Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[I:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(I)cc3c2C1
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(CCn2c3c(c4cc(I)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.2 %

Procedure:
To a solution of 8-Iodo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g. 0.0016 mol) in N-methyl 2-pyrolidone (5 mL) was added powdered potassium hydroxide (0.9 g, 0.016 mol) and allowed to stir for 10 min at RT, 2-Methyl-5-vinyl-pyridine (0.969 g, 0.0048 mol) was added and stirred for further 24 hours at 100° C., after completion (TLC), reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×150 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was semi-purified through column chromatography (6% Methanol:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), then further purified by preparative HPLC to get the desired compound as brown solid (0.105 g, 15.2% yield). 8-Iodo-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.095 g, 0.00022 mol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.0277 g, 0.00022 mol) in THF (2.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.09 g, 79% yield).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[F:16][C:2]([F:1])([F:15])[C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:13]=2)[N:6]=[CH:5][CH:4]=1
Reactant: Oc1ccc(-n2nccc2C(F)(F)F)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: FC(F)(F)c1ccnn1-c1ccc(OCCN2CCCCC2)cc1
Yield: 48 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyrazol-1-yl)phenol (0.1 g, 0.43 mmol), 1-(2-chloroethyl)piperidine hydrochloride (0.16 g, 0.88 mmol) using the general procedure C with a yield of 48% (70 mg); 1H NMR (400 MHz, CDCl3) 7.84 (d, J=2 Hz, 1H), 7.58 (d, J=9.2 Hz, 2H), 6.98 (d, J=9.2 Hz, 2H), 6.65 (d, J=1.6 Hz, 1H), 4.14 (t, J=12, 6 Hz, 2H), 2.78 (t, J=12, 6 Hz, 2H), 2.53 (br, 4H), 1.61-1.47 (m, 6H); LC/MS (ESI): 94%.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:11])[NH:6][CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O.[CH3:12]I>[Zn].C(O)(=O)C>[CH3:12][O:11][C:5]1[C:4]([NH2:1])=[C:9]([CH3:10])[CH:8]=[CH:7][N:6]=1
Reactant: CI
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1nccc(C)c1N

Procedure:
3-Nitro-4-methyl-2-pyridone was methylated with methyl iodide and reduced with zinc and acetic acid to give 2-methoxy-3-amino-4-methylpyridine. This material was converted to the title compound according to the procedure described in Example 28.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:14][OH:15])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: NO
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(C=NO)ccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.5 %

Procedure:
In a mixture of ethanol (20 mL) and water (10 mL), 4-fluoro-3-nitrobenzaldehyde (2 g), hydroxylamine hydrochloride (1.07 g) and sodium acetate (1.45 g) were dissolved, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-fluoro-5-hydroxyiminomethylnitrobenzene (1.95 g).
Reaction SMILES: Cl[C:2]([O:4][C:5](Cl)(Cl)Cl)=[O:3].[C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2O)[CH:14]=[CH:13][CH:12]=[CH:11]C=1.C(N(CC)CC)C.[CH3:29][C:30]([CH3:48])([CH3:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:34][CH:33]=1>C(Cl)Cl>[C:9]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:4][C:2](=[O:3])[N:39]([CH2:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C:30]([CH3:29])([CH3:48])[CH3:47])=[CH:33][CH:34]=1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCCCNCc1ccc(CC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCN(Cc1ccc(CC(C)(C)C)cc1)C(=O)Oc1ccccc1-c1ccccc1
Reaction time: 2.5 h

