Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:56]=[CH:55][C:5]([O:6][CH:7]2[CH2:18][N:17]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[CH2:16][CH2:15][CH2:14][N:13]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH2:12][CH2:11][CH2:10][N:9]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[N+:52]([O-:54])=[O:53])(=[O:45])=[O:44])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:57]([OH:63])[CH2:58][CH2:59][CH2:60][C:61]#[CH:62]>C1COCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:63][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][C:2]1[CH:56]=[CH:55][C:5]([O:6][CH:7]2[CH2:8][N:9]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[N+:52]([O-:54])=[O:53])(=[O:44])=[O:45])[CH2:10][CH2:11][CH2:12][N:13]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N+:40]([O-:42])=[O:41])(=[O:32])=[O:33])[CH2:14][CH2:15][CH2:16][N:17]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])(=[O:20])=[O:21])[CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC(Oc2ccc(I)cc2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCC1
Reactant: C#CCCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC(Oc2ccc(CCCCCCO)cc2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 5b (250 mg, 0.26 mmol) and 5-hexyn-1-ol (43 μL, 0.39 mmol) were dissolved in the mixture of dry THF (6 mL) and triethylamine (2 mL) and the mixture was deaerated with argon. Pd(Ph3P)2Cl2 (3.6 mg, 0.005 mmol) and CuI (1.9 mg, 0.01 mmol) were added, and the mixture was stirred overnight at RT in dark. All volatiles were removed in vacuo. The residue was suspended in dichlormethane, washed twice with water and dried over Na2SO4. Purification on silica gel (eluent: MeOH: CH2Cl2, 1:9, v/v) yielded the title compound. 1H NMR (CDCl3): 7.99 (1H, m); 7.87 (2H, m); 7.78-7.57 (tot 9H); 7.29 (2H, d, J 8.8); 6.97 (2H, d, J 8.8); 5.12 (1H, m); 4.08 (2H, dd, J 4.6 and 15); 3.81-3.69 (tot 10H); 3.13 (2H, dd, J 5.1 and 15); 2.42 (2H, t, J 6.6); 1.78-1.63 (tot 4H); 1.32 (1H, t, J 4.7). ESI-TOF MS: required for C39H43N6O14S3+ (M+H)+ 915.19; found 915.24.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO.CCOCC>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(C=Cc2ccnc3ccccc23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: OCc1ccc(C=Cc2ccnc3ccccc23)cc1
Reaction time: 0.33 h

Procedure:
A 50 mL solution of (1) in MeOH was cooled to 0° C. and NaBH4 (2 molar excess) was added. Stirring continued for 20 minutes at a temperature of about 0° to 20° C. The reaction mixture was diluted with Et2O, filtered through a thin layer of SiO2 and evaporated to provide a 1.59 g (≈100%) yield of (2).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(O[C@@H](CCN[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])C(=O)OC1C(F)=C(F)C(F)=C(F)C=1F)(=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:38]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]
Reactant: O=C(NCC[C@H](OC(=O)c1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)Oc1ccccc1[N+](=O)[O-]
Yield: 26.3 %

Procedure:
To a stirring solution of 3′,4′,3′″,4′″-tetra-dehydro-3,2′,6′,2′″,6′″-penta-Cbz-neomycin (4, 190 mg, 0.156 mmol) in DMF (2 mL) was added succinimidyl benzoyloxy(2-Cbz-aminoethyl)carbamate (3, 81 mg, 0.18 mmol) and the reaction was stirred under a nitrogen atmosphere. DIPEA (67 μL, 0.38 mmol) was added and the reaction was stirred for 2 days. The reaction mixture was purified on a 2-inch reverse-phase HPLC column, followed by treatment with sat. aq. NaHCO3 to remove the benzoyl protecting group to yield a crude, which was purified on a 1-inch reverse-phase column to yield (5) (60 mg, 0.041 mmol, 26.3% yield): MS m/z (M+Na)+ calc. 1475.5, obs. 1475.4.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CC(C)n1cc(Br)ccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (100 mg, 0.21 mmol) in 1,4-dioxane (2 mL) was added 5-bromo-1-isopropylpyridin-2(1H)-one (54.2 mg, 0.25 mmol). Then catalysts of Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cs2CO3 (1 mL, 2 M) were added. The vessel was sealed with a septum and placed into the microwave cavity. Microwave irradiation of 100 W was used, the temperature being ramped from room temperature to 120° C. Once this temperature was reached, the reaction mixture was held at this temperature for 30 min. After the mixture cooled to rt, the mixture was filtered. The filtrate was extracted with EtOAc (20 mL×4), the organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product which was purified by preparative HPLC to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (22 mg, 21%). 1H NMR (CDCl3): 1.13 (s, 3H), 1.19 (s, 3H), 1.40 (6H), 1.53 (d, 3H), 2.18-2.30 (m, 4H), 2.40 (m, 1H), 2.88 (m, 1H), 5.31 (m, 1H), 5.70 (m, 1H), 6.73 (d, 1H), 7.02 (d, 2H), 7.15 (d, 2H), 7.27-7.38 (m, 5H), 7.43 (d, 1H), 7.50 (d, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=[O:33])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:33])=[CH:27][CH:26]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCO)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCOC(=O)Cc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxybutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and (4-fluorophenyl)acetyl chloride: ESMS m/e: 455.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:17]([O-:20])(=[O:19])[CH3:18].[K+]>C(O)(=O)C>[C:17]([O:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:20][C:17](=[O:19])[CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)(=[O:19])[CH3:18]
Reactant: ClCc1ccc(-c2ccc(CCl)cc2)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(-c2ccc(COC(C)=O)cc2)cc1
Yield: 68 %

