Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16](Br)=[N:15][CH:14]=[CH:13][N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][CH:14]=[CH:13][N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nccnc2Br)ccn1
Reactant: Nc1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)c2nccnc2Nc2ccccc2)ccn1
Temperature: 150 °C
Reaction time: 0.83 h

Procedure:
3-Bromo-pyrazine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (130 mg, 0.44 mmol) and aniline (54 mg, 0.58 mmol) were dissolved in 4 mL dry dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (51 mg, 0.09 mmol), cesium carbonate (290 mg, 0.89 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (46 mg, 0.044 mmol) were added and the reaction mixture was stirred under microwave irradiation for 50 minutes at 150° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 1:1->100% ethyl acetate). The desired product was obtained as a yellow solid (47 mg, 35%), MS: m/e=306.2 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH-:5][B:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[Li+].[CH2:15]([N:17]1[CH:21]=[CH:20][C:19]([SiH:23]([CH3:25])[CH3:24])(Cl)[B:18]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:16]>C1COCC1>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]([Si:23]([CH:19]2[CH:20]=[CH:21][N:17]([CH2:15][CH3:16])[B:18]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:24])[CH3:25])[B:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCN1C=CC(Cl)([SiH](C)C)B1c1ccccc1
Reactant: CCN1C=C[CH-]B1c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1C=CC([Si](C)(C)C2C=CN(CC)B2c2ccccc2)B1c1ccccc1

Procedure:
The title compound was prepared in the same manner as Example 3B) from lithium (1-ethyl-2-phenyl-1,2-azaborolide) (1C), 0.41 g, 2.31 mmol) in 15 mL of THF and 1-ethyl-3-chlorodimethylsilyl-2,3-dihydro-2-phenyl-1H-1,2-azaborole (Ex. 3A), 0.01 g, 2.31 mmol) in 15 mL of THF. The product was obtained as a yellow oil (0.85 g, 92 percent).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[C:12]=1[NH2:13].[CH2:22]([C:34]1[CH:38]=[N:37][N:36]([CH:39]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40](O)=[O:41])[N:35]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.ClCCl>[CH2:22]([C:34]1[CH:38]=[N:37][N:36]([CH:39]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:40]([NH:13][C:12]2[C:14]([O:20][CH3:21])=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=2[O:10][CH3:9])=[O:41])[N:35]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCc1cnn(C(C(=O)O)c2ccccc2)n1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCc1cnn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
Triethylamine (1.2 mL, 8.4 mmol) was added to a suspension of 2,4,6-trimethoxyaniline hydrochloride (1.68 g, 7.7 mmol) in 100 mL THF and stirred for 1 hour before filtering to remove triethylamine hydrochloride. The filtrate was concentrated and redissolved in 100 mL dichloromethane along with (±)-4-dodecyl-α-phenyl-2H-1,2,3-triazole-2-acetic acid (2.59 g, 7.0 mmol) at 0° C. Dicyclohexylcarbodiimide (1.51 g, 7.3 mmol) was added in one portion and the resulting suspension was warmed to room temperature and stirred for 16 hours. Filtered to remove a white solid and partitioned the filtrate between chloroform and 1N HCl. The organic layer was dried over MgSO4, filtered, and concentrated to give a pale lavender solid. Recrystallization from ethyl acetate/hexanes (4:1) gave the title compound as a white solid (2.80 g, 75%); mp 123°-125° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:35][C@H:36]([OH:63])[C:37]#[C:38][C@H:39]([CH3:62])[C@H:40]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[C@@H:41]([CH3:53])[CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[Si:1]([O:8][C@@H:9]([CH2:35][C@H:36]([OH:63])/[CH:37]=[CH:38]\[C@H:39]([CH3:62])[C@H:40]([O:54][Si:55]([C:58]([CH3:59])([CH3:61])[CH3:60])([CH3:57])[CH3:56])[C@@H:41]([CH3:53])[CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:50])([CH3:51])[CH3:52])([CH3:48])[CH3:47])[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C[C@H](O)C#C[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C[C@H](O)/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 100367.2 %

