Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH2:19])=[CH:7]2.Cl[C:21]1[C:22]2[CH:29]=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH:19][C:21]1[C:22]3[CH:29]=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)=[CH:7]2
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc2cc(CNc3ncnc4[nH]ccc34)c(-c3ccccc3)nc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-phenylquinolin-3-yl)meth-anamine (0.050 g, 0.186 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.034 g, 0.22 mmol, 1.2 eq) and DIEA (0.38 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-phenylquinolin-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [PI3Kδ IC50=270 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.65-8.76 (m, 1 H), 8.53 (s, 1 H), 8.11-8.20 (m, 4 H), 8.07 (d, J=1.96 Hz, 1 H), 7.91-8.00 (m, 2 H), 7.86 (s, 1 H), 7.51-7.58 (m, 2 H), 4.73-4.85 (m, 2 H), Mass Spectrum (ESI) m/e=386 (M+1).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([CH2:16][C:17]1[CH:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:19]([C:25]([OH:27])=O)=[C:20]([CH3:24])[NH:21][C:22]=1[CH3:23])([OH:15])=[O:14].[CH:35]1[CH:36]=[CH:37][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:39][CH:40]=1>O1CCCC1>[C:38]1([N:41]2[CH2:46][CH2:45][N:44]([C:25]([C:19]3[CH:18]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])[C:17]([CH2:16][C:13]([OH:15])=[O:14])=[C:22]([CH3:23])[NH:21][C:20]=3[CH3:24])=[O:27])[CH2:43][CH2:42]2)[CH:39]=[CH:40][CH:35]=[CH:36][CH:37]=1
Reactant: CC1=C(CC(=O)O)C(c2ccccc2Cl)C(C(=O)O)=C(C)N1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1=C(CC(=O)O)C(c2ccccc2Cl)C(C(=O)N2CCN(c3ccccc3)CC2)=C(C)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.1 g (6.5 mmol) of carbonyldiimidazole are added to 1.60 g (5 mmol) of 5-carboxymethyl-4-(2-chlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid suspended in 20 ml of absolute tetrahydrofuran. The mixture is stirred at room temperature for 30 minutes and at a reflux temperature for 30 minutes. 1.62 g (10 mmol) of phenylpiperazine in 5 ml of absolute tetrahydrofuran are added to the resulting solution. This mixture is heated to reflux for 3.5 hours and then evaporated, the residue is taken up in methylene chloride, and the solution is washed successively with 1N hydrochloric acid, 1N sodium hydroxide solution and water, dried with magnesium sulphate and again evaporated. The residue crystallizes from isopropanol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][NH:8][C:9](=O)[CH3:10].N1C(C)=CC=CC=1C.[C:20]([NH:28][NH2:29])(=O)[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:7][N:8]1[C:9]([CH3:10])=[N:29][N:28]=[C:20]1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CNC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1nnc(-c2ccncc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
860 μl (10 mmol) oxalyl chloride was slowly added to a solution of 731 mg (10 mmol) N-methyl-acetamide and 2.33 ml (20 mmol) 2,6-lutidine in 20 ml CH2Cl2 at 0° C. After 15 min 1.37 g (10 mmol) isonicotinic acid hydrazide was added in one portion. The resulting mixture was stirred at room temperature for 1 h and the neutralized with NaHCO3(sat). The phases were separated and the water phase was extracted with CH2Cl2. The combined organic phases were dried and concentrated. The residue was dissolve in 20 ml acetic acid and heated at 120° C. for 2 h. After cooling the solvent was removed. Flashchromatography (CH2Cl2/MeOH 10:1) afforded 765 mg (44%) of a grey/white solid. 1H NMR (CDCl3), d (ppm): 2.52 (s, 3 H) 3.66 (s, 3 H) 7.58 (d, 2 H) 8.76 (d, 2 H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2)=C.I([O-])(=O)(=O)=[O:14].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH:1]=[O:14])=[CH:12][CH:11]=2)[N:6]=[CH:7][CH:8]=1
Reactant: C=Cc1ccc2nccnc2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1ccc2nccnc2c1