Procedure:
0.1 moles 4,4'bis(chloromethyl)biphenyl (prepared by method A above), 0.25 moles potassium acetate and 100 mls glacial acetic acid were reflux for 17 hours with stirring. The reaction mixture was filtered and the filtrate evaporated to dryness at 80° C. under water pump vaccum. The residue was recrystallised from methanol to yield 0.068 moles product=68 percent of theory.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.FC(F)(F)COP([CH2:31][C:32]([O:34][CH3:35])=[O:33])(OCC(F)(F)F)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:48](=O)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>O1CCCC1.C1(C)C=CC=CC=1>[C:49]1(/[CH:48]=[CH:31]\[C:32]([O:34][CH3:35])=[O:33])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C\c1ccccc1
Temperature: -78 °C

Procedure:
9.4 g of 18-crown-6 and 1.7 ml of methyl [bis(2,2,2-trifluoroethoxy)-phosphoryl]acetate are dissolved under argon in 120 ml of dry tetrahydro-furan and cooled to −78° C. 14.3 ml of a 0.5 molar solution of potassium bis(trimethylsilyl)amide in toluene are added to this mixture, followed by 0.85 ml of benzaldehyde. After stirring at −78° C. for thirty minutes, the reaction mixture is quenched by adding saturated ammonium chloride solution and extracted with five portions each of 50 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and then the solvent is removed in vacuo. The residue is purified on silica gel with n-heptane:ethyl acetate=20:1 as eluent. 1.1 g of methyl (Z)-3-phenylacrylate are obtained as an oil.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].[NH2:15][C:16]1[CH:36]=[CH:35][C:19]([O:20][C:21]2[CH:26]=[C:25]([NH:27][C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[N:24]=[CH:23][CH:22]=2)=[C:18]([Cl:37])[CH:17]=1.C(OCC)C.CCCCCC>C(#N)C>[Cl:37][C:18]1[CH:17]=[C:16]([NH:15][C:12]([NH:13][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:11])[CH:36]=[CH:35][C:19]=1[O:20][C:21]1[CH:26]=[C:25]([NH:27][C:28]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)=[O:29])[N:24]=[CH:23][CH:22]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c(Cl)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC#N
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
2-Phenylacetyl chloride (0.86 ml) was dissolved in acetonitrile (5 ml) under a nitrogen atmosphere, and then potassium thiocyanate (127 mg) was added thereto at 60° C., followed by stirring at the same temperature for 3 hrs. The reaction mixture was cooled down to room temperature, and then a solution of 4-(4-amino-2-chlorophenoxy)-6-[(pyrrolidin-1-yl)carbonylamino]pyridine (145 mg) in acetonitrile (5 ml) was added thereto, followed by stirring at room temperature for 1.5 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether/hexane (1/2) was added to suspend. The resultant solid was filtered off and dried under aeration to provide the titled compound (122 mg, 55%) as white powder.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[F-].[K+].O>CN(C)C=O>[C:4]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])#[CH:3]
Reactant: C[Si](C)(C)C#Cc1ccccc1C=O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of 2-trimethylsilanylethynyl-benzaldehyde (6 g, 29.70 mmol) in N,N-dimethylformamide (10 mL) was added potassium fluoride (1 g, 17.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The resulting solution was poured into water, and then extracted with dichloromethane. The collected organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (RediSep® Flash column, 230-400 mesh, 0-25% ethyl acetate in hexane) gave 2-ethynyl-benzaldehyde (2.8 g, 73%) as a white solid. MS (ESI+) cald for C9H6O [(M+H)+] 130, obsd. 131.
Reaction SMILES: [CH:1]1([C:5]([NH:7][C@H:8]([C:24]([NH:26][CH:27]([P:35](=[O:40])([O:38]C)[O:36]C)[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[O:6])[CH2:4][CH2:3][CH2:2]1.C[Si](Br)(C)C.C(O)(C)C.N>ClCCl.O>[CH:1]1([C:5]([NH:7][C@H:8]([C:24]([NH:26][CH:27]([P:35](=[O:36])([OH:40])[OH:38])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COP(=O)(OC)C(Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)C1CCC1
Agent: C[Si](C)(C)Br
Agent: N
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: O=C(NCCCC[C@H](NC(=O)C1CCC1)C(=O)NC(Cc1ccccc1)P(=O)(O)O)OCc1ccccc1
Reaction time: 8 h