Procedure:
The procedure for 34 was used with alkyne 65 (1.69 g, 1.85 μmol) and Lindlar catalyst (ca. 200 mg) to yield 66 (1.70 g, quantitative) as a pale yellow oil: IR (CHCl3) 3477, 2955, 2856, 1471, 1448, 1386, 1254, 1057, 835, 773, 705 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.63-7.60 (m, 6H), 7.43-7.27 (m, 9H), 5.88-5.77 (m, 2H), 5.70 (t, J=10.1 Hz, 1H), 5.49 (dd, J=10.6, 8.4 Hz, 1H), 4.78 (m, 1H), 4.06 (m, 1H), 3.76-3.72 (m, 4H), 3.58 (t, J=3.6 Hz, 1H), 2.89 (m, 1H), 2.63 (m, 1H), 2.20 (d, J=2.8 Hz, 1H), 1.73-1.48 (m, 7H), 1.18 (d, J=6.9 Hz, 3H), 1.15 (d, J=7.0 Hz, 3H), 1.08-1.02 (m, 27H), 0.29-0.20 (m, 18H); 13C NMR (75 MHz, CDCl3) δ 144.3, 134.9, 134.4, 131.5, 128.6, 127.7, 127.0, 126.8, 86.7, 79.8, 72.8, 65.0, 64.7, 63.5, 42.1, 39.7, 37.9, 35.9, 31.4, 29.9, 26.2, 26.0, 25.9, 20.1, 18.4, 18.3, 18.0, 14.9, 14.5, −3.6, −3.8, −4.5, −4.6, −5.3; LRMS (ESI) 937.5 [M+Na]+; HRMS (ESI) calcd for C55H90O5Si3Na 937.5994 [M+Na]+, found 937.6016; [α]20D+2.1 (c 0.92, CHCl3).
Reaction SMILES: [CH:1]1([C:6]2[CH2:10][CH2:9][C:8](=[O:11])[C:7]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14](SC)[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[O:21][S:22]([O-:24])=O.[K+].[CH2:26]1COCC1.CO.O>>[CH:1]1([C:6]2[CH2:10][CH2:9][C:8](=[O:11])[C:7]=2[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([S:22]([CH3:26])(=[O:24])=[O:21])[CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S([O-])OO
Reactant: CSc1cccc(C2=C(C3CCCC3)CCC2=O)c1
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1cccc(C2=C(C3CCCC3)CCC2=O)c1
Reaction time: 3 h

Procedure:
To a solution of 120 mg 3-cyclopentyl-2-(3-methylthiophenyl)-2-cyclopenten-1-one in 12 ml 1:1:1 mixture of THF/methanol/water, was added 800 mg OXONE®, and the reaction mixture was stirred for 3 hours. Then the reaction mixture was concentrated under reduced pressure and extracted with water/ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/ethyl acetate=3:1) to yield 120 mg 3-cyclopentyl-2-(3-methylsulfonylphenyl)-2-cyclopenten-1-one. The methylsulfone compound was condensed with hydroxylamine hydrochloride according to a procedure similar to that described in STEP 4 for Example 1 to afford 80 mg of 3-cyclopentyl-2-(3-methylsulfonylphenyl)-2-cyclopenten-1-one oxime as a solid. mp=164-165° C.; 1H NMR (CDCl3, 300 MHz): δ 7.90-7.85 (m, 2H), 7.62-7.52 (m, 2H), 7.19 (bs, 1H), 3.08 (s, 3H), 2.85 (m, 1H), 2.80 (m, 2H), 2.64 (m, 2H), 1.73 (m, 4H), 1.58 (m, 4H); APCI MS: m/z 320.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH:9]=2)=O)=[C:4](F)[CH:3]=1.C[NH:21][NH2:22]>C(O)CCC>[C:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:6]2[C:5]3[C:4](=[CH:3][C:2]([Br:1])=[CH:18][CH:17]=3)[NH:22][N:21]=2)[CH2:9][CH2:10]1)(=[O:16])[CH3:15]
Reactant: CNN
Reactant: CC(=O)N1C=CC(C(=O)c2ccc(Br)cc2F)=CC1
Solvent: CCCCO
Product: CC(=O)N1CCC(c2n[nH]c3cc(Br)ccc23)CC1

