Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)([OH:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:35][S:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.O>CN(C)C=O.O>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([C:9]([OH:11])([CH3:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[S:36][CH3:35])=[CH:3][CH:4]=2)[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Reactant: CSc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccccc3SC)cc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (61 mg, 0.075 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 11) (354 mg, 0.75 mmol), sodium carbonate (239 mg, 2.25 mmol) and [2-(methylthio)phenyl]boronic acid (252 mg, 1.5 mmol) in N,N-dimethylformamide/water (2:1) (22.5 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[2′-(methylthio)biphenyl-4-yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]2[N:9]=[C:19]([C:18]3[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1c(Cl)cnc(N)c1N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Cl)cnc2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc12
Temperature: 80 °C

Procedure:
5-Chloro-4-methoxypyridin-2,3-diamine (0.500 g, 2.88 mmol) was dissolved in DMF (7 ml). Iron(III)chloride hexahydrate (0.062 g, 0.23 mmol) was added and the mixture heated to 80° C. 4-Nitrobenzaldehyde (0.434 g, 2.87 mmol) dissolved in DMF (4 ml) was added dropwise, and the reaction mixture was heated at 110° C. for 11 h with air bubbling through the solution. The DMF was removed by evaporation, the solid residue was dissolved in warm methanol and filtered through a short plug of silica gel. Following evaporation and recrystallization (methanol) the subtitle compound was isolated. Yield: 0.569 g (65%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])[N:12]=[C:11]3[NH:25][N:26]=[CH:27][C:10]=23)=[CH:5][CH:4]=1)#[N:2].[OH-:28].[K+].Cl>C(O)(C)(C)C.O>[C:15]([C:14]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:28])=[CH:8][CH:7]=2)=[C:10]2[CH:27]=[N:26][NH:25][C:11]2=[N:12][C:13]=1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[F:24])#[N:16]
Reactant: N#Cc1ccc(-c2c(C#N)c(-c3ccc(O)cc3F)nc3[nH]ncc23)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: N#Cc1c(-c2ccc(O)cc2F)nc2[nH]ncc2c1-c1ccc(C(N)=O)cc1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A solution of 0.06 g (0.17 mmol) of 4-(4-cyanophenyl)-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 0.08 g (1.40 mmol) of potassium hydroxide in 6 ml of tert-butanol is refluxed for 4 h. The mixture is then cooled to room temperature, diluted with water, acidified with 1N HCl, and extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered, and concentrated. The solid obtained is then purified by chromatography on silica (methanol gradient in dichloromethane: 0 to 10%) to yield 0.019 g (30%) of 4-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-4-yl)benzamide in the form of yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CCO>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([S:10]([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:11])[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: CCO
Product: CN1CCN(S(=O)(=O)c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-nitrobezenesulfonyl chloride (664 mg, 3.0 mmol) and methylpiperazine (600 mg, 6.0 mmol) in EtOH was stirred for 2 h at RT. The reaction was concentrated and triturated in Et2O to yield a yellowish solid, 3-[(4-methylpiperazinyl)sulfonyl]-1-nitrobenzene, and was used in next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:42][C:43]1[CH:48]=[CH:47][C:46]([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]5[O:21][C:20]([NH:22][CH2:23][C:24]6[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=6)=[N:19][N:18]=5)[CH:15]=4)[N:10]([S:32]([C:35]4[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=4)(=[O:34])=[O:33])[CH:9]=3)[CH:5]=[N:4][CH:3]=2)=[CH:45][CH:44]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(-c5ccc(F)cc5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Yield: 36.3 %

Procedure:
To a solution of 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (500 mg, 0.853 mmol) and 4-fluorophenylboronic acid (143.5 mg, 1.02 mmol) in 1,4-dioxane/H2O (3:1, 15 mL), was added K2CO3 (235.5 mg, 1.71 mmol) and Pd(PPh3)4 (49 mg, 0.0427 mmol). The reaction was heated at reflux for 24 h then quenched with H2O and extracted with EtOAc. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 50% EtOAc in Hex) to give 5-(3-(6-(4-fluorophenyl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (200 mg, 36.5%). MS (ESI, pos. ion) m/z: 647.1 (M+1); 1H-NMR (400 MHz DMSO-d6): δ 12.11 (s, 1H), 9.18 (s, 1H), 9.08-8.98 (m, 2H), 8.52 (d, J=2.8 Hz, 1H), 8.36-8.33 (m, 2H), 8.14-8.03 (m, 1H), 7.74 (d, J=8 Hz, 1H), 7.65-7.55 (m, 2H), 7.46-7.7.28 (m, 4H), 6.92-6.88 (m, 2H), 4.41 (m, 2H), 3.73 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CCC(=O)O)c1

