Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCC(OC)=O.C[O-].[Na+].[CH3:10][O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]C>>[CH3:10][O:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:14]
Reactant: CCCCCCCCO
Reactant: COCC(=O)OC
Agent: COC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCCOC(=O)COC
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 74 %

Procedure:
537.2 g (4.95 mol) of methyl chloroacetate are initially introduced and stirred at 25° C. 936.4 g (5.2 mol) of 30% strength sodium methoxide solution are added dropwise in the course of 2.5 h such that a reaction temperature of 65° is not exceeded. After the addition, stirring is continued at reflux temperature for a further 3 h. 511.9 g of methanol are then removed from the reaction mixture by distillation. 1,289.3 g (9.9 mol) of n-octanol are added to the residue and the mixture is heated under reflux. In the course of this, methanol is removed through a 0.5 m long Multifil column at a reflux ratio of approximately 1:1 (303.5 g of distillate), the bottom temperature rising to 210° C. during the removal. After 6.5 h, the conversion of the methyl methoxyacetate to the n-octyl methoxyacetate is >98%. The reaction mixture is fractionated through a 0.5 m long Multifil column. Initially, n-octanol and methyl methoxyacetate are distilled off n-Octyl methoxyacetate (740.0 g, yield 74%) is then obtained as a main fraction with a purity >99%, a chlorine content of 10 ppm and a water content of <0.05%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:12][C:4]1[CH:3]=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20 g of Tin (II) Chloride in portions. The reaction was heated to 55° C. and monitored by TLC until complete. Solvent was concentrated and extraction was performed in Ethyl Acetate and water with TEA to reduce emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give 3.9 g of methyl 4-amino-2-chlorobenzoate. 1 g of methyl 4-amino-2-chlorobenzoate was cooled to 0° C. in DCM with 485 μL of Pyridine before Methanesulfonyl Chloride was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with saturated bicarbonate solution and then brine. The crude material was dried over Magnesium Sulfate, filtered and concentrated to give 1.54 g of methyl 2-chloro-4-(methylsulfonamido)benzoate. 107 μL of 1-bromo-2-methoxyethane and 556 mg of Cesium Carbonate were added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate. 182 mg of methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 169 mg of crude 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid. 65 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methylsulfonamido)benzamide. MS (Q1) 494 (M)+.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][C:14]=2[O:27]CC2C=CC=CC=2)[CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3]>CO.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[OH:27])[CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)COC(=O)N1CCC(c2ccc(O)cc2O)C1
Reaction time: 18 h

Procedure:
In a 25 ml round-bottomed flask, 0.22 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid isobutyl ester is dissolved in 6 ml of methanol in the presence of 0.1 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 18 hours under a hydrogen atmosphere. The reaction mixture is filtered and the residue is then chromatographed on silica gel (1/1 heptane/ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])=[O:22]
Reactant: COc1ccccc1N=C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: COc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 27 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-methoxy phenyl isocyanate (1 mmol.) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (82 mg, 27%). EI-MS m/z 302 (M−H)−
Reaction SMILES: Cl.C([NH:5][C:6]1[C:7]([F:28])=[CH:8][C:9]2[N:13]=[N:12][N:11]([C:14]3[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[C:10]=2[CH:27]=1)(=O)C.O>CO.S(=O)(=O)(O)O>[NH2:5][C:6]1[C:7]([F:28])=[CH:8][C:9]2[N:13]=[N:12][N:11]([C:14]3[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[C:10]=2[CH:27]=1
Reactant: COC(=O)C(C)Oc1ccc(-n2nnc3cc(F)c(NC(C)=O)cc32)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)C(C)Oc1ccc(-n2nnc3cc(F)c(N)cc32)cc1
Temperature: 25 °C

Procedure:
Concentrated hydrochloric acid (6.3 mL) is added to a solution of methyl 2-[p-(6-acetamido-5-fluoro-1H-benzotriazol-1-yl)phenoxy]propionate (4.77 g, 0.013 mol) in methanol. The reaction mixture is refluxed for 18 hours, cooled to room temperature and concentrated in vacuo to obtain a solid. 1HNMR spectral analysis of the solid indicates that ester hydrolysis has occurred. A solution of the solid, sulfuric acid (4 drops) and methanol is refluxed for 6 hours, cooled to room temperature and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a brown powder which is identified by NMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([N+:18]([O-])=O)=[CH:13][CH:12]=3)[N:9]=[C:8]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:5]2=[N:6][CH:7]=1.[H][H]>N1C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[CH:13][CH:12]=3)[N:9]=[C:8]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:5]2=[N:6][CH:7]=1
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Product: Nc1ccc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N

