Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a mixture of 2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione and 30 ml of dry dimethylformamide was added 0.6 g of approximately 50 % sodium hydride. The mixture was stirred for 30 minutes at room temperature and for additional 10 minutes at a temperature of 70°-80°C. To the mixture was further added dropwise 3.4 g of benzyl bromide and stirring was continued for 30 minutes. The solvent was removed from the resulting mixture by distillation, and to the residue was added water to give a crude precipitate. This product was recrystallized from a mixture of methanol and dimethylformamide to yield 3.3 g of 1-(m-nitrophenyl)-3-benzylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 219°-220°C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.I[CH:24]([CH3:26])[CH3:25]>>[CH:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: CC(=O)N[C@@H](C)CCc1ccc(Oc2ccc(O)cn2)cc1
Reactant: CC(C)I
Product: CC(=O)N[C@@H](C)CCc1ccc(Oc2ccc(OC(C)C)cn2)cc1

Procedure:
N—{(S)-3-[4-(5-Hydroxypyridin-2-yloxy)phenyl]-1-methylpropyl}acetamide (153 mg, 0.51 mmol) was reacted with 2-iodopropane in analogy to example 1a. Yield: 61 mg (35%), M+H+: 343.15.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3ccc([N+](=O)[O-])cc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3ccc(N)cc32)cc1
Yield: 38.9 %

Procedure:
3-Methyl-6-nitro-1-(toluene-4-sulfonyl)-1H-indazole (750 mg, 2.26 mmol) was dissolved in 30 ml of methanol at room temperature. 10% Palladium on Carbon (200 mg) was added and the mixture was stirred under a balloon of hydrogen overnight. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 4:1 Hexanes/Ethyl Acetate) to give 3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-ylamine (265 mg, 38.9%) as a light tan crystalline solid.
Reaction SMILES: [OH:1][C:2]1[C:19]2[C@@H:18]3[C@@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1.[N:22]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([S:28]([O:1][C:2]2[C:19]3[C@@H:18]4[C@@H:9]([C@H:10]5[C@@:14]([CH2:16][CH2:17]4)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]5)[CH2:8][CH2:7][C:6]=3[CH:5]=[C:4]([O:21][S:28]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:30])=[O:29])[CH:3]=2)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1CCC2=O
Product: C[C@]12CC[C@@H]3c4c(cc(OS(=O)(=O)N5CCCCC5)cc4OS(=O)(=O)N4CCCCC4)CC[C@@H]3[C@@H]1CCC2=O

Procedure:
The above compound is prepared from 1,3-dihydroxy-8α-estra-1,3,5(10)-trien-17-one by reaction with piperidinosulfonyl chloride analogously to Example 24.
Reaction SMILES: [N+:1]([CH:4](O)[CH3:5])([O-:3])=[O:2].[C:7]([OH:10])(=[O:9])[CH3:8].C1C=CC=CC=1>OS(O)(=O)=O.O>[N+:1]([CH2:4][CH2:5][O:10][C:7](=[O:9])[CH3:8])([O-:3])=[O:2]
Reactant: CC(O)[N+](=O)[O-]
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)OCC[N+](=O)[O-]

Procedure:
64 g nitroethanol, 50 ml glacial acetic acid, 250 ml benzene and 5 drops conc. H2SO4 were refluxed, using a water separator for 8 hours; 12 ml of H2O were collected. The solution was evaporated and vacuum distilled (1 mm at 60° C) yielding 89 g colorless nitroethylacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Fc1ccc(OCCCBr)cc1
Reaction time: 24 h
Yield: 14.7 %