Procedure:
3-Nitrocinnamic acid (50 g) was suspended in ethanol (600 cm3) and reduced in the presence of palladium catalyst until no further hydrogen uptake was observed. After filtering the solvent was evaporated under reduced pressure to give the pure product in quantitative yield as a brown oil which slowly crystallised.
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3].C([O-])=O.[NH4+]>CC(O)=O.O.[Pd]>[CH:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3]
Reactant: COc1ccc(O)c(C(C)(C)O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(O)c(C(C)C)c1
Temperature: 100 °C
Yield: 96.8 %

Procedure:
To a solution of 2-(1-hydroxy-1-methyl-ethyl)-4-methoxy-phenol (50.57 g, 278 mmol) in 550 ml AcOH was added 10% Pd/C (as a slurry in 20 ml H2O) Ammonium formate (87.52 g, 1388 mmol) was added in portions. The mixture was warmed to 100° C. for 1 hour, cooled and filtered through a pad of celite. The celite pad was washed with ethyl acetate. The mother liquor was mixed with H2O and extracted with ethyl acetate. The combined organics were washed with H2O, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 2-isopropyl-4-methoxy-phenol (44.74 g, 97%) as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH:13]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[C:23]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[N:22]=[CH:21][N:20]=2)[CH:13]=1
Reactant: Clc1cc(Nc2cccc(CNc3nc4ccccc4[nH]3)c2)ncn1
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1cc(Nc2cccc(CNc3nc4ccccc4[nH]3)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
246 mg (1H-Benzoimidazol-2-yl)-[3-(6-chloro-pyrimidin-4-ylamino)-benzyl]-amine (prepared in Example 59) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water was added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (146 mg, 50% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][O:27][CH:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36]C)=[O:35])[CH2:30][CH2:29]3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][O:27][CH:28]3[CH2:29][CH2:30][CH:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)C1CCC(OC[C@@H]2CCCN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)N3CCC[C@H]3COC3CCC(C(=O)O)CC3)cc2o1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
In THF (10 ml) and methanol (5 ml) was dissolved methyl 4-(1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-(2S)-pyrrolidinylmethoxy)cyclohexanecarboxylate (580 mg, 1.1 mmol), that is, a mixture of two diastereomers (cis and trans forms). After addition of 1N NaOH (1.5 ml, 1.5 mmol), the mixture was stirred at 70° C. for 24 hours. The residue obtained by distilling off the solvent under reduced pressure, was acidified weakly with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure. The resulting crystals were washed with water and dried under reduced pressure, whereby 4-(1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-(2S)-pyrrolidinylmethoxy)cyclohexanecarboxylic acid was obtained as a mixture of two diasteromers. The mixture was separated by HPLC (C18 column, eluting with 0.02N acetate buffer-acetonitrile (1:1, v/v)), whereby Isomer A (150 mg, 27%) was obtained as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:7])=[C:4]([OH:21])[CH:3]=1.[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:20][C:19]1[C:2]([F:1])=[CH:3][C:4]2[O:21][CH2:22][N:8]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[C:6](=[O:7])[C:5]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1cc(F)c(F)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2cc(F)c(F)cc2OCN1c1ccc([N+](=O)[O-])cc1
Yield: 0.7 %

Procedure:
To 4,5-difluoro-2-hydroxy-N-(4-nitrophenyl)benzamide (0.13 g, 0.44 mmol) in toluene (5 ml) was added paraformadehyde (0.3 g, 10 mmol) and p-toluenesulfonic acid (0.01 g, 0.05 mmol) and the reaction heated to 120° C. for 3 hr with azeotropic removal of water. Saturated sodium bicarbonate (10 ml) was added and product extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 0.11 mg (81%) of 6,7-difluoro-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 2.54 min; ES-MS (M+H)+=307.0; 1H-NMR (MeOH-d4) δ (ppm): 5.78 (s, 2 H), 7.04 (dd, 1 H), 7.64 (d, 2 H), 7.82 (dd, 1 H), 8.3 (d, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH:35]([CH3:37])[CH3:36]>O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH:35]([CH3:37])[CH3:36])=[CH:21][C:14]=3[O:13]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CC(C)Br
Reactant: COc1cc(C=C2Oc3cc(O)ccc3C2=O)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=C2Oc3cc(OC(C)C)ccc3C2=O)cc(OC)c1
Reaction time: 4 h
Yield: 55.4 %