Procedure:
A solution of 3.3 g of 4-(4-bromo-2-fluorobenzoyl)-1-acetylpyridine, 1.1 g of (0.013 mole) of methylhydrazine and 30 ml of n-butanol was heated under reflux for 16 hrs. The reaction mixture was concentrated in vacuo and the residue was diluted with water. The aqueous suspension was made basic with ammonium hydroxide solution and extracted with dichloromethane. The extract was washed with water, dried over anhydrous potassium carbonate and the solvent was concentrated to give 3-(1-acetyl-4-piperidinyl)-6-bromo-1H-indazole, as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([O-:11])=[O:10].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:8])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cccc(F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
3-Fluorotoluene (1 mole) in concentrated sulfuric acid (200 ml.) is stirred at 0° C. while a cold solution of potassium nitrate (1.5 mole) in concentrated sulfuric acid (750 ml.) is added slowly during 3 hours, the temperature being kept below 5° C. with an ice-ethanol bath After the addition is complete, the ice-bath is removed and stirring is continued for 3 hours at room temperature. Water (400 ml.) is added, and the organic layer is separated, dried (MgSO4) and filtered. The oil is separated by vapor-phase chromatograph on a 200×1 cm. silicone oil column (DC 200 20%) on Chromosorb R (60/80) at 191° C. and a helium flow rate of 86 ml./min. The desired pure nitro-isomer is collected.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[O:23][CH3:24])=[O:11].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:54]([O:58][CH3:59])(=[O:57])[CH:55]=[CH2:56]>C(#N)C(C)C.CC#N.CC#N.Cl[Pd]Cl.O>[CH3:59][O:58][C:54](=[O:57])[CH2:55][CH:56]1[C:2]2[C:3](=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=2)[NH:9][C:10](=[O:11])[N:12]1[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[O:23][CH3:24]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1c(F)cccc1Br
Agent: Cl[Pd]Cl
Agent: CC(C)C#N
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC1c2cccc(F)c2NC(=O)N1c1cc(C(F)(F)F)ccc1OC
Temperature: 102 °C