Procedure:
300 mg (0.785 mmol) of the compound from example 39A were initially charged in pyridine (35 ml), then 119 mg of palladium (10% on charcoal) were added and the mixture was hydrogenated at standard hydrogen pressure overnight. The reaction mixture was filtered through kieselguhr and washed through with ethanol, and the filtrate was concentrated. This gave 219 mg (92% purity, 73% of theory) of the title compound in solid form.
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].CO>C(O)C>[C:1]([NH:9][C@@H:10]([C:11]([OH:13])=[O:12])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=Cc1ccccc1)NC(=O)c1ccccc1
Reactant: [H][H]
Solvent: CO
Solvent: CCO
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1ccccc1
Yield: 97.7 %

Procedure:
3.2 grams of α-benzamido-cinnamic acid were dissolved in 40 ml of absolute ethanol and treated with 0.3 ml of the catalyst solution produced in Example 19. The reaction mixture was sucked into a 100 ml autoclave. It was pressurized with 6 bars of hydrogen pressure. After taking up the theoretical amount of hydrogen it was worked up as customary (e.g. see Example 6). There were isolated 3.15 grams of N-benzoyl-(R)-phenylalanine having the rotary value of [α]D27 =+38.6° (c=1/CH3OH), corresponding to an optical yield of 95.8%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[S:14](Cl)(=[O:17])(=[O:16])[NH2:15].C(N(CC)CC)C>C(#N)C>[CH3:13][C:6]1[C:5]2[CH:4]=[CH:3][C:2]([O:1][S:14](=[O:17])(=[O:16])[NH2:15])=[CH:11][C:10]=2[O:9][C:8](=[O:12])[CH:7]=1
Reactant: NS(=O)(=O)Cl
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(=O)oc2cc(OS(N)(=O)=O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A slurry of 7-hydroxy-4-methylcoumarin (17.6 g, 0.10 mole) in acetonitrile (100 ml) was treated with a total of 84 ml of 3M sulfamoyl chloride (0.255 mole) in acetonitrile. The mixture was then treated dropwise with triethylamine (25.8 g, 0.255 mole). The reaction temperature was allowed to rise to 45° without any cooling. The mixture was stirred overnight at ambient temperature. The precipitate was collected, triturated with water, and dried in a vacuum oven at 70° C. for 15 hr to give 10.5 g (41%) of white powder, mp 161°-164° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:36])[CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([F:36])[CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Fc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5cc(F)ccc5n4)cc3CC[C@@H]12
Yield: 62.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-6-fluoro-quinoline (84 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 96 mg (62%) of the title compound as a solid. mp 152°-155°. FDMS: m/e=406. α[D]589 =+63.16 (c=0.61, chloroform).
Reaction SMILES: C[C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:17]>CN(C)C=O>[F:8][C:7]1[CH:2]=[C:3]([C:10]([O:12][CH3:13])=[O:11])[NH:4][C:5](=[O:17])[CH:6]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1c(C)c(F)cc[n+]1[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cc(=O)[nH]1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (3, 1 g, 5.84 mmol) in dimethylformamide (25 mL) is added trifluoroacetic anhydride (1.62 mL, 11.68 mmol). The reaction is stirred at 50° C. for 3 h. The resulting mixture is concentrated and purified via flash chromatography to afford methyl 4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (4).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[NH:12][C:11]([CH:13]=[C:14]4[N:36]=[C:17]([C:18]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[C:19]5[NH:29][C:22](=[CH:23][C:24]6[CH:25]=[CH:26][C:27]=2[N:28]=6)[CH:21]=[CH:20]5)[CH:16]=[CH:15]4)=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:50])C=CC=1)=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[I:50][C:23]1[C:24]2[CH:25]=[CH:26][C:27]([N:28]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[NH:12][C:11]([CH:13]=[C:14]3[N:36]=[C:17]([C:18]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:19]4[NH:29][C:22]=1[CH:21]=[CH:20]4)[CH:16]=[CH:15]3)=[CH:10][CH:9]=2
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Reactant: C1=Cc2nc1cc1ccc([nH]1)c(-c1ccccc1)c1nc(cc3ccc([nH]3)c2-c2ccccc2)C=C1
Agent: II
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Ic1c2nc(c(-c3ccccc3)c3ccc(cc4nc(c(-c5ccccc5)c5ccc1[nH]5)C=C4)[nH]3)C=C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
50 mg (0.11 mmol) of 5,15-diphenylporphyrin was dissolved in 50 ml of dry CHCl3. To the stirred solution was added 3 ml of a solution of iodine in chloroform (0.055M). Finally, a solution of 50 mg (0.12 mmol) bis(trifluoroacetoxy)iodobenzene dissolved in 25 ml of chloroform was added dropwise, followed by 200 μl of pyridine. The mixture was stirred at 25° C., in the dark, for one hour. After evaporation of the solvent in vacuo, the residue was chromatographed on silica gel, eluting with 50% 1,1-dichloromethane in hexane to give 44 mg of 10-iodo-5,15-diphenylporphyrin (70% yield). UV-Vis (CH2Cl2): λmax 422, 520, 560, 600, 660 nm; MS (EI) m/e 588(100). Annotated wavelengths for electronic absorption spectrum shown in FIG. 1:
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4].N1C=CN=C1.[OH:14][CH:15]([C:26]1[S:41][C:29]2[N:30]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:31](=[O:36])[N:32]([CH3:35])[C:33](=[O:34])[C:28]=2[CH:27]=1)[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH3:1][Si:2]([CH3:7])([C:3]([CH3:6])([CH3:5])[CH3:4])[O:14][CH:15]([C:26]1[S:41][C:29]2[N:30]([CH2:37][CH:38]([CH3:39])[CH3:40])[C:31](=[O:36])[N:32]([CH3:35])[C:33](=[O:34])[C:28]=2[CH:27]=1)[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(O)c3cccc4ccccc34)sc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(O[Si](C)(C)C(C)(C)C)c3cccc4ccccc34)sc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.9 %