Procedure:
To a solution of 4-fluorophenol (0.0567 g, 0.506 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.520 mL, 5.12 mmol) followed by Cs2CO3 (0.252 g, 0.774 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0173 g, 14.7%). EI-MS Rt (2.25 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].C[Si]([C:19]#[CH:20])(C)C.C([O-])([O-])=O.[K+].[K+]>C(N(CC)CC)C.CO.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>[C:19]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13])#[CH:20]
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution (flushed for 15 minutes with a stream of argon) of 13.55 g (53.8 mmol) of 6-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound H) in 280 ml of triethylamine was added 1.87 g (2.66 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.53 g (2.66 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then 100 ml (938.7 mmol) of trimethylsilyl acetylene was added. The reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100° C.) for 24 hours. The reaction mixture was then filtered through celite, washed with Et2O and the filtrate concentrated in vacuo to give crude 6-(2-trimethylsilyl)ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one. To a solution of this crude TMS-acetylenic compound in 50 ml of methanol was added 2.8 g (20.3 mmol) of K2CO3. The mixture was stirred for 8 hours at ambient temperature and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O (100 ml), washed with water (10 ml), 10% HCl (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[F:11].[C-:12]#[N:13].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[F:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:2][C:12]#[N:13]
Reactant: [C-]#N
Reactant: COc1ccc(CBr)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC#N)c(F)c1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a mixture of 1-Bromomethyl-2-fluoro-4-methoxy-benzene (4.5 g, 21 mmol) and Tetrabutylammonium iodide (0.66 g, 2.1 mmol) in CH2Cl2 (50 mL) was added a solution potassium cyanide (4.0 g, 60 mmol) in water (50 mL). The resulting biphasic mixture was stirred vigorously for 8 hours. The reaction was poured into water (100 mL) and extracted with CH2Cl2 (2×50 mL). The organics were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (10–30% EtOAc in hexanes) to give the product (2.6 g, 75% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ: 3.66 (s, 2 H), 3.82 (s, 3 H), 6.69 (m, 2 H), 7.31 (m, 1 H).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([OH:30])[CH2:10][NH:11][CH:12]([CH3:29])[CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)[CH:33]=[O:34]>>[C:1]1([S:7][CH2:8][CH:9]2[O:30][C:33](=[O:34])[N:11]([CH:12]([CH3:29])[CH2:13][O:14][C:15]3[CH:28]=[CH:27][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])=[CH:17][CH:16]=3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)CSc1ccccc1
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)N1CC(CSc2ccccc2)OC1=O

Procedure:
A procedure similar to that described in Example 4 was repeated, except that 1.2 g of 5-{4-[2-(3-phenylthio-2-hydroxypropylamino)propoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Example 37), 0.52 g of N,N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide were used, to give 1.15 g of the title compound as a 1:1 mixture of two kinds of diastereomers having an Rf value of 0.30 (polar) and an Rf value of 0.38 (less polar) (on silica gel thin layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:27])[CH2:11][CH2:12][CH:13]([C:24]([OH:26])=[O:25])[CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)C1C=CC=CC=1.[OH-].[Na+:29]>[Pd].O>[Na+:29].[Na+:29].[C:24]([CH:13]([CH2:12][CH2:11][C:10]([NH:9][OH:8])=[O:27])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O-:21])=[O:20])=[CH:22][CH:23]=1)([OH:26])=[O:25].[C:24]([CH:13]([CH2:12][CH2:11][C:10](=[O:27])[NH:9][OH:8])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O-:21])=[O:20])=[CH:22][CH:23]=1)([OH:26])=[O:25]
Reactant: O=C(CCC(Cc1ccc(C(=O)O)cc1)C(=O)O)NOCc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCC(Cc1ccc(C(=O)[O-])cc1)C(=O)O)NO
Reaction time: 7 h
Yield: 96.9 %

