Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.Br[CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C(=O)C>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([N:18]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:16][CH2:17]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: BrCCCCBr
Reactant: Cc1c(O[C@H]2CC[C@H](N)CC2)ccc2c1cnn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(O[C@H]2CC[C@H](N3CCCC3)CC2)ccc2c1cnn2C1CCCCO1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of trans-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexylamine (106 mg, 0.321 mmol), 1,4-dibromobutane (69.3 mg, 0.321 mmol), potassium carbonate (110 mg, 0.80 mmol) and N,N-dimethylacetamide (2.0 ml) was stirred at 80° C. for 2 hours. A 1N-aqueous sodium hydroxide solution (20 ml) was added to the reaction solution, followed by extraction with chloroform (20 ml) (twice). The extract solution was dried over magnesium sulfate and then concentrated to dryness, and the residue oil was purified by elution by a silica gel column chromatography (hexane/ethyl acetate=1:2→hexane/ethyl acetate/triethylamine=20:40:3) to obtain 4-methyl-5-[(trans-4-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole (67.1 mg, 55%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]2[CH2:13][CH2:14][CH2:15][C:16](=[O:17])[C:4]=12.P(Cl)(Cl)(Cl)=O.[CH:23]([Cl:26])(Cl)Cl>CN(C)C=O>[Cl:26][C:23]1[C:4]2[C:5](=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:7][C:3]=2[S:2][CH3:1])[CH2:13][CH2:14][C:15]=1[CH:16]=[O:17]
Reactant: CCOC(=O)c1sc(SC)c2c1CCCC2=O
Reactant: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(SC)c2c1CCC(C=O)=C2Cl
Temperature: 25 °C
Yield: 73.8 %

Procedure:
Ethyl 4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (5.47 g) was dissolved in chloroform (130 ml) and added dropwise to a solution of phosphorus oxychloride (50.71 g) in N,N-dimethylformamide (40 ml) at 0° C. This mixture was stirred at room temperature, after which it was refluxed under heating in a nitrogen stream for 4.5 hours. The reaction mixture was poured over ice water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield ethyl 4-chloro-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (4.72 g, 73.8%), which was then recrystallized from ethyl acetate. Yellow prisms. Melting point 79-80° C.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[O:5])=[N-]>O1CCOCC1.[Cu]>[CH3:10][C:9]1([CH3:11])[CH:3]2[CH:8]1[CH2:7][O:6][C:4]2=[O:5]
Reactant: CC(C)=CCOC(=O)C=[N+]=[N-]
Agent: [Cu]
Solvent: C1COCCO1
Product: CC1(C)C2COC(=O)C21
Reaction time: 5.5 h

Procedure:
A solution of 3-methyl-2-butenyl diazoacetate (980 mg, 6.4 mmoles) in dioxane (15 ml) was added dropwise to a solution of bis[2-butoxy-α-[2-butoxy-5-(1,1-dimethylethyl)phenyl]-5-(1,1-dimethylethyl)-α-[(S)-1-[[2-hydroxyphenyl)methylene]amino]ethyl]benzenemethanolato (2-)]-copper (83 mg, 0.064 mmole) in dioxane (55 ml) at 110°. When the evolution of nitrogen started, the temperature was slowly lowered to 52°-3°. The addition took 5.5 hours, and the evolution at almost theoretical amounts of nitrogen was observed. After the addition was completed, the reaction mixture was stirred at 52°-3° for 2 hours, evaporated to dryness, and distilled under vacuum to afford 6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]-hexane enriched with the (1R,5S) isomer (500 mg). The optical rotation of the product was [α]D29 =-53.5° (CHCl3).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8][CH3:9])(=[O:6])[O:4]C.[OH-].[Na+:11]>>[Na+:11].[CH3:1][O:2][P:3]([CH2:7][CH2:8][CH3:9])(=[O:4])[O-:6]
Reactant: CCCP(=O)(OC)OC
Agent: [Na+]
Agent: [OH-]
Product: CCCP(=O)([O-])OC
Temperature: 110 °C
Yield: 100 %