Procedure:
The dimethyl ester product from part (e) (1.04 g., 1.81 mmole) is dissolved in dichloromethane (10 ml.) and treated with trimethysilylbromide (0.52 ml., 605 mg., 3.96 mmole). The mixture is stirred under argon overnight then concentrated in vacuo. Dioxane (15 ml.) and water (5 ml.) are added and the resulting mixture is stirred for 15 minutes and then concentrated. Residual water is chased three times with acetonitrile (20 ml.) giving 1.06 g. of [1-[[N2 -(cyclobutylcarbonyl)-N6 -[(phenylmethoxy)carbonyl]-L-lysyl]-2-phenylethyl]phosphonic acid as an organe-yellow foam. TLC (silica gel; isopropanol:ammonia:water, 7:2:1) Rf =0.42.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>[Ni].C(O)C>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2[nH]nnc2c1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2[nH]nnc2c1
Yield: 73.4 %

Procedure:
5-Nitrobenztriazole (10 g) was shaken with Raney nickel (3 spoons) and ethanol (200 ml) under hydrogen at atmospheric pressure until the uptake of hydrogen ceased. The Raney nickel was removed by filtration through Keiselguhr, and the dark ethanolic solution was evaporated to dryness. Crystallization from aqueous ethanol afforded 5-aminobenzotriazole (6 g, 75 percent).
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].C(O)(=O)C.Br(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2nc(C)sc2C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [O-][Br+2]([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc(-c2ccc(O)cc2)c(C(C)C)s1
Reaction time: 18 h
Yield: 84.1 %

Procedure:
While 35.8 g of 5-isopropyl-4-(4-methoxy-phenyl)-2-methyl-1,3-thiazol (5) prepared in Example 3 were added to 86 ml of acetic acid and stirred, 500 ml of 48% bromic acid were added. Subsequently, the temperature was gradually increased and stirring under reflux was continued for 18 hr. The temperature was decreased to room temperature, and 400 ml of dichloromethane were added and stirring was further continued for 30 min. Then, the dichloromethane layer was removed. Thereafter, the obtained reaction solution was added with a saturated aqueous solution of potassium carbonate to be neutralized at pH 7-8, after which the precipitated solid was filtered and then washed with water, thus obtaining 28.4 g (yield: 84%) of a title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:23])[C:11]([OH:22])([CH3:21])[CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:5][C:4]=1[C:24]([F:27])([F:26])[F:25])#[N:2].[OH2:28].[OH:29]OS([O-])=O.[K+]>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:23])[C:11]([OH:22])([CH3:21])[CH2:12][S:13]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)(=[O:29])=[O:28])=[CH:5][C:4]=1[C:24]([F:27])([F:26])[F:25])#[N:2]
Reactant: CC(O)(CSc1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CO
Product: CC(O)(CS(=O)(=O)c1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 40 g (0.1 mol) of N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-thio]-2-hydroxy-2-methyl-propionamide in 600 ml of methanol and 400 ml of water 100 g (0.16 mol) of Oxone® oxidizing agent [2KHSO5KHSO4K2SO4 salt] was added. The reaction mixture was stirred at 25° C. for 6 h, then the methanol was distilled off under diminished pressure and the residue was extracted twice with 500 ml of dichloromethane. The organic layer was washed twice with 400 ml of 10% aqueous sodium thiosulfate solution, then with brine, dried over sodium sulfate and concentrated under diminished pressure. The residue was recrystallized from a 1:4 mixture of ethyl acetate/petroleum ether, which has a boiling range of 40–70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]2[C:6]([C:7](=[O:31])[N:8]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[C:9](=[O:19])[NH:10]2)=[CH:5][CH:4]=1.C(O)C.[H][H]>[C].[Pd].O1CCOCC1>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:8]2[C:7](=[O:31])[C:6]3[C:11](=[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:10][C:9]2=[O:19])=[CH:23][CH:24]=1
Reactant: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc([N+](=O)[O-])cc3)c(=O)[nH]c12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc(N)cc3)c(=O)[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
7-Methoxy-3-[2-(4-nitrophenyl)ethyl]-8-pentyloxy-1H-quinazoline-2,4-dione (45.0 g, 105 mmol) obtained in Example 7-39, ethanol (1300 ml) and dioxane (700 ml) were mixed, and 10% palladium-carbon catalyst (4.5 g) was added to this solution. The reaction mixture was stirred in a stream of hydrogen at room temperature for 16.5 hours, followed by filtration. Activated charcoal (2.6 g was added to the filtrate, and the reaction mixture was stirred at 50° C. for 1 hour and then filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=3/1). The precipitated crude crystals were recrystallized from ethanol-hexane to give 3-[2-(4-aminophenyl)ethyl]-7-methoxy-8-pentyloxy-1H-quinazoline-2,4-dione (33.82 g, 81%) as pale-yellow crystals.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[NH:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:19][O:18][C:14]1[N:13]=[N:12][C:17]([S:1][C:2]2[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:16][CH:15]=1
Reactant: Sc1cc2ccccc2[nH]1
Reactant: COC1=CC=CN(Cl)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Sc2cc3ccccc3[nH]2)nn1
Yield: 31 %

