Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24](=O)[C:25]#[CH:26])[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1.Cl.[OH:31][C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[NH:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][N:35]=[C:33]([C:32]([OH:31])([CH3:37])[CH3:36])[N:34]=3)[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(F)n3)c(Cl)c2=O)c1
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2cccc(F)n2)c(Cl)c1=O
Temperature: 75 °C
Yield: 30.8 %

Procedure:
To a solution of 5-chloro-6-(6-fluoro-pyridin-2-ylmethoxy)-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-3H-pyrimidin-4-one of Step D (78 mg, 0.19 mmol) in acetonitrile (3 mL) was added 2-hydroxy-2-methylpropionamidine HCl (39 mg, 0.28 mmol) and potassium carbonate (78 mg, 0.57 mmol) and the slurry heated at 75° C. for eighteen hours. After cooling to room temperature the reaction was filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a yellow oil (29 mg, 31% yield). MS (M+H): 496; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.15 (s, 3H), 2.21 (s, 3H), 5.54-5.65 (m, 2H), 6.90 (d, J=7.83 Hz, 1H) 7.48 (d, J=6.65 Hz, 1H), 7.55-7.57 (m, 2H), 7.85-7.93 (m, 2H), 8.14 (d, J=8.22 Hz, 1H), 8.78 (d, J=5.09, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:18])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([O:18][CH2:23][CH:22]=[CH2:21])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)C(=O)Oc1ccc(O)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OC(=O)C(C)(C)C)c(C(C)(C)C)c1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Under a nitrogen stream, 4.48 g of 3-t-butyl-4-trimethylacetoxyphenol synthesized in Example 15-2) was dissolved in 20 ml of dimethylformamide and a suspension of 0.86 g of oily sodium hydride in 20 ml of dimethylformamide at 0° C. was added dropwise. After stirring for 30 minutes, 1.86 ml of allyl bromide was added dropwise and the solution was stirred for 3 hours and allowed to attain room temperature. After the reaction was quenched with a saturated aqueous ammonium chloride solution, the mixture was extracted with water and n-hexane. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% ethyl acetate) to give 4.31 g of 3-t-butyl-4-trimethylacetoxy-1-(2-propenyloxy)benzene as a colorless oil (yield 83%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:7]1[C@:8]1([CH3:27])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:4].ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:7]1[C@:8]1([CH3:27])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@@H:11]2[O:36][C@@H:10]2[CH2:9]1)=[O:4]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
11β-Chloroacetoxy-5α-pregn-2-en-20-one (1.25 g) in chloroform (50 ml) was treated with m-chloroperbenzoic acid (85%; 700 mg) and the solution was stirred at room temperature for 4 hours. Chloroform (50 ml) was added, and the solution was washed with potassium bicarbonate solution and with water; it was then dried over sodium sulphate and evaporated to a white foam which was triturated with ether to give title compound (1.05 g) as colourless prisms, m.p. 163°-169°, [α]D +107°.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:25]([O:27][CH2:28]C)=[O:26])=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)[CH3:2]>OS(O)(=O)=O.CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:25]([O:27][CH3:28])=[O:26])=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(CC)cc2)c(-c2ccc(C(F)(F)F)cc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCc1ccc(-c2ccc(C(=O)OC)nc2-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
Following General Procedure E, ethyl 5-(4-ethylphenyl)-6-(4-(trifluoromethyl)phenyl)pyridine-2-carboxylate (Compound 48, 60 mg, 0.15 mmol) and conc. H2SO4 (10 drops) in methanol were reacted to produce the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=[O:10].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:9](=[O:10])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Cc1ccccc1CC(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 44.6 %

Procedure:
To a stirred solution of 0.334 g of 2-methylphenylacetyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0,500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered through a pad of hydrous magnesium silicate and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl acetate to give 0.385 g of the desired product as white crystals, m.p. 198°-200° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]([CH2:30][C:31](=[O:40])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=2)[N:7]=1)=[O:5])C.C(O)(=O)C>C1COCC1.[OH-].[K+]>[C:14]([SiH2:13][O:12][C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:9]1[N:8]([CH2:30][C:31](=[O:40])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)n(CC(=O)Nc2ccc(Cl)cn2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cc(C(=O)O)nn1CC(=O)Nc1ccc(Cl)cn1
Reaction time: 16 h