Procedure:
A 100-mL three neck round bottomed flask was charged with the 4-[5-(benzyloxyamino)-2-carboxy-5-oxopentyl]benzoic acid (0.500 g, 1.3 mmol), 0.5 N NaOH (5.2 mL, 2.6 mmol), water (8.3 ml), and a spatula full of 10% Pd on carbon. The mixture was stirred under hydrogen (1 atm) for 7 h. The catalyst was removed by filtration and the filtrate was lyophilized to give 0.382 g of 4-[2-carboxy-5-(hydroxyamino)-5-oxopentyl]benzoic acid disodium salt as an off white powder (89% yield): 1H NMR (D2O) δ 1.75-1.90 (m, 2H), 2.10-2.30 (m, 2H), 2.45-2.60 (m, 1H), 2.75-3.00 (m, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0 Hz, 2H). Anal. Cacld. for C13H13NNa2O6.0.78H2O: C, 46.02; H, 4.33; N, 4.13. Found: C, 46.06; H, 4.14; N, 3.79.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:22][C:23]#[N:24].[K+]>O>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][C:23]([NH2:24])=[O:22])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 60 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine and potassium cyanate are added to stirring water, and the mixture is heated to 60° C., then cooled to room temperature. The resulting precipitate is collected by filtration, washed with cold water, and dried under vacuum to give (6-benzenesulfonyl-naphthalen-1-ylmethyl)-urea.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:22][CH:21]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Brc1ccc(Br)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 55.1 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 1,4-dibromobenzene (11.8 g, 50 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.50 g (55%) of the product 4-(4-bromo-phenyl)-1H-indole as a white solid.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([OH:21])=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22]CCl>CN(C)C=O>[C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([Cl:22])=[O:21])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a suspension of 3-(4-phenylsulfamoyl-phenyl)-acrylic acid (43a) (0.25 g, 0.82 mmol) in dichloromethane (4.7 ml) oxalyl chloride (0.32 ml, 3.68 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.24 g, 92%).
Reaction SMILES: N1([C:6]([O:8][C@:9]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=2[F:45])([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[C@H:10]([S:12][C@@H:13]2[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=3[F:31])[O:15][CH2:14]2)[CH3:11])=[O:7])C=CN=C1.[Si:46]([O:63][CH2:64][CH2:65][OH:66])([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.P([O-])([O-])([O-])=O>ClCCl.CC(C)([O-])C.[K+]>[C:6](=[O:7])([O:8][C@:9]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[F:45])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11])[O:66][CH2:65][CH2:64][O:63][Si:46]([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)n1ccnc1)c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)OCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(F)cc1F
Yield: 72.7 %

Procedure:
(1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl imidazole-1-carboxylate (637 mg, 1.00 mmol) obtained from Example 15-(1) and the crude 2-[(tert-butyldiphenylsilyl)oxy]ethanol (315 mg, ca. 1.05 mmol) obtained from Example 15-(2) were dissolved in dichloromethane (3 ml), and potassium tert-butoxide (5 mg) was added thereto. The mixture was heated under reflux for 15 minutes with stirring. After cooling, a phosphate buffer solution (pH 7) was poured into the mixture, and the reaction product was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d.×600 mm) and JAIGEL-2H (20 mm i.d.×600 mm) connected in series for use; solvent, chloroform] to afford the title compound (631.4 mg, 73% yield) as a colorless amorphous solid.
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24]Cl)=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2].[N-:29]=[N+:30]=[N-:31].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:29]([CH2:24][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:10]([CH2:9][C:8]2[CH:26]=[CH:27][CH:28]=[C:6]([O:5][CH:1]([CH2:3][CH3:4])[CH3:2])[CH:7]=2)=[N:11][CH:12]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(C)Oc1cccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCC(C)Oc1cccc(Cc2ncc(CN=[N+]=[N-])c3cc(OC)c(OC)cc23)c1
Temperature: 65 °C
Yield: 54.1 %

Procedure:
A solution of 1-(3-sec-butoxy-benzyl)-4-chloromethyl-6,7-dimethoxy-isoquinoline (1.0 g, 2.5 mmol) in dimethylsulfoxide (2 mL) was added to a solution of sodium azide (813 mg, 12.5 mmol) in dimethylsulfoxide (10 mL) prewarmed to 65° C. The solution was stirred at 65° C. for 1½ hrs. The reaction mixture was cooled and dissolved in ethyl acetate (100 mL). This ethyl acetate solution was washed with saturated aqueous sodium bicarbonate solution (2×20 mL), saturated aqueous sodium chloride solution (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 4-azidomethyl-1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinoline (550 mg, 54%) as a light yellow solid which was used without further purification: APCI-MS m/e calcd for C23H26N4O3 (M+H+) 407.5, found 406.9; 1H NMR (300 MHz) compatible.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([NH:7][CH3:8])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[OH:1][C@@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[N:7]([CH3:8])[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CN[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O
Solvent: c1ccncc1
Product: CC(=O)N(C)[C@@H]1CNC[C@H]1O
Reaction time: 3 h