Procedure:
Trichloromethyl chloroformate (2.1 mL, 17.4 mmol) is added dropwise over ten minutes under a nitrogen atmosphere to a solution of 2-phenylphenol (3.0 g, 17.6 mmol) in 50 mL of methylene chloride at ice bath temperature. After the addition of trichloromethyl chloroformate, triethylamine (2.5 mL, 17.9 mmol) is added dropwise over a ten minute period and the reaction mixture is stirred at ice bath temperature for 2.5 hours. A solution of N-[[4-(2,2-dimethylpropyl)phenyl]methyl]heptylamine (4.8 g, 17.4 mmol) and triethylamine (2.5 mL, 17.9 mmol) in methylene chloride (15 mL) is added at ice bath temperature over a thirty minute period. Then the ice bath is removed and the reaction mixture is stirred overnight. The reaction mixture is washed with 1N HCl, 5% NaHCO3, dried over MgSO4 and the solvent removed in vacuo to give, after purification by high pressure liquid chromatography (hexane-methylene chloride) the title compound as a light brown oil (2.37 g, 29% of theory), MS/me, 471 (M+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]=[CH:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([O:24][CH3:25])=[C:12]3[C:16]([C:17](=[O:23])[C:18]([O:20]CC)=[O:19])=[CH:15][NH:14][C:13]=23)[N:4]=1.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[OH:1][CH2:2][C:3]1[N:7]=[CH:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([O:24][CH3:25])=[C:12]3[C:16]([C:17](=[O:23])[C:18]([OH:20])=[O:19])=[CH:15][NH:14][C:13]=23)[N:4]=1
Reactant: CCOC(=O)C(=O)c1c[nH]c2c(-n3cnc(CO)n3)ncc(OC)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cnc(-n2cnc(CO)n2)c2[nH]cc(C(=O)C(=O)O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(7-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (70 mg, 0.203 mmol) and K2CO3 (56.0 mg, 0.405 mmol) were dissolved in MeOH (2 mL) and water (2.000 mL). The mixture was stirred at room temperature overnight, and neutralized with 1N HCl to pH 3. All solvents were removed under vacuum to give 2-(7-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid. LCMS: m/z 318.2 (M+H)+, 1.04 min (method 8).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9][OH:10])=[CH:2]1.C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:23][C:22]([Si:19]([CH3:21])([CH3:20])[O:10][CH2:9][CH2:8][CH2:7][CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[OH:11])([CH3:25])[CH3:24]
Reactant: OCCCC(O)c1ccsc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCC(O)c1ccsc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
The product from step (a) (0.79 g, 4.58 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (1.28 ml, 9.16 mmol) and 4-dimethylaminopyridine (0.02 g) added. The solution was cooled to 0° C. and t-butyldimethylsilylchloride (0.655 g, 4.35 mmol), as a solution in dimethylformamide (35 ml), was added dropwise over half an hour. The reaction was stirred at 0° C. for 2 h, then allowed to warm to room temperature slowly. After stirring for a further 18 h, water (50 ml) was added and the reaction extracted with ethyl acetate (3×70 ml). The combined extracts were washed with water (3×20 ml), dried (magnesium sulphate) and evaporated. The residue was chromatographed on flash silica, eluting with hexane:ethyl acetate (4:1) to give the title compound as a colourless oil (1.164 g, 89%).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[S:9]1[CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:11][CH2:10][SH:9])[CH2:5]1
Reactant: CC1CNCC(C)O1
Reactant: C1CS1
Solvent: Cc1ccccc1
Product: CC1CN(CCS)CC(C)O1

Procedure:
In a 500 ml three necked flask 115.2 g (1 mol) 2,6-dimethylmorpholine in 250 ml of toluene is heated at 90° C. Then 60.12 g (1 mol) thiirane is added to the resulting reaction mixture dropwise and the reaction mixture is heated for 5 hours under reflux. The reaction mixture is concentrated in vacuum with a rotary evaporator and is fractionally distilled using a Vigreux column.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:7]([F:8])[CH2:6][C@@H:5]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:5]4[CH2:4][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:7]([F:8])[CH2:6]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1C[C@H](N)[C@@H](F)C1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1C[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1F

Procedure:
Starting from N-[(1S*,3S*,4S*)-3-amino-4-fluorocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f70) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C@@H:11]([OH:13])[CH3:12])=[CH:7][CH:8]=1
Reactant: CC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: C[C@H](O)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 99.1 %