Procedure:
To a solution of 2 g 5-(tert-Butyl-diphenyl-silanyloxymethyl)-1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-pyrazole-3-carboxylic acid ethyl ester in 10 ml THF, 7 ml aqueous KOH solution (10%) were added at RT and the mixture was stirred for 16 h. Then the solution was acidified by addition of 10 ml half concentrated acetic acid and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Yield: 1.8 g.
Reaction SMILES: [C:1]([C:4]1[C:5]([N:16]([CH3:18])[CH3:17])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Cl>C(O)(C)C>[C:1]([C:4]1[C:5]([N:16]([CH3:18])[CH3:17])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[Cl:19])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)[nH]c(-c2ccccc2)c1N(C)C
Reactant: ClCc1ccccc1Cl
Solvent: CC(C)O
Product: CC(=O)c1c(N(C)C)c(-c2ccccc2)n(Cc2ccccc2Cl)c1C
Yield: 67 %

Procedure:
The title compound is prepared in a 67% yield by starting from the compound of Example 43 and o-chlorobenzyl chloride, using procedure (a) of Example 49; m.p. 103°-5° C. (from isopropanol).
Reaction SMILES: C(O[CH:4]([O:8]CC)[C:5]([NH2:7])=[S:6])C.Br[CH2:12][C:13]([C:15]1[O:19][N:18]=[C:17]([CH3:20])[CH:16]=1)=O>C(O)C>[CH3:20][C:17]1[CH:16]=[C:15]([C:13]2[N:7]=[C:5]([CH:4]=[O:8])[S:6][CH:12]=2)[O:19][N:18]=1
Reactant: Cc1cc(C(=O)CBr)on1
Reactant: CCOC(OCC)C(N)=S
Solvent: CCO
Product: Cc1cc(-c2csc(C=O)n2)on1
Reaction time: 8 h

Procedure:
A solution of diethoxythioacetamide (6.65 g; 0.04077 mol) and 2-bromo-1-(3-methylisoxazol-5-yl)ethanone (10 g; 0.04077 mol), prepared as described in the above step, in absolute ethanol (31.3 ml) was kept overnight at room temperature and then refluxed for 30 minutes.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]([OH:21])[CH:13]=1.Br[CH2:23][CH:24]=[CH2:25]>C1(C)C=CC=CC=1>[N+:18]([C:17]1[CH:16]=[CH:15][C:14]([O:21][CH2:25][CH:24]=[CH2:23])=[CH:13][CH:12]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.7 %

Procedure:
Potassium carbonate (49.7 g, 0.36 mol) was added to an N,N-dimethylformamide (250 ml) solution of p-nitrophenol (25.0 g, 0.18 mol) under nitrogen atmosphere and suspended, and 3-bromopropene (21.7 g, 0.18 mol) was dropwise added thereto. After finishing dropwise adding, the solution was stirred at a room temperature for 5 hours, and then extracting practice with diethyl ether was carried out after adding water to the solution. The organic layer was washed with water and then dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue thus obtained was refined by means of silica gel chromatography (eluent solvent: toluene). Toluene was distilled off under reduced pressure, and then the resulting residue was recrystallized from ethanol to obtain allyl p-nitrophenyl ether (25.7 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:15])[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:8]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])=[O:15]
Reactant: Cc1occc1C(=O)Cc1ccncc1
Reactant: COC(OC)N(C)C
Product: Cc1occc1C(=O)C(=CN(C)C)c1ccncc1
Temperature: 100 °C
Yield: 85.8 %

Procedure:
A mixture of 1-(2-methyl-3-furanyl)-2-(4-pyridinyl)ethanone (1.006 g, 5 mmol) in N,N-dimethylformamide dimethyl acetal (0.664 ml, 5 mmol) was heated at 100° C. for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water and brine, dried and evaporated to give the title compound as an oil (1.1 g, 86%). LC/MS [M+H]+=257.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccccc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccccc1Oc1ccccc1Cl