Procedure:
N-(2-Bromo-6-fluorophenyl)-N′-[2-methoxy-5-(trifluoromethyl)phenyl]urea (300 g) is suspended in isobutyronitrile (1.2 l) under a nitrogen atmosphere, then triethylamine (210 ml), bis(acetonitrile)dichloropalladium (7.5 g), tris-(o-tolyl)phosphine (18.0 g) and methyl acrylate (210 ml) are added in this sequence. The resulting suspension is stirred under reflux (ca. 102° C.) for 16 h and then cooled to room temperature. Water (1.2 l) is added and the mixture is stirred at room temperature for 1 h, then filtered off with suction and washed with water/methanol (1:1, 300 ml) and acetonitrile (100 ml). The residue is dried overnight at 45° C. in the VDO using entraining nitrogen. A total of 208 g of methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate are obtained as a solid, corresponding to 68.5% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][CH2:14][C:15]([NH:17][NH2:18])=[O:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=N)[CH3:20]>C(O)C>[CH2:19]([O:21][C:22](=[N:18][NH:17][C:15](=[O:16])[CH2:14][CH2:13][C:11]1[O:10][N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:12]=1)[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH3:20]
Reactant: NNC(=O)CCc1nc(-c2cccc(Cl)c2)no1
Reactant: CCOC(=N)c1cccs1
Solvent: CCO
Product: CCOC(=NNC(=O)CCc1nc(-c2cccc(Cl)c2)no1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazide (266.69 mg, 1 mmol) was mixed with thiophene-2-carboximidic acid ethyl ester (191.6 mg, 1 mmol) in ethanol (6 ml) and stirred at room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate, dried and concentrated in vacuo. The crude product was triturated with hexane to yield 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid (ethoxy-thiophen-2-yl-methylene)-hydrazide as a white solid (305 mg, 75%). 1H-NMR(CDCl3) d(ppm): 8.99 (ws, 1H), 8.09 (s, 1H), 7.98 (d, 1H), 7.41(m, 4H), 7.08 (dd, 1H), 4.27 (q, 2H), 3.34 (m, 4H) and 1.41 (t, 3H). Step 2: 3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]oxadiazole: 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid (ethoxy-thiophen-2-yl-methylene)-hydrazide (81 mg, 0.2 mmol) was mixed with 2M methylamine (0.3 ml in THF) in ethanol (2 ml) at 70˜80° C. overnight. The reaction mixture was concentrated with silica gel and purified by column chromatography with 0.5˜2.0% methanol in ethyl acetate to give 54 mg (72.5%) of 3-(3-chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]oxadiazole. 1H-NMR(CDCl3) d (ppm): 8.08 (s, 1H), 7.97 (d, 1H), 7.41 (m, 4H), 7.20 (dd, 1H), 3.80 (s, 3H), 3.68 (dd, 2H), 3.38 (dd, 2H).
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])[N:23]([CH2:24][CH2:25][NH2:26])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1.Cl.CON(OC)CCCN=C=NCC>ClCCl>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])[N:23]([CH2:24][CH2:25][NH:26][C:7]([CH:5]3[CH2:4][CH2:3][C:2](=[O:1])[O:6]3)=[O:9])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C1CC[C@@H](C(=O)O)O1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Agent: CCN=C=NCCCN(OC)OC
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)C1CCC(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-(+)-5-oxo-2-tetrahydrofurancarboxylic acid (0.23 g, 1.7 mmole in anhydrous dichloromethane (30 mL) was slowly added to a solution of 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) in anhydrous dichloromethane (100 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then a solution of 1-[3-(dimethoxyamino)propyl]-3-ethylcarbodiimide hydrochloride (0.37 g, 1.9 mmol) in anhydrous dichloromethane (50 mL) was added dropwise. The reaction mixture was stirred at ambient temperature overnight and then filtered to remove solids. The filtrate was washed twice with 10% sodium hydroxide and then with brine, dried, and then concentrated under vacuum to provide 0.3 g of crude product. This material was purified by column chromatography (silica gel eluting with dichloromethane) followed by recrystallization from acetonitrile to provide 0.1 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-5-oxotetrahydro-2-furancarboxamide as a white powder, m.p. 153-154° C. Analysis: Calculated for C20H24N6O3: % C, 60.59; % H, 6.10; % N, 21.19; Found: % C, 60.34; % H, 6.14; % N, 21.13. HRMS (EI) calcd for C20H24N6O3 (M+) 396.1909 found 396.1905
Reaction SMILES: O[CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8].S(Cl)([Cl:18])=O>>[Cl:18][CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CO
Reactant: O=S(Cl)Cl
Product: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Hydroxymethyl-2-methyl-7-nitrobenzo[b]furan (1.0 g) was added to thionyl chloride (1.8 ml) with ice cooling. The mixture was stirred at ambient temperature for 30 minutes and concentrated in vacuo. To the residue was added toluene and the mixture was concentrated again. The residue was crystallized from a mixture of diethyl ether and n-hexane to give 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (1.01 g).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]2[CH:29]=[C:28]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])[C:27]([C:38]3[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][CH:39]=3)=[N:26][C:25]=12)=[O:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]2[CH:29]=[C:28]([C:30]3[C:31]([F:37])=[CH:32][CH:33]=[CH:34][C:35]=3[F:36])[C:27]([C:38]3[CH:39]=[CH:40][C:41]([CH2:44][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:42][CH:43]=3)=[N:26][C:25]=12)=[O:20]
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Reactant: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(C=O)cc3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(CN4CC(c5n[nH]c(-c6cccc(C)n6)n5)C4)cc3)nc12
Reaction time: 1 h

Procedure:
394.5 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure) are dissolved in 7 mL NMP. After addition of 0.3 mL triethylamine the reaction mixture is stirred for one hour. 350 mg (0.89 mmol) 6-(2,6-Difluorophenyl)-5-(4-formylphenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester and 0.09 mL acetic acid are added. The reaction mixture is stirred overnight at room temperature. 207.4 mg (0.98 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 5 hours. The reaction mixture is treated with saturated NaHCO3. The precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 191.9 mg (34.6%) of the desired product are obtained.
Reaction SMILES: [CH2:1](I)[CH:2]=[CH2:3].[C:5]1([CH:12]=[CH:11][C:9]([OH:10])=[CH:8][CH:7]=1)[OH:6].C([O-])([O-])=O.[K+].[K+].CC(C)=O>>[CH2:1]([O:6][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCI
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(O)cc1
Temperature: 40 °C
Yield: 41.2 %