Procedure:
To a solution of 2-mercaptoindole (6.7 mmol, 1.0 g) in acetone (20 mL) was added 2-chloro-6-methoxy-pyridazine (144 mmol, 1.52 g) and potassium carbonate (70 mmol, 0.98 g) and the reaction mixture was refluxed for 2 hours. Excess acetone was removed and the residue was partitioned between CHCl3 (20 mL) and H2O (20 mL). The CHCl3 layer was collected, dried, filtered and the filtrate was evaporated to a residue, which was purified by silica gel chromatography (eluent: hexanes:EtOAc::4:1) to obtain 3-methoxy-6-(indole-2-sulfenyl)-pyridazine (31%, 534 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C([O:20][C:21](=O)[C:22](OCC)=[O:23])C.CC(C)([O-])C.[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:17])[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:22]([OH:23])[C:21]2=[O:20])=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=C1C(O)=C(c2ccccc2)C(=O)N1c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
After the addition of anhydride THF (20 ml) to compound 5d (1.40 g, 7.34 mmol), the temperature was adjusted to 0° C. Diethyloxalate (1.45 g, 9.50 mmol) and potassium t-butoxide (1.35 g, 11.9 mmol) were added thereto and the agitation for 3 hours was carried out. After the identification of the reaction progress with TLC, the solution was poured into the distilled water and acidified with 1N HCL aqueous solution. Three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4 and solvents were removed. Crude purification was carried out by the column chromatography but the next reaction was followed since the purified compound was small in quantity.
Reaction SMILES: B1([C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]=2)OC(C)(C)C(C)(C)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1I.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:43]1[C:52]2[C:47](=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][N:44]=1>O1CCOCC1.O.C(OCC)C>[CH:43]1[C:52]2[C:47](=[C:48]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[C:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH:11]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][N:44]=1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Reactant: OB(O)c1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3cnccc23)CC1
Temperature: 100 °C
Yield: 76.2 %

Procedure:
A solution of Cl2Pd(dppf)-CH2Cl2 adduct (Strem Chemicals Inc., Newburyport, Mass., 1.157 g, 1.416 mmol), (n-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (8.76 ml, 28.3 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (9.94 g, 28.3 mmol), and potassium phosphate (36.1 g, 170 mmol) in 100 mL dioxane, 40 mL water was heated to 100° C. 3 hours. LC/MS showed complete consumption of starting material. Isoquinolin-5-ylboronic acid (4.90 g, 28.3 mmol) and Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 1.003 g, 1.416 mmol) were added, and the reaction mixture was again heated to 100° C. for an additional hour. The reaction mixture was allowed to cool to room temperature and was diluted with diethyl ether. The organics were washed with water, then brine, dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 4-(2-(isoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (9.80 g, 21.56 mmol).