Procedure:
A solution of 2-chloro-(2-nitrophenoxy)benzene (5.00 g) in tetrahydrofuran (100 mL) was shaken in a Parr Hydrogenator over Raney nickel at 5 psi hydrogen at room temperature for 4 hours. The catalyst was filtered from the reaction, and the solution was evaporated under vacuum to a yellowish oil which crystallized on standing. The solid was crushed, suspended in hexane and filtered to yield the title compound as a light orange solid. Mp: 44°-45° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([BH3-])#N.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: Clc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1cccc2c1CCN2
Temperature: 12 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a stirred solution of 4-chloroindole (5 g, 33.0 mmol) in Acetic Acid (50 mL) at 12° C. under nitrogen was added sodium cyanoborohydride (6.84 g, 109 mmol) portionwise. The reaction was stirred at 12° C. for 2 hours. LCMS indicated complete conversion, so the reaction mixture was diluted with water (300 mL), cooled in an ice-bath and quenched with sodium hydroxide pellets portionwise until the mixture was strongly basic. The mixture was then extracted with diethyl ether (3×200 mL) and the combined organics dried over sodium sulfate, concentrated and the residue purified by flash chromatography (0-30% EtOAc in hexanes) to afford 4-chloro-2,3-dihydro-1H-indole (4.0 g) as a colourless oil. LC-MS (ES) m/z=154 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.94 (t, J=8.59 Hz, 2H), 3.47 (td, J=8.72, 1.77 Hz, 2H), 5.83 (br. s., 1H), 6.40 (d, J=7.83 Hz, 1H), 6.50 (d, J=8.08 Hz, 1H), 6.90 (t, J=7.96 Hz, 1H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.[Cu](I)I>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[C:30]([N:1]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4](=[O:5])[C:2]3=[O:3])[CH:31]=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Brc1cccc(-c2ccc(OCc3ccccc3)cc2)c1
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(c2cccc(-c3ccc(OCc4ccccc4)cc3)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isatin (0.12 g, 0.81 mmoles) in anhydrous DMF (30 mL) was cooled in an ice bath under nitrogen and treated with sodium hydride (21 mg, 1.1 equivalents). The reaction was stirred in ice for 0.5 hour and then warmed to room temperature. This solution was then treated with 4-(3-bromophenyl)phenol benzyl ether (Hajduk, et al., J. Am. Chem. Soc., 1997, 119, pp. 5818-5827), (0.16 g, 0.47 mmoles) followed by copper iodide (0.32 g, 1.68 mmoles). The reaction was heated in an oil-bath at 140° C. After ˜16 hours, the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (˜75 mL) and filtered. The filtrate was concentrated under reduced pressure to afford a sticky, brown solid which was purified by preparative TLC on silica gel using 25% ethyl acetate in hexanes as the developing solvent. Rf (product)=0.38. Yield=47 mg (25%); MALDI-TOF MS 407.02 obs. (405.5 calc.); 1H-NMR (CDCl3) 5.12 (s, 2H), 6.95 (d, 1H, J=8 Hz), 7.06 (d, 2H, J=8.8 Hz), 7.18 (t, 1H, J=7.5 Hz), 7.33-7.47 (m, 7H), 7.53 (d, 2H, J=8.8 Hz), 7.57-7.60 (m, 2H), 7.71 (d, 1H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:14]=[CH:13]C(C)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].S(=O)(=O)(O)O.[C:23]([O:26][C:27](=[O:29])[CH3:28])(=[O:25])[CH3:24]>O.[O-2].[O-2].[O-2].[Cr+6]>[C:23]([O:26][CH:27]([O:29][C:27](=[O:26])[CH3:28])[C:28]1[CH:11]=[CH:10][C:9]([C:3]([O:8][C:23](=[O:25])[CH3:24])([C:2]([F:1])([F:16])[F:17])[C:4]([F:5])([F:6])[F:7])=[CH:14][CH:13]=1)(=[O:25])[CH3:24]
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: CC(=O)OC(OC(C)=O)c1ccc(C(OC(C)=O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 156 g (0.60 mole) of 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]toluene in 675 ml of acetic anhydride is added 135 ml of concentrated sulfuric acid at 0°. To the solution stirred at 0° is added a soluton of 168 g (1.68 mole) of chromium trioxide in 750 ml of acetic anhydride dropwise over a two-hour period. After stirring is continued for an additional two hours, the resulting reaction mixture is poured into five liters of ice and is diluted with five liters of water to obtain an aqueous mixture which is allowed to stand for 18 hours. An oily solid with water above it is obtained. Water is decanted from the oily solid. The solid is dissolved in ether to obtain a solution which is washed with water and sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to give an oily solid. The solid is triturated with ether, filtered and recrystallized from chlorobutane to give 60 g of α,α -bis-acetyloxy-4-[1-(acetyloxy)-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]toluene, m.p. 93°-94.6°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[CH3:25][C@H:26]1[O:31][C@@H:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>>[CH3:32][C@@H:30]1[O:31][C@H:26]([CH3:25])[CH2:27][N:28]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)[N:3]=2)[CH2:29]1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(N2C[C@@H](C)O[C@@H](C)C2)n1

Procedure:
The title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and cis-2,6-dimethylmorpholine in analogy to example 1c. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a yellowish solid in 58% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[N:13]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH:12]=3)=[CH:10][C:3]=12.CO>[OH-].[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[N:13]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCN1CCN(C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3[nH]1)cn2CCN1CCN(C)CC1
Yield: 59.9 %