Procedure:
tert-Butyl trans-3-hydroxy-4-methylaminopyrrolidin-1-carboxylate (1.0 g, tetrahedron: Asymmetry 2001, 12, 2989) was mixed with pyridine (1.5 g) and acetic anhydride (0.567 g). After 3 hours, volatile fractions were removed under high vacuum. The residue was treated by method G. This resulted in the product with the molecular weight of 158.20 (C7H14N2O2); MS (ESI): 159 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.C[N+]1([O-])CCOCC1>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:31](=[O:36])[C:32]([F:34])([F:33])[F:35])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:46][CH:47]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)C(F)(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(=O)C(F)(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethanol (preparation described previously in Example 269) (104 mg, 0.161 mmol) and 4 Å molecular sieves in dichloromethane (3.00 mL) was added TPAP (Sigma Aldrich, Inc., 5.64 mg, 0.016 mmol), NMO (Sigma Aldrich, Inc.), 24.45 mg, 0.209 mmol) at room temperature and the mixture was stirred at the same temperature for 1 h and then concentrated. The dark residue was rediluted with ethyl acetate and filtered through a short path of Celite® (diatomaceous earth)/SiO2. The filtered solid was washed with ethyl acetate (3×10 mL). The combined organic phases were concentrated to give a yellow crude residue 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethanone which was used directly for the next step without further purification.
Reaction SMILES: C([O:3][C:4]([O:6]/[N:7]=[C:8](/[NH2:42])\[C:9]1[CH:14]=[C:13]([C:15]2[N:20]3[CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=[C:19]3[C:18]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:17][CH:16]=2)[CH:12]=[N:11][CH:10]=1)=O)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[O:39]1[CH2:38][CH2:37][N:36]([C:18]2[C:19]3[N:20]([CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:15]([C:13]3[CH:14]=[C:9]([C:8]4[N:42]=[C:4]([OH:3])[O:6][N:7]=4)[CH:10]=[N:11][CH:12]=3)=[CH:16][N:17]=2)[CH2:41][CH2:40]1
Reactant: CCOC(=O)O/N=C(/N)c1cncc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Oc1nc(-c2cncc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)c2)no1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Compound 77a (26.5 mg, 0.469 mmol) was placed in an 8 mL vial equipped with a stir bar. ACN (1 mL) and DBU (0.358 μL, 0.00235 mmol) were added. The reaction was stirred at 100° C. for 18 h and then cooled to rt. The precipitate was collected by filtration and then the solid was washed with ACN (2×5 mL). The residual solvent was removed under reduced pressure to afford the title compound 28. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.06 (d, J=2.0 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.32-8.37 (m, 2H), 8.27 (s, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.87 (d, J=3.5 Hz, 1H), 7.90 (d, J=4.0 Hz, 1H), 7.75 (t, J=7.1 Hz, 1H), 7.66 (d, J=16.2 Hz, 1H), 7.56 (t, J=7.3 Hz, 1H), 7.52 (s, 1H), 4.29-4.39 (m, 4H), 3.81-3.87 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H22N8O3: 519.2 (M+H). found: 519.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[CH3:12].C(O)(C)C>Cl.O>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([F:11])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Cc1c(F)ccc(N)c1Cl
Temperature: 82 °C
Yield: 61.1 %

Procedure:
To a mixture of 2-chloro-6-fluoro-3-nitrotoluene (140 g), isopropanol (560 ml) and water (147 ml), hydrogen reduced iron (172.2 g) was added hydrochloric acid (43 drops) and with vigorous stirring the whole heated to reflux temperature (82° C.) for 4 hours. The cooled mixture was then filtered and the filtrate evaporated under reduced pressure giving an oil which on distillation gave 2-chloro-4-fluoro-3-methylaniline (72 g).