Procedure:
Allyl iodide (8.2 mL, 89 mmoles) was added to a solution of hydroquinone (7.84 g, 71.2 mmoles) and K2CO3 (19.7 g, 142.4 mmoles) in acetone (102 mmoles). The resulting mixture was heated to 40° C. overnight and concentrated under reduced pressure. The crude products were filtered through a pad of silica with 1:1 hexanes:ethyl acetate. The residue was purified by flash chromatography on a prepacked Biotage column (hexane to 1:1 hexane:ethyl acetate) on silica gel to provide the title compound (4.40 g, 41%).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([CH:12]=[CH2:13])=[N:3][CH:4]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1cc(F)cnc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ncc(F)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-5-fluoro-3-nitropyridine (20 g, 90.50 mmol) in 1, 4 dioxane (270 mL) was added tributyl vinyl tin (34.54 g, 108.60 mmol). The reaction mixture was degassed using nitrogen for 30 min. Bis-(triphenylphosphin)-palladium(II)-chloride (3.17 g, 4.5 mmol) was added to the reaction mixture. Reaction mass was stirred at 110° C. for 16 h. The reaction mixture was cooled to 25° C. Water was added to the reaction mass and extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo and purified by column chromatography on silica gel using 0-2% EtOAc in hexane to give 5-fluoro-3-nitro-2-vinylpyridine: 1H NMR (400 MHz, DMSO-d6): δ 5.742 (dd, 1H, J=2 Hz, 10.8 Hz), 6.45 (dd, 1H, J=2 Hz, J=16.8 Hz), 7.11-7.17 (m, 1H), 8.489-8.516 (m, 1H), 8.959 (d, 1H, J=2.4 Hz).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:21])=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:21])=[CH:9][CH:8]=1
Reactant: COc1ccc(CCCCCCCCBr)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(CCCCCCCCBr)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A 1M solution of boron tribromide in dichloromethane (5 ml, 5 mmol) was added to an ice water cooled solution of 8-(4-methoxyphenyl)octylbromide (1.5 g, 5 mmol) in dichloromethane (10 ml). After 4 hours at room temperature, water was added and the dichloromethane separated, washed with water, dried over anhydrous magnesium sulphate, and evaporated to give an oil, which was chromatographed over flash silica, eluting with chloroform, followed by 2% methanol in chloroform to give 8-(4-hydroxyphenyl)octylbromide as an oil (MS: M+ =284).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][C:5]([N:7]1[CH:11]([CH3:12])[CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]1=[O:19])=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:34]([O:38][C:39](=[O:42])[CH2:40]Br)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:42])[CH2:40][C@@H:4]([C:5]([N:7]1[C@@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:9][C:8]1=[O:19])=[O:6])[CH2:3][C:2]([CH3:1])([CH3:23])[CH2:20][CH2:21][CH3:22])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCC(C)(C)CCC(=O)N1C(=O)OC(c2ccccc2)C1C
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCCC(C)(C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Yield: 49.2 %

Procedure:
According to example 1, 5.07 g (16 mmol) of 3-(4,4-dimethyl-heptanoyl)-4-methyl-5-phenyl-oxazolidin-2-one, 18 mL (1N, 18 mmol) of NaHMDS solution and 4.72 mL (32 mmol) of bromo-acetic acid tert-butyl ester gave 3.40 g (49.3%) of the title compound as a crystalline solid. 1HNMR (400 MHz; CDCl3): 0.85–0.89 (m, 12H), 1.18–1.32 (m, 6H), 1.41 (s, 9H), 1.88 (dd, 1H, J=6 Hz, 8.4 Hz), 2.41 (dd, 1H, J=6 Hz, 16 Hz), 2.62 (dd, 1H, J=8.4 Hz, 16 Hz), 4.30–4.40 (m, 1H), 4.72 (m, 1H), 5.62 (d, 1H, J=7 Hz), 7.30–7.40 (m, 5H). m.p.: 83–85° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.CCN(CC)CC.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.3 %

Procedure:
2-(4-Bromo-phenoxy)-ethanol (125 g, 0.576 mol) was dissolved in CH2Cl2 (650 mL), and the sol. was cooled to 0° C. Et3N (110 mL, 0.864 mol), then mesyl chloride (67.1 mL, 0.864 mol) were dropped at such a speed that the temperature did not raise above 10° C. (about 60 min). The mixture was stirred at 0° C. for 1 h, then at rt overnight. The mixture was diluted with CH2Cl2, and washed with brine (2×). The aq. phase was extracted back with CH2Cl2. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (174 g, quantitative yield) that was used further without purification. LC-MS: tR=0.92 min.