Procedure:
Dimethyl-(1,1-dimethylethyl)silyl chloride (230 mg) and imidazole (130 mg) were added to a solution of (±)6-(1-hydroxy-1-[1-naphthalenyl]methyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (500 mg) in dimethylformamide (10 ml). The solution was stirred at ambient temperature for 3 days. The reaction mixture was quenched with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was separated and washed twice with dilute hydrochloric acid and once with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by chromatography on silica gel eluting with isohexane:ethyl acetate (4:1 to 2:1) gave the subtitle product (0.47 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:17](=[O:25])[C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])(=O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:17](=[O:25])[C:18]([CH3:23])([O:24][Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])[C:19]([F:22])([F:21])[F:20])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CC(O)(C(=O)NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC(C)(C(=O)NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-amino-6-bromo-W-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-5-(trifluoromethyl)picolinohydrazide (step 1) (4 g, 9.11 mmol) in DCM (60 ml), triethylamine (1.270 ml, 9.11 mmol) was added to give a yellow solution. The solution was cooled to 0° C. (ice bath) and treated with triisopropylsilyl trifluoromethanesulfonate (4.94 ml, 18.22 mmol). The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to RT and stirred for 3 days. The reaction mixture was partitioned between DCM (100 ml) and water (100 ml), phases shaken and separated. The organic portion was washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo. The resulting oil was purified by chromatography on silica eluting with 0-30% DCM in iso-hexane to afford the title compound; LC-MS Rt=1.58 min [M+H]+ 595/597 Method 2minLC_v003.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=2[C:20]([F:36])([F:35])[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1ccccc1)c1ccccc1C(F)(F)F
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: FC(F)(F)c1ccccc1C(OC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1

