 g, 49.94 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL), followed by the addition of N-bromosuccinimide (9.8 g, 55.06 mmol, 1.10 equiv) in several batches at 0° C. The resulting solution was stirred at room temperature for 2 h and diluted with 500 mL of water. The precipitate was filtered and dried in a vacuum oven to afford 9.5 g (71%) of 119a as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9]C(=O)[C:7]2=[O:12].[OH-:15].[Na+].[Na+].[Cl-].OO>O.C(Cl)Cl>[NH2:9][C:10]1[C:2]([Cl:1])=[C:3]([O:13][CH3:14])[CH:4]=[CH:5][C:6]=1[C:7]([OH:12])=[O:15]
Reactant: [OH-]
Reactant: COc1ccc2c(c1Cl)NC(=O)C2=O
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)O)c(N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A suspension of compound 103d (6.03 g, 28.52 mmol), NaOH (1.25 g, 31.37 mmol), and NaCl (3.49 g, 59.89 mmol) in water (60 mL) was stirred at room temperature for 30 min and was then ice-cooled. H2O2 was added dropwise. The mixture was stirred at 0° C. for 20 min and at room temperature for 3 hrs. The reaction mixture was quenched with glacial AcOH, filtered, and washed with water. The solid obtained was dissolved in DCM, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (DCM/MeOH) to yield compound 104d as an orange solid in 36% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][NH2:29])=[CH:24][CH:23]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:17][CH3:18])[CH:3]=1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NOc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 72.1 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (450 mg, 1.43 mmol), O-(4-chlorophenyl)hydroxylamine hydrochloride (257 mg, 1.43 mmol) and anhydrous NaOAc (125 mg, 1.52 mmol) in EtOH (23 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2). The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:5) to afford N-{4-chloro-2-[1-(4-chlorophenoxyimino)propyl]phenyl}trifluoromethanesulfonamide 128 (455 mg, 72%), as a yellow solid. M.p. 87-88° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.18, br s, 1H, 7.71, d, J=8.8 Hz, 1H, 7.58, d, J=2.6 Hz, 1H, 7.41, dd, J=2.6 and 8.8 Hz, 1H, 7.35, d, J=8.8 Hz, 2H, 7.11, d, J=8.8 Hz, 2H, 3.02, q, J=7.6 Hz, 2H, 1.30, t, J=7.6 Hz, 3H.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([NH:19][NH2:20])=[O:18]>C(O)(=O)C>[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([NH:19][N:20]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:18]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1cccc(O)c1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1cccc(O)c1
Temperature: 100 °C
Yield: 65 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-hydroxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 133 mg of the title compound (65%) as a yellow solid in 99.4% purity by HPLC (Rt: 4.83, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:33]=[CH:32][C:23]([O:24][CH2:25][C:26](N(OC)C)=[O:27])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]([Mg]Cl)([CH3:38])[CH3:37]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:33]=[CH:32][C:23]([O:24][CH2:25][C:26](=[O:27])[CH:36]([CH3:38])[CH3:37])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)(c1ccc(OCC(=O)N(C)OC)c(C)c1)c1ccc(OCc2ccccc2)c(C)c1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)C)c(C)c1)c1ccc(OCc2ccccc2)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a 0° C. solution of 2-{4-[1-(4-benzyloxy-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-N-methoxy-N-methyl-acetamide (2.36 g, 4.98 mmol) in THF (50 mL) is added 2.0 M iPrMgCl (3.0 mL, 5.98 mmol). The reaction is stirred at 0° C. for 30 m, then at RT for 1 h. It is quenched with satd NH4Cl (20 mL), diluted with H2O (50 mL), extracted with EtOAc (2×100 mL), washed with 0.1 M HCl (50 mL), H2O (50 mL); MgSO4 dried, concentrated and purified to give the title compound (1.01 g, 2.21 mmol, 44%).