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a mixture of 6-vinylquinoxaline (0.68 g,4.35 mMol) in dioxane (44 mL) and water (35 mL) was added osmium tetraoxide (2.5% wt in t-BuOH, 2.18 mL, 0.17 mMol) followed by sodium periodate (2.79 g, 13.1 mMol) and the reaction stirred for three hours. The solution was diluted with ethyl acetate (150 mL) and then washed with water (3×75 mL) followed by brine (75 mL). The organics were dried with magnesium sulfate, filtered, and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography on silica gel using 10-20% ethyl acetate in dichloromethane as eluant yielded 470 mg (68% yield) of quinoxaline-6-carboxaldehyde as a white solid. 1H NMR (DMSO-d6): δ=10.30 (s, 1H), 9.11 (d, 2H, J=1.9 Hz), 8.74 (d, 1H, J=1.4 Hz), 8.26 (m, 2H). LC/MS (Method A), rt=0.69 mins., purity=94.8%, calculated mass=158, [M+H]+=159.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([NH:31][CH3:32])[CH2:17][CH2:16][C@@:15]35[OH:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([CH2:42][S:43](Cl)(=[O:45])=[O:44])[CH:38]=[CH:39][C:40]=1[Cl:41]>N1C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]([CH3:32])[S:43]([CH2:42][C:37]1[CH:38]=[CH:39][C:40]([Cl:41])=[C:35]([Cl:34])[CH:36]=1)(=[O:45])=[O:44])[CH2:17][CH2:16][C@@:15]35[OH:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O[Si](C)(C)C(C)(C)C)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: CN([C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O[Si](C)(C)C(C)(C)C)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5)S(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
203.9 mg of 3-tert-butyldimethylsilyloxy-17-cyclopropylmethyl-4,5α-epoxy-14β-hydroxy-6α-methylaminomorphinan 7 obtained in reference example 5 was dissolved in 3 ml of pyridine followed by the addition of 124 mg of 3,4-dichorophenylmethanesufonylchloride and stirring for 30 minutes at room temperature. After concentrating the reaction system, 3 ml of saturated aqueous sodium bicarbonate and 3 ml of chloroform were added to separate layers, after which the aqueous layer was extracted twice with 3 ml of chloroform. After drying with anhydrous sodium sulfate, the organic layer was concentrated to obtain the oily crude product. This was then purified with silica gel column chromatography (30 g benzene/ethyl acetate=5/1) to obtain 235.4 mg of the target compound (yield: 78%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=[CH:5][N:4]=1.O1CCCC1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[C:27]([Cl:35])=[C:28]([N:32]=[C:33]=[S:34])[CH:29]=[CH:30][CH:31]=1>O>[Cl:2][C:3]1[C:8]([CH2:9][NH:10][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[C:27]=2[Cl:35])=[S:34])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: NCc1cccnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: S=C(NCc1cccnc1Cl)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To an oven-dried, N2-purged, 25-mL, round-bottomed flask containing a magnetic stir bar were added the product of Example 141A, anhydrous tetrahydrofuran (5 mL), and diisopropylethylamine (646 mg, 0.886 mL, 5.00 mmol). The flask was sealed with a septum and neat dichlorophenylisothiocyanate (306 mg, 0.213 mL, 1.50 mmol) was added via syringe. The reaction mixture was stirred at room temperature overnight. Water (10 mL) was added, and the reaction was transferred to a separatory funnel. The mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a brown solid. The product was recrystallized from ethyl acetate/hexanes to give 197 mg (47%) of the title compound as a white powder. MS (ESI″) m/z 345.9 (M+H)+; 1H NMR (DMSO-d6) δ 4.75 (d, J=5.1 Hz, 2H), 7.37 (dd, J=8.0, 8.0 Hz, 1H), 7.46 (dd, J=7.5, 4.7 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.76 (dd, J=7.6, 1.5 Hz, 1H), 8.32 (dd, J=4.7, 1.7 Hz, 1H), 8.44 (br s, 1H), 9.68 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([C:11](=[O:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[O:18][CH2:19][CH3:20].C(O)C.[BH4-].[Na+].[OH-].[Na+]>O>[NH2:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([CH:11]([OH:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[O:18][CH2:19][CH3:20]