Procedure:
This material was prepared from 1-benzhydrol-3-azetidinol (1) (7.5 mmol) and 2-(trifluoromethyl)benzhydrol (131) (15 mmol) using the procedure described for compound (3) (1.81 g, 51%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:7][CH:6]=1.C(O[CH2:34][CH3:35])(=O)C>N1CCCCC1>[OH:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:11]4[CH2:35][CH2:34][CH2:6][CH2:7][CH2:8]4)=[CH:6][CH:7]=3)[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)=[N:13]2)=[CH:18][CH:17]=1
Reactant: O=c1c2ccc(O)cc2nc(-c2ccc(O)cc2)n1-c1ccc(OCCCl)cc1
Reactant: CCOC(C)=O
Solvent: C1CCNCC1
Product: O=c1c2ccc(O)cc2nc(-c2ccc(O)cc2)n1-c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
A solution containing 0.25 g (0.000612 mol) of 3-[4-(2-chloro-ethoxy)-phenyl]-7-hydroxy-2-(4-hydroxy-phenyl)-3H-quinazolin-4-one in 7 mL of piperidine was stirred and heated to reflux for 2 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture and the solvents were co-evaporated to near dryness in a rotary evaporator. The dark residue was extracted with ethyl acetate and water. The aqueous layer was removed and chilled on ice. The precipitate which then formed was collected by vacuum filtration (0.052 g, mp 185-190° C.) and was shown to be the hydrochloride salt monohydrate.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]2[N:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[N:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Li+].I[CH3:23]>COCCOC.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][N:10]([C:11]3[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=3[F:17])[C:5]2=[N:4][C:3]=1[O:19][CH3:23]
Reactant: CI
Reactant: O=c1[nH]c2c(cnn2-c2c(F)cccc2F)nc1Br
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COc1nc2c(cnn2-c2c(F)cccc2F)nc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
A mixture of 5-bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (981 mg, 3.0 mmol) in 10 mL of DME and 1 mL of DMF at RT was treated with lithium hydride (119 mg, 15 mmol) in small portions. Iodomethane (0.62 mL, 9.9 mmol) was added 30 min later. The mixture was stirred at RT for 18 h, and poured into an ice cold sat. NH4Cl solution, then extracted twice with EtOAc. The combined EtOAc layes were washed with brine, dried and concentrated. Purification of the crude material on a silical gel column (25-85% EtOAc in Hexanes) provided: (1) 5-bromo-1-(2,6-difluorophenyl)-6-methoxy-1H-pyrazolo[3,4-b]pyrazine (65 mg, 6.4% yield) as an off white crystalline solid. MS (ES+): 341.0/343.0 (M+H)+; and (2) 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (616 mg, 60% yield) as an off white amorphous solid. MS (ES+): 341.0/343.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].[OH:10]O>C(O)(=O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10])[CH2:2][CH3:3]
Reactant: OO
Reactant: CCCc1ccccn1
Solvent: CC(=O)O
Product: CCCc1cccc[n+]1[O-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 2-n-propylpyridine (187.4 g, 1.505 mol) in 900 ml of acetic acid was added 149 ml of 35% aqueous hydrogen peroxide and the mixture was stirred and heated to 70-80° C. After three hours a further 104 ml of the hydrogen peroxide solution was added, and the mixture was maintained at the same temperature for an additional nine hours. The mixture was concentrated to about 300 ml in volume, 300 ml of water was added, and the mixture was concentrated as far as possible. The residue was made alkaline with anhydrous sodium carbonate, shaken with 750 ml of dichloromethane, and allowed to stand overnight. The resulting deposit of sodium carbonate and sodium acetate was removed by filtration. The filtrate was dried over magnesium sulfate, the solvent removed, and the residue distilled under reduced pressure. This gave 176 g (81%) of 2-n-propylpyridine-N-oxide. B.p. 120-140° C./9-15 mbar. 1H-NMR (CDCl3, 200 MHz) δ: 1.05 (t, 3H); 1.80 (sext, 2H); 2.89 (t, 2H); 7.10-7.28 (m, 3H); 8.28 (d, 1H).
Reaction SMILES: I.CS[C:4]1[NH:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[NH2:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>C(#N)C.C(O)(C(F)(F)F)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][NH:13][C:4]=1[NH:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: CSC1=Nc2ccccc2CN1
Agent: I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: c1ccc2c(c1)CNC(N[C@@H]1CCc3ccccc31)=N2
Temperature: 85 °C
Yield: 24.4 %

Procedure:
2-Methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (50 mg, 0.28 mmol) and (R)-1-aminoindane (37 mg, 0.28 mmol) were suspended in acetonitrile (1 ml) and heated in a screw-capped vial to 85° C. (6 h). The product was isolated from the reaction mixture by preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min) to give the title compound (18 mg, 24%).