Procedure:
(E)-4-(4-(Trifluoromethyl)phenyl)but-3-en-2-one (15 g, 70 mmol) was taken up in 500 mL of toluene. (R)-(+)-2-Methyl-CBS-oxazaborolidine (1.09 M in toluene) (6.4 mL, 7.0 mmol) was added, and the mixture was chilled to −78° C. Catecholborane (13 mL, 119 mmol) was added dropwise via addition funnel in 125 mL of toluene. The mixture was stirred for 25 minutes and then gradually warmed to −45° C. and stirred for 2 hours. The yellow color taken on during the catecholborane addition faded during this time and the solution cleared. The mixture was quenched with 300 mL of water and warmed to room temperature. The mixture was partitioned in a separatory funnel. The organic portion was washed 3 times with 200 mL of 5% aq. KOH (to remove the catechol), twice with 200 mL of 10% aqueous HCl (to remove the CBS catalyst), and once with 200 mL of brine, and then dried over MgSO4. Filtration and concentration under reduced pressure afforded (S,E)-4-(4-(trifluoromethyl)phenyl)but-3-en-2-ol (15 g, 99% yield) as a yellow oil that slowly crystallized. 1H NMR (400 MHz, CDCl3) δ ppm 7.57 (d, J=8.22 Hz, 2H) 7.50-7.45 (m, 2H) 6.62 (d, J=16.04 Hz, 1H) 6.36 (dd, J=16.04, 6.06 Hz, 1H) 4.49-4.57 (m, 1H) 1.61 (d, J=4.30 Hz, 1H) 1.39 (d, J=6.46 Hz, 3H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C(Cl)[Cl:29]>C(O)C.CCOCC>[ClH:29].[O:1]([CH2:8][CH2:9][CH2:10][NH:20][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccccc1
Reactant: ClCCl
Reactant: NCCc1ccccc1
Solvent: CCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cl
Product: c1ccc(CCNCCCOc2ccccc2)cc1

Procedure:
A mixture of 30 g (0.14 mole) of 3-phenoxypropyl bromide and 16.82 g (0.139 mole) of phenethylamine in 500 ml of absolute ethanol and in the presence of excess triethylamine was refluxed for 18 hr. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. This was dissolved in a mixture of ether and methylene chloride, and the solution was extracted with dilute sulfuric acid and then with dilute sodium hydroxide. The organic solution was treated with an excess of ethereal hydrogen chloride, and 12.43 g (30.68%) of the product precipitated as a white, crystalline solid, mp 196°-197° C.
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]([CH2:12][C:13]#[N:14])[C:9]([CH2:15][CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20]([C:22]1[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:23]=1[CH3:29])=O)C.CCCCCCC.CC(C)([O-])C.[K+]>COCCOCCOC>[C:1]1([N:7]2[N:11]=[C:10]([CH:12]([C:20]([C:22]3[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:23]=3[CH3:29])=[O:19])[C:13]#[N:14])[C:9]([CH2:15][CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(C)c(C)nn1C
Reactant: CCc1nn(-c2ccccc2)nc1CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCCCCCC
Product: CCc1nn(-c2ccccc2)nc1C(C#N)C(=O)c1c(C)c(C)nn1C
Temperature: 92.5 °C
Yield: 68 %

Procedure:
In a 2 L-reaction flask equipped with a rectification column, 106 g (0.5 mol) of 2-phenyl-4-cyanomethyl-5-ethyl-1,2,3-triazole, 91 g (0.5 mol) of 1,3,4-trimethylpyrazol-5-carboxylic acid ethyl ester, 530 g of heptane, and 106 g of diethylene glycol dimethyl ether were added, then azeotropic dehydration was carried out by heating at 90 to 95° C. Thereafter 61.7 g (0.55 mol) of potassium-tert-butoxide was carefully added under nitrogen atmosphere, then the resulting solution was heated at 95° C. and reacted for 15 hours while removing the eluent from the rectification column. After cooling to 30° C. or less, 3000 g of water was added to separate out heptane phase, and the resulting aqueous phase was further washed with 600 g of heptane to separate into phases. A quantitative analysis of the obtained aqueous phase with liquid chromatography showed that the aqueous phase contained 118.5 g (yield 68%) of 2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethyl-5-pyrazolyl)-3-oxopropionitrile. The aqueous solution was warmed at 40° C., pH was adjusted to 1 by adding 35% hydrochloric acid with stirring. The crystal obtained by cooling to 15° C. over 2 hours was filtered. The crystal cake was washed three times with 200 ml of water and then dried to obtain 116 g (yield 66.5%) of 2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethyl-5-pyrazolyl)-3-oxopropionitrile (melting point 119° C.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][N:5]=[C:4]([S:23][CH3:24])[N:3]=1.[CH2:25]([Mg]Br)[CH3:26]>C1COCC1.CN1C(=O)CCC1>[CH2:25]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][N:5]=[C:4]([S:23][CH3:24])[N:3]=1)[CH3:26]
Reactant: CC[Mg]Br
Reactant: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(Cl)n1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCc1nc(SC)ncc1-c1ccnc(Nc2ccc(C#N)cc2)n1
Yield: 26.7 %