Reactant: CCOc1cc(C(=O)CS(C)(=O)=O)cc(OCC)c1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cc(C(O)CS(C)(=O)=O)cc(OCC)c1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of 26 g. of 4'-amino-3',5'-diethoxy-2-(methylsulfonyl)-acetophenone in 350 ml. of ethanol and 350 ml. of water was treated with a solution of 7.0 g. of sodium borohydride in 90 ml. of water. There was also added 0.5 g. of sodium hydroxide. The mixture was stirred for 17 hours at room temperature, cooled with ice, diluted with 500 ml. of water and filtered under vacuum. After recrystallization from methanol, there was obtained 4-amino-3,5-diethoxy-α-[(methylsulfonyl)-methyl]-benzyl alcohol having a melting point of 166°-168° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][CH3:25])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[CH2:24]([C:20]1[CH:19]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[N:26][CH:27]=[N:28][CH:29]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:23]=[CH:22][N:21]=1)[CH3:25]
Reactant: CCc1cc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)ccn1
Reactant: OB(O)c1cncnc1
Product: CCc1cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3ccccc32)ccn1
Yield: 58 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-ethylpyridin-4-yl)-1H-isoindol-3-amine (Example 110) as described in Example 67 Scheme #10, D in 58% yield using pyrimidine-5-boronic acid. 1H NMR (DMSO-d6) δ 9.11 (s, 1 H), 8.93 (s, 2 H), 8.28 (d, J=5.30 Hz, 1 H), 7.86 (dd, J=6.06, 1.77 Hz, 1 H), 7.80-7.68 (m, 1 H), 7.64-7.54 (m, 2 H), 7.47-7.36 (m, 4 H), 7.19-7.10 (m, 1 H), 7.07 (dd, J=5.18, 1.64 Hz, 1 H), 6.85 (br s, 2 H), 2.59 (q, J=7.58 Hz, 2 H), 1.08 (t, J=7.58 Hz, 3 H); MS (ESI) m/z 392 [M+1]+.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:31])[CH3:30])[C:13]([O:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].C(N(CC)CC)C.[C:40]1([CH2:46][C:47](Cl)=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:47](=[O:48])[CH2:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:30])[CH3:31])[C:13]([O:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 16.46 g of diphenylmethyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 160 ml of methylene chloride are added 9.6 ml of triethylamine and 9 ml of phenylacetyl chloride under ice-cooling, and the mixture stirred at room temperature for 2 hours. The reaction mixture is then washed with water, dried on magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on 200 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 17 to 19 g of diphenylmethyl α-(3ξ-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 80 to 90% yield.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[NH2:14][CH2:15][C:16]1([N:20]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][O:18][CH2:17]1.[CH2:35](N(CC)CC)C>CO>[Cl:1][C:2]1[N:11]=[C:10]([NH:14][CH2:15][C:16]2([N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:19][O:18][CH2:17]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][CH3:35])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CCN(CC)CC
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Solvent: CO
Product: CCc1ccc2nc(Cl)nc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 338.3 %

Procedure:
A solution of 2,4-dichloro-6-methylquinazoline (1.0 g, 4.69 mmol) in methanol (10 mL) was added 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine (1.4 g, 5.16 mmol, 60% purity) and triethylamine (0.1 g, 1 mmol). After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 20% ethyl acetate in petroleum ether) to afford 1.6 g of the product as a white solid (yield was 76%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH3:10])[CH3:9].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([OH:21])[CH:15]=1.O>CN(C)C=O.C(OC(=O)C)C>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([O:20][CH:8]([CH3:10])[CH3:9])[CH:19]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(O)cc(OC(C)C)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 30042.8 %