Procedure:
973 g (6.4 mol) of propanephosphonic acid dimethyl ester are heated to 90° C. and 1280 g (6.4 mol) of 20% strength sodium hydroxide solution are added dropwise, while stirring vigorously. During this procedure, the temperature is increased slowly to 110° C., and at the same time 238 g of a methanol/water mixture distill off over a Vigreux column. The resulting solution is evaporated in vacuo and the residue which remains is dried in a vacuum drying cabinet. 1020 g of propanephosphonic acid monomethyl ester sodium salt are obtained with a purity of 92%, according to 31-P-NMR. This corresponds to a yield of about 100%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: Cc1ccnc(N2CCNCC2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccnc(N2CCN(S(C)(=O)=O)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a cooled (0° C.) solution of 1-(4-methyl-2-pyridyl)piperazine (228 mg, 1.286 mmol) in DCM (10 ml) were added triethylamine (360 μl, 2.59 mmol) and methanesulfonyl chloride (105 μl, 2.59 mmol). The mixture was stirred at 0° C. for one hour, then a saturated solution of sodium bicarbonate was added, the layers were separated, the aqueous layer was extracted with DCM (2×), the organic layers were combined, dried (sodium sulfate) and concentrated under reduced pressure to yield 316 mg of a white solid (1.238 mmol, yield 96%) MS (ESI) m/z=256.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[N:12]=2)=[O:8])=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]4=[O:23])=[CH:18][CH:17]=3)[N:12]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccn(-c2ccc(I)cc2)n1)c1ccc(Cl)s1
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1ccn(-c2ccc(-n3ccccc3=O)cc2)n1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 26.1 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-3-yl)methyl)thiophene-2-carboxamide (60 mg, 0.14 mmol), 2-hydroxypyridine (30 mg, 0.32 mmol), 8-hydroxyquinoline (10 mg, 0.070 mmol) and K2CO3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with Argon before being charged with CuI (15 mg, 0.080 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the titled compound (15 mg). MS 411.0 and 413.0 (M+H, Cl pattern).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](C(CC)(CC)C([O-])([O-])[O-])[CH3:35]>ClCCCl.C1CCN2C(=NCCC2)CC1>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][CH:25]=[C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=3)[N:1]=[C:34]2[CH3:35])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: COc1cc(NC(=O)c2cc(Oc3ccccc3)ccc2N)ccc1OCCN1CCCC1
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-n2c(C)nc3ccc(Oc4ccccc4)cc3c2=O)ccc1OCCN1CCCC1
Temperature: 80 °C