Procedure:
Reflux bisazaindole 35 (40 mg, 0.066 mmol) in KOH at 3%/MeOH (10 mL) for 16 h, then concentrate under vacuum. The residue is dissolved in EtOAc, washed with saturated NaHCO3, dried (Na2SO4) and submitted to flash chromatography on SiO2 (MeOH at 4%/CH2Cl2, 0.25% of NH3) to give 36 (18 mg, 60.2%) as a white solid: 1H NMR (CDCl3. δ 10.94 (s broad, 1H), 8.07 (d, 1H, J=5.2 Hz), 7.61 (s, 1H), 7.15 (s, 1H), 7.05 (d, 1H, J=5.2 Hz), 6.65 (d, 1H, J=2 Hz), 4.23 (s overlapping t, 5H, J=6.5 Hz), 3.97 (s, 3H), 2.79 (t, 2H, J=6.5 Hz), 2.55-2.45 (m broad, 8H), 2.29 (s, 3H), TLC (MeOH at 10%/CH2Cl2, 0.25% of NH3) Rf=0.35, m/z obs.=455.11 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>CO>[C:17]1([CH:15]([C:12]2[S:13][CH:14]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[N:11]=2)[CH3:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(c1ccccc1)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Solvent: CO
Product: CC(c1ccccc1)c1nc(-c2ccc(N)cc2)cs1
Reaction time: 12 h

Procedure:
4-(4-nitrophenyl)-2-(1-phenylethyl)-1,3-thiazole (1-5, 0.13 g, 0.42 mmol) was dissolved in anhydrous MeOH (5.0 mL) and deoxygenated under vacuum. 10% Pd/C (0.02 g) was added and the reaction was purged with an H2 baloon. The vigorously stirred reaction was kept under H2 for 12 h, and then filtered through celite. The reaction was then concentrated and subjected to reverse phase HPLC (C-8, 5-95% MeOH—H2O w/0.1% TFA) to provide pure 4-[2-(1-phenylethyl)-1,3-thiazol-4-yl]aniline (4-1). 1H NMR (300 MHz, CDCl3) δ 8.20 (d, J=8.6 Hz, 2H), 7.71 (s, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.34 (d, J=7.8 Hz, 2H), 7.32 (dd, J=7.8, 7.3 Hz, 2H), 7.24 (dd, J=7.3, 7.1 Hz, 1H), 5.01 (br s, 2H), 4.52 (q, J=7.1 Hz, 1H), 1.79 (d, J=7.1 Hz, 3H); MS 281.0 found 281.4 (M+H+) required.
Reaction SMILES: C[O:2][C:3]1([CH3:10])O[CH:8]2[CH:5]([CH2:6][CH2:7]2)[O:4]1.C[Si](C)(C)[Cl:13]>C(Cl)Cl>[Cl:13][C@@H:8]1[CH2:7][CH2:6][C@H:5]1[O:4][C:3](=[O:2])[CH3:10]
Reactant: C[Si](C)(C)Cl
Reactant: COC1(C)OC2CCC2O1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CC[C@H]1Cl
Yield: 88.8 %

Procedure:
14.4 g (0.1 mol) of 3-methoxy-3-methyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) and 16.2 g (0.149 mol) of trimethylchlorosilane in 50 ml of methylene chloride are heated under reflux for 15 hours. Stripping off the solvent and fractional distillation of the residue gives 13.2 g (89%) of trans-1-chloro-2-acetoxy-cyclobutane. Boiling point10 66°, nD20 1.4472.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[CH:12][N:13]2[C:18]=1[C:17](=[O:19])[NH:16][C:15]([CH3:20])=[N:14]2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH2:1]([N:16]1[C:17](=[O:19])[C:18]2=[C:10]([Cl:9])[CH:11]=[CH:12][N:13]2[N:14]=[C:15]1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nn2ccc(Cl)c2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
Benzyl bromide (9.97 ml, 83.9 mmol) was added to a solution of 5-chloro-2-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (14 g, 76.3 mmol) and Cs2CO3 (29.7 g, 91.5 mmol) in dioxane (300 mL). The reaction mixture was stirred at 95° C. for 3 h, cooled to room temperature, filtered through Celite® and the filtrate concentrated in vacuo. The residue was dissolved in CHCl3 (100 mL), treated with saturated NaCl solution (200 mL), and extracted with CHCl3 (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated with Et2O, the solid filtered, washed with petroleum ether and dried in vacuo to afford the title compound (19.5 g, 94%) as a white solid: 1H NMR (DMF-d7) δ 7.57 (m, 1H), 7.32–7.41 (m, 5H), 6.65 (m, 1H), 5.31 (s, 2H), 2.38 (s, 3H); MS (ESI+) 274 (M++H), HRMS (ESI+): calculated: 274.0747 (M++H). found: 274.0757 (M++H).