Procedure:
4-(4′-Chloro-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile (35) (205 mg, 0.526 mmol) and ferric acetylacetonate (18.57 mg, 0.053 mmol) were dissolved in THF (3305 μl) and NMP (248 μl), then ethylmagnesium bromide (789 μl, 0.789 mmol) was added dropwise under nitrogen. The reaction was quenched with 1N HCl, then was extract with EtOAc. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was dry-loaded onto silica gel and purified by Biotage™ silica gel chromatography [25 g SNAP column, 30% EtOAc/heptane to 100% EtOAc] to obtain 49 mg of the desired product (21%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.58 Hz, 3 H) 2.59 (s, 3 H) 2.95 (q, J=7.58 Hz, 2 H) 7.25 (d, J=5.05 Hz, 1 H) 7.68-7.78 (m, 2 H) 7.95-8.03 (m, 2 H) 8.67-8.75 (m, 2 H) 10.33 (s, 1 H). MS (ES+): m/z=349.5 [M+1] (100). HPLC: tR=1.57 minutes over 3 minutes. Purity: 93% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[S:18][N:17]=[C:16]([CH3:19])[N:15]=1)=[O:12].F[C:29]1[CH:41]=[CH:40][C:32]2[C:33](=[O:39])[N:34]([CH3:38])[CH2:35][CH2:36][O:37][C:31]=2[CH:30]=1>CC(N(C)C)=O>[CH3:35][CH:36]1[N:34]([CH3:38])[C:33](=[O:39])[C:32]2[CH:40]=[CH:41][C:29]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=3)[C:11]([NH:13][C:14]3[S:18][N:17]=[C:16]([CH3:19])[N:15]=3)=[O:12])=[CH:30][C:31]=2[O:37]1
Reactant: CN1CCOc2cc(F)ccc2C1=O
Reactant: Cc1nsc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc4c(c3)OC(C)N(C)C4=O)cc(O[C@@H](C)CO)c2)n1
Temperature: 160 °C
Yield: 64.4 %

Procedure:
Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide (155 mg, 0.5 mmol) and 8-fluoro-4-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (117 mg, 0.6 mmol) in DMA (5 mL) and the stirred mixture heated at 160° C. in a microwave reactor for 8 hours. The mixture was cooled to RT and pressure, the DMA removed in vacuo, and the residue partitioned between water (25 mL) and ethyl acetate (30 mL). The mixture was adjusted to pH 2, the organic layer washed with brine, dried (MgSO4) and evaporated in vacuo to a residue which was chromatographed on silica, eluting with ethyl acetate, to give desired compound (156 mg). 1H NMR δ (CDCl3): 1.3 (d, 3H), 1.5 (d, 2H), 2.4 (s, 3H), 3.0 (s, 3H), 3.7 (d, 2H), 4.5 (m, 1H), 5.35 (q, 1H), 6.4 (s, 1H), 6.6 (d, 1H), 6.75 (s, 1H), 7.15 (s, 1H), 7.2 (s, 1H), 7.8 (d, 1H); m/z 485 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].[CH3:20][C:21](C)=[O:22]>>[C:13]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:21](=[O:22])[CH3:20])[CH:8]=2)[CH:3]=1)(=[O:15])[CH3:14]
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=O
Product: CC(=O)Oc1ccc2cc(OC(C)=O)ccc2c1