Procedure:
A solution of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-benzamide [Example D1] (25 mg, 0.055 mmol) in 1,2-dichloroethane (1 ml) was treated with triethylorthoacetate (2 ml) and the mixture heated to 80° C. for 2 hours. The mixture was cooled, 1 drop of DBU added and the mixture evaporated. The residue was subjected to flash chromatography on silica gel eluting with (methanol-dichloromethane-aqueous ammonia) to give the title compound;
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.CS(O[CH2:17][CH:18]1[CH2:20][CH:19]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=O)=O.O>CN(C=O)C>[N:3]1([CH2:17][C@@H:18]2[CH2:20][C@H:19]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: CCOC(=O)C1CC1COS(C)(=O)=O
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1Cn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
To a suspension of sodium hydride (60%, 55 mg, 1.4 mmol) in DMF (5 mL) was added indole (135 mg, 1.2 mmol). After stirring at room temperature for 10 min, ethyl 2-(((methylsulfonyl)oxy)methyl)cyclopropanecarboxylate (307 mg, 1.4 mmol) was added. After stirring at room temperature for 6 h, the mixture was poured into water, and the aqueous layer was extracted with EtOAc twice. The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10:1-5:1) to give 153 mg (54%) of the title compound as a pale brown oil;
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].[H-].[Na+].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.Cl>CN(C)C=O>[CH:1]([NH:4][CH2:5][CH2:6][O:7][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)NCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)NCCOc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
2-Isopropylamino-ethanol (5 g, 48 mmol) (Fluka) was added to a cooled (−5° C.) mixture of sodium hydride (5 g, 48 mmol) in N,N-dimethylformamide (200 mL) and stirred for 10 minutes at 0° C., 30 minutes at room temperature, and then 30 minutes at 450° C. After cooling to −1° C., 1-fluoro-4-nitrobenzene (8.21 g, 57.6 mmol) (Aldrich) was added and stirred for 20 minutes at −10° C. and 90 minutes at room temperature. The reaction was adjusted to pH 2 with 6N hydrochloric acid and the mixture extracted with ether (4×100 mL). The aqueous layer was adjusted to pH 9 with 4N sodium hydroxide and extracted with ethyl acetate. (4×100 mL), dried (Na2SO4), filtered and the solution concentrated in vacuo and the residue was dried under high vacuum to give 6.14 g (57%) of isopropyl-[2-(4-nitro-phenoxy)-ethyl]-amine.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].F[C:10]1[CH:15]=[CH:14][C:13]([S+: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)=[CH:12][CH:11]=1.[OH-].[Na+].[CH:31]1([SH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH:31]1([S:37][C:10]2[CH:15]=[CH:14][C:13]([S+:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Fc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reactant: SC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Br-]
Solvent: ClCCl
Product: c1ccc([S+](c2ccccc2)c2ccc(SC3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
26.7 g of 4-fluorophenyl diphenylsulfonium trifluoromethanesulfonate was dissolved in 200 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 200 g of 10 wt % sodium hydroxide aqueous solution, 5.8 g of tetra-n-butylammonium bromide, and 6.71 g of cyclohexane thiol were added. The mixture was stirred for 30 minutes at room temperature and transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the mixture was shaken and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried using anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 19.2 g of 4-cyclohexylthiophenyl diphenylsulfonium trifluoromethane sulfonate.
Reaction SMILES: Br[C:2]1[C:6](=[CH:7][Br:8])[O:5][C:4](=[O:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F-].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:10]1([C:2]2[C:6](=[CH:7][Br:8])[O:5][C:4](=[O:9])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1C=C(Br)C(=CBr)O1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(c2ccccc2)C(=CBr)O1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture containing 4-bromo-5-bromomethylene-2(5H)-furanone (1 mmol), phenylboronic acid (2.2 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.05 mmol), tetrabutylammonium iodide (0.05 mmol) and cesium fluoride (3 mmol) in toluene (10 mL) and water (10 mL) were stirred for 48-72 h under nitrogen at room temperature. Brine (50 mL) was added and the product extracted with ethyl acetate (3×50 mL). The organic fractions were combined, washed with brine (3×50 mL), dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting solid was chromatographed (silica gel: eluent 25:75 dichloromethane/light petroleum, 50:50 dichloromethane/light petroleum or 100% dichloromethane) giving the desired product—4-phenyl-5-bromomethylene-2-(5H)-furanone.
Reaction SMILES: [CH2:1]([C:4]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[C:12]=2[F:14])[NH:7][C:6](=[O:16])[N:5]1[CH2:17][C:18]([F:21])([F:20])[F:19])[CH:2]=C.[O:29]=[O+][O-].CSC>CO.CCOC(C)=O>[F:14][C:12]1[C:11]([F:15])=[CH:10][CH:9]=[C:8]2[C:13]=1[C:4]([CH2:1][CH:2]=[O:29])([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[N:5]([CH2:17][C:18]([F:21])([F:19])[F:20])[C:6](=[O:16])[NH:7]2
Reactant: C=CCC1(c2ccc(F)cc2)c2c(ccc(F)c2F)NC(=O)N1CC(F)(F)F
Reactant: O=[O+][O-]
Solvent: CO
Solvent: CSC
Solvent: CCOC(C)=O
Product: O=CCC1(c2ccc(F)cc2)c2c(ccc(F)c2F)NC(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of 2.6 g (6.495 mmol) 4-allyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one in 25 ml MeOH was bubbled ozone. After 15 mins at −78° C., the ozone was removed and the reaction mixture was quenched with 4.8 mL (64.946 mmol) dimethyl sulfide. After stirring at room temperature overnight, the reaction mixture was diluted with EtOAc and washed three times with water and brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Afforded [5,6-difluoro-4-(4-fluorophenyl)-2-oxo-3-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]acetaldehyde. 1H NMR (CDCl3, 400 MHz) δ 9.79 (s, 1H, O═CH); 8.61 (br s, 1H, ArNHC═O); 7.38-7.27 (m, 2H, ArH); 7.15-7.03 (m, 3H, ArH); 6.57-6.53 (m, 1H, ArH); 4.08 (m, 1H, C); 3.72 (dd, 1H, J=17.4 Hz, CH2C═O); 3.50 (dd, 1H J=1.28 Hz, 17.58 Hz, CH2C═O); 3.32 (m, 1H, CH2C═O). ES MS+1=403.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17](=O)[CH3:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1.CC([O-])=O.[Na+].Cl.[NH2:26][OH:27]>CO>[CH3:1][C:2]1[C:3]([C:17](=[N:26][OH:27])[CH3:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1
Reactant: CC(=O)c1cc2ncn(C3CCCCO3)c2cc1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1cc2ncn(C3CCCCO3)c2cc1C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a mixture of 1-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanone (1.1 g, 4.3 mmol) and NaOAc (3.5 g, 43 mmol) in MeOH (20 mL) at RT was added hydroxylamine hydrochloride (896 mg, 12.9 mmol). The reaction mixture was stirred at 80° C. for 0.5 h then concentrated in vacuo. Water (200 mL) was added, and the mixture was extracted with EtOAc (50 mL×3), dried (MgSO4), and concentrated in vacuo to afford 1-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanone oxime as a yellow solid (1.1 g, 90.2%). MS (ESI): m/z=194.3 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])=[CH:3][C:4]=2[CH3:24])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C)CC2)c(C)c1

Procedure:
Using (4-bromo-2-methylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (775 mg) described in Preparation Example 130 and pyrrolidin-2-one (0.16 mL) and by the reaction and treatment in the same manner as in Example 1, the title compound (