Procedure:
To a solution of 2-[(3,5-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g, potassium carbonate 0.58 g and dimethylformamide 5 ml, 2-bromopropane 0.306 g was added. After the mixture was refluxed for 2.5 hours, water 50 ml was added. The resulting compound was extracted with ethyl acetate 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to -obtain crystals. The crystals were dissolved in ethyl acetate 2 ml and hexane 10 ml, and the solution was allowed to stand at room temperature for four hours. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 316.1 mg.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=O.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:37](=[N:40]O)([NH2:39])[CH3:38]>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:8]2[O:10][N:40]=[C:37]([CH3:38])[N:39]=2)[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: CC(N)=NO
Reactant: COCOc1cc(C(=O)O)ccc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(-c2nc(C)no2)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-methoxymethoxy-4-methyl-benzoic acid (1.96 g, 10 mmol) (from Example 50 supra), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.92 g, 10 mmol) (Aldrich) and 1-hydroxybenzotriazole hydrate (1.35 g, 10 mmol) (Aldrich) in N,N-dimethylformamide (25 mL) was stirred at room temperature for 30 minutes. Acetamide oxime (0.74 g, 10 mmol) (GFS Chemicals) was added and mixture heated at 140 C for 2 hours. After cooling, mixture was partitioned between ethyl acetate (2×) and saturated aqueous bicarbonate solution. Ethyl acetate solutions were combined and concentrated and residue purified by flash chromatography to give 5-(3-methoxymethoxy-4-methyl-phenyl)-3-methyl-[1,2,4]oxadiazole. (Yield 1.23 g, 52.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][N:10]([N:14]=[O:15])[C:9]2=[O:13])=[CH:6][CH:7]=1
Reactant: O=C1NCCN1c1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCN(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a solution of glacial acetic acid (2750 ml) and water (250 ml) was dissolved 150 g (0.75 mol) of 1-(4-chlorophenyl)-2-imidazolidinone with heating. The solution was cooled to room temperature, and sodium nitrite (70 g, 1.0 mol) in water (200 ml) was added dropwise over 1 hr. The mixture was stirred for another 6 hrs, diluted with water (1.5 l) and the product (137 g, 81%) was collected m.p. 154°-156°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].IC.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1oc2ccc(Cl)c(O)c2c1C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1oc2ccc(Cl)c(OC)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To 5-chloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (120 mg, 0.47 mmol) was added 0.3 mL (4.7 mmol) of iodomethane, 130 mg (2 eq) of K2CO3 and 4 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Removal of the solvent in vacuo gavel 19 mg (94% yield) of 5-chloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1>CN(C=O)C.C1COCC1>[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][O:7][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(C#N)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of sodium hydride (NaH) 60% dispersion in mineral oil (4.5 g, 111 mmol, 1.1 eq.) in anhydrous DMF (200 mL) was added 2-dimethylaminoethanol (11.5 mL, 111 mmol. 1.1 eq.). The reaction mixture was heated to 50° C. for 30 min. Then, 6-chloronicotinonitrile (14.8 g, 101 mmol, 1 eq.) in THF (100 mL) was added dropwise and the mixture was stirred overnight at 50° C. The solvents were removed under reduced pressure, the resulting residue was dissolved in water and acidified with conc. HCl (hydrochloric acid) to pH 1. The solution was washed with CH2Cl2 (2×200 mL), the aqueous layer was basified with conc. NaOH (sodium hydroxide) to pH about 10 and extracted with diethyl ether. The organic phase was washed with brine, dried over Na2SO4, and filtered. Removal of the solvent in vacuo gave the title compound as an off-white solid (19.32 g, 99%) (m.p.:58° C.).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH2:2][CH3:3].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](O)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)([O:6][CH2:5][CH:4]([CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH3:3])(=[O:18])=[O:17]
Reactant: CCCC(CO)CCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCC(CCC)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 19 h
Yield: 96.9 %

Procedure:
To a mixture of 52 g 2-propylpentanol and 86 g of p-toluenesulfonic acid in 175 ml of chloroform was added at 0°-3° C. and under N2 -atmosphere 48 g of pyridine. The mixture was kept at 0° C. for 30 minutes and at room temperature for 19 hrs. After cooling the reaction mixture, 3M HCl (300 ml) was added. The organic phase was separated and washed with water and rine. Drying with Na2SO4 and evaporation gives 110 g of 2-propylpentyl tosylate.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:24])[C:12]([CH3:23])([S:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:24])[C:12]([CH3:13])([S:14]([C:17]2([CH3:25])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)(=[O:15])=[O:16])[CH3:23])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)no1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2(C)CCOCC2)no1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 14.9 %

Procedure:
To a solution of 202 mg (0.56 mmol) of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (prepared according to Method E) in anhydrous THF (10 mL) at −78° C. under nitrogen atmosphere were added 0.8 mL (1.4 mmol) of lithium diisopropylamide (1.8 M solution in THF/heptane/ethylbenzene) and the reaction was stirred at −78° C. for 0.5 h. Then 0.1 mL (1.6 mmol) of methyl iodide were added in one portion and stirring was continued for further 0.5 h at −78° C., before the reaction was warmed to room temperature. After 18 h at room temperature the reaction was quenched by the addition of saturated aqueous NH4Cl solution (25 mL). The mixture was extracted with ethyl acetate (3×25 mL). The organic extracts were combined, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue purified by mass-triggered preparative LCMS to afford 31 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(4-methyl-tetrahydro-pyran-4-sulfonyl)-propionamide.