Procedure:
After adding 41.0 g (0.30 mmol) of potassium carbonate and 23.8 g (0.19 mmol) of 2-bromopropane to a solution of 25.0 g (0.15 mol) of 3,5-dihydroxybenzoic acid methyl ester in N,N-dimethylformamide (250 ml), the reaction mixture was stirred at 80° C. for 4 hours. Water was added to the reaction mixture, extraction was performed with acetic acid ethyl ester, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=5:1) to obtain 12.0 g of 5-hydroxy-3-isopropoxybenzoic acid methyl ester (yield: 38%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].O[NH:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=3)[N:26]=2)[CH2:17][CH2:16]1)=[NH:14].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:14]=[C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:22]=[CH:23][C:24]5[N:25]([C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=5)[N:26]=4)[CH2:19][CH2:20]3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N=C(NO)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4noc(-c5cccc(Cl)c5)n4)CC3)nn12
Temperature: 150 °C
Reaction time: 1 h

Procedure:
3-Chlorobenzoyl chloride (92 mg, 0.53 mmol) was added to a stirred partial solution of N-hydroxy-4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboximidamide (165 mg, 0.5 mmol) and DIPEA (97 mg, 0.75 mmol) in THF (3 mL). The reaction mixture became a clear solution over 30 minutes and LCMS after 1 hour showed complete initial acylation. The reaction mixture was heated at 150° C. for 15 minutes by microwave after which LCMS showed complete cyclisation to the desired product. The reaction mixture was evaporated and the residue was boiled briefly with ethanol, cooled and filtered off to give 6-[4-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (104 mg, 46%) as a crystalline powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[Br:11]Br.O>C(OCC)C.ClC(Cl)(Cl)Cl>[Br:11][CH:7]1[CH2:8][CH2:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:10]
Reactant: BrBr
Reactant: O=C1CCCc2sccc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: O=C1c2ccsc2CCC1Br
Temperature: -10 °C
Reaction time: 18 h

Procedure:
6,7-Dihydro-5H-benzo[b]thiophen-4-one (198, 5.8 g, 38.3 mmol) is dissolved in 200 ml of dry diethyl ether and cooled down to −10° C. A solution of bromine (6.1 g, 38.3 mmol) in 30 ml of tetrachloromethane and 2-3 drops of diethyl ether is slowly added. The mixture is stirred for 15 min at −10° C., 15 min at 0° C. and 18 h at room temperature. Then water and diethyl ether is added slowly. The organic layers are washed with water, dried over Na2SO4 and evaporated.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].C(=O)C1C(=CC=CC=1)[CH:14]=[O:15].OC[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26]>>[C:5]1([CH2:4][OH:3])[CH:6]=[CH:7][CH:8]=[C:9]([CH2:14][OH:15])[CH:10]=1.[OH:2][CH2:1][C:28]1[CH:27]=[C:24]([CH:23]=[CH:30][CH:29]=1)[CH:25]=[O:26]
Reactant: O=Cc1ccccc1CO
Reactant: O=Cc1ccccc1C=O
Reactant: O=C1OCc2ccccc21
Product: O=Cc1cccc(CO)c1
Product: OCc1cccc(CO)c1

Procedure:
A particularly advantageous feature of the oxidative method is shape selectivity, as illustrated by the oxidation of three benzenedimethanol isomers as shown in FIG. 1 (Example 6 below). Oxidation of 1,2-benzenedimethanol resulted in very low conversion, yielding a mixture of phthalide, phthalaldehyde, and 2-(hydroxymethyl)benzaldehyde (a mono-oxidized product). Oxidation of 1,3-benzenedimethanol yielded only the mono-oxidized product 3-(hydroxymethyl)benzaldehyde. Oxidation of 1,4-benzenedimethanol yielded terephthalaldehyde. These results show that the H-K-OMS-2 catalyst gives shape selective reaction products.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:38])([F:37])[C:12]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[CH2:34]([N:33]([CH2:32][C:12]([CH2:13][NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)([OH:31])[C:11]([F:10])([F:37])[F:38])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:35][CH3:36]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 1 from benzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]#[N:16])[CH2:11][CH2:10]2)[C:7]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:6]=2[N:5]=1)[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl>C(O)CCC.O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:6]2[N:5]=[C:4]([C@@H:2]([NH:1][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH3:3])[N:8]([CH:9]3[CH2:14][CH2:13][CH:12]([C:15]#[N:16])[CH2:11][CH2:10]3)[C:7]=2[CH:17]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CCC(C#N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CCC(C#N)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
A mixture of 4-[2-((S)-1-aminoethyl)-6-fluorobenzoimidazol-1-yl]cyclohexanecarbonitrile (100 mg, 0.35 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (91 mg, 0.38 mmol) and DIPEA (0.10 mL, 0.72 mmol) in n-butanol (0.7 mL) was heated for 48 h at 105° C. After cooling to RT, the crude reaction mixture was treated with 4N HCl in dioxane (0.5 mL) and stirred for 1 h at RT. The crude mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-8% MeOH in DCM), then triturated with hot EtOAc and purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a gradient 0-40%, 0.1% HCO2H in acetonitrile/water) to afford 174 as a white solid (26 mg, 18%). LCMS (Method K): RT 2.93 min [M+H]+ 405.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.45 (1H, s), 8.34-7.94 (3H, m), 7.71-7.56 (2H, m), 7.05-6.96 (1H, m), 5.96 (1H, bs), 4.62-4.59 (1H, m), 3.09-2.95 (1H, m), 2.38-2.25 (1H, m), 2.21-2.07 (2H, m), 1.93 (1H, bd, J=12.75 Hz), 1.84 (1H, bd, J=12.00 Hz), 1.73-1.65 (5H, m), 1.02 (1H, bs). Broad signals due to presence of rotamers/tautomers
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a stirred solution of 2,4-dichloro-6-hydroxybenzaldehyde (1.85 g, 9.69 mmol) in N,N-dimethylformamide (20 mL) at ambient temperature was added solid potassium carbonate (1.47 g, 10.7 mmol), and the resulting yellow mixture was stirred at ambient temperature for 30 minutes. Iodomethane (2.42 mL, 38.7 mmol) was added, and the resulting mixture was stirred in an oil bath set to 50° C. for 30 minutes. The mixture was cooled to ambient temperature and diluted with water (200 mL). After stirring for 10 minutes, the precipitate that formed was collected by filtration, washed with water, and dried under vacuum to afford 2,4-dichloro-6-methoxybenzaldehyde as an off-white powder (1.93 g, 97% yield).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][CH2:5]O>[Pd]>[CH3:1][N:2]([CH3:1])[C@@H:3]1[CH2:4][CH2:5][CH2:5][CH2:4][C@H:3]1[NH2:2]
Reactant: CNC
Reactant: CCO
Agent: [Pd]
Product: CN(C)[C@@H]1CCCC[C@H]1N
Reaction time: 19 h

Procedure:
A solution of the benzylamino compound was hydrogenated in two batches each containing 30.5 g. (0.131 mole), 175 ml. EtOH, 3.4 g Pd-C and 56.5 g. (0.394 mole) of 70% HClO4, at initial pressure of 51.5 p.s.i. for 19 hours. The two batches were combined, filtered through Celite and evaporated in vacuo at 45°. The residue was cooled in ice, basified with 40% KOH to pH 11. The resulting thick suspension was extracted with ether (5×200 ml), the ether extract was dried (MgSO4) and evaporated through a 9" Vigreux. The residue was distilled at 13 mm to give 32.5 g. (87% yield), b.p. 77°-78.5°. Vpc 100% at 3.8 mm. ir and nmr was identical to those of the sample prepared by the reaction of 7-azabicyclo[3.1.0]heptane with dimethylamine.