Procedure:
In a process for producing 2,6-dihydroxynaphthalene from 2,6-diisopropylnaphthalene, 2,6-diisopropylnaphthalene is oxidized in the presence of a specific proportion of a basic compound to hydroxylate or hydroperoxylate 2,6-diisopropylnaphthalene in a high conversion, and the resulting intermediate is then subjected to acid cleavage in the presence of hydrogen peroxide to produce 2,6-dihydroxynaphthalene in a high yield. The yield of 2,6-dihydroxynaphthalene increases by subjecting the reaction mixture containing the above intermediate to a purifying operation or dehydrating operation or adding acetone to it before it is submitted to the acid cleavage. 2,6-Dihydroxynaphthalene may be reacted with acetic anhydride to obtain 2,6-diacetoxynaphthalene.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Cl:12])=[CH:4][N:3]=1.Br[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([CH3:23])[C:17]([Cl:24])=[CH:16][N:15]=1.I([O-])(=O)(=O)=O.[Na+].[OH2:31]>C1COCC1.[Os](=O)(=O)(=O)=O>[Cl:12][C:5]1[C:6]([CH3:11])=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([CH:14]=[O:31])=[N:3][CH:4]=1.[Cl:24][C:17]1[C:18]([CH3:23])=[C:19]([N+:20]([O-:22])=[O:21])[C:14]([CH:2]=[CH2:7])=[N:15][CH:16]=1
Reactant: O
Reactant: Cc1c(Cl)cnc(Br)c1[N+](=O)[O-]
Reactant: Cc1c(Cl)cnc(N)c1[N+](=O)[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C=Cc1ncc(Cl)c(C)c1[N+](=O)[O-]
Product: Cc1c(Cl)cnc(C=O)c1[N+](=O)[O-]
Yield: 56 %

Procedure:
2-Amino-3-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (26 mg) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (78 mg). 1-(6-Chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 105 part a to d except using 5-chloro-4-methyl-3-nitropyridine-2-carboxaldehyde (1.3 g) in part a to yield [2-(tert-butyldimethylsilanyloxy)propyl]-(5-chloro-4-methyl-3-nitropyridin-2-yl-methyl)amine (1.4 g, 57%). 5-Chloro-4-methyl-3-nitro-pyridine-2-carboxaldehyde was prepared using a procedure similar to that described in Example 136 part a to c except starting from 2-amino-5-chloro-4-methyl-3-nitropyridine (32 g) in part a to generate 2-bromo-5-chloro-4-methyl-3-nitropyridine (25.2 g, 59%). Oxidative cleavage using a 4% solution of osmium tetroxide in water (1.5 mL) and sodium periodate (2.5 g) was carried out in a mixture of THF and water (10:1, 60 mL) in part c instead of ozonolysis following a procedure similar to that described in Example 61 to afford 5-chloro-4-methyl-3-nitropyridine-2-carboxaldehyde (1.3 g, 56%) from 5-chloro-4-methyl-3-nitro-2-vinylpyridine (2.3 g). 2-Amino-5-chloro-4-methyl-3-nitropyridine (4.6 g, 75%) was prepared using a procedure similar to that described in Example 38 part a except starting from 2-amino-4-methyl-3-nitropyridine (5 g) and using N-chlorosuccinimide (5.8 g) instead of N-bromosuccinimide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:47]2[CH:48]=[CH:49][C:44]([C:41]3[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=3)=[CH:45][CH:46]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(-c3ccccc3)cc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 4-bromobiphenyl according to the general procedure C. Obtained as a yellow solid (1.29 g).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([NH2:8])=[N:5][N:4]=1)[CH3:2].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].O>O1CCCC1>[CH2:1]([C:3]1[O:7][C:6]([NH:8][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[N:5][N:4]=1)[CH3:2]
Reactant: CCc1nnc(N)o1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nnc(NC(=O)OCC(Cl)(Cl)Cl)o1
Yield: 29.9 %

Procedure:
To a solution of 5-ethyl-1,3,4-oxadiazol-2-ylamine (1.00 g, 8.84 mmol) and pyridine (2.10 ml, 26.5 mmol) in tetrahydrofuran (29 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (2.45 ml, 17.7 mmol), and the mixture was stirred at room temperature for 1.5 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 763 mg (29.9%) of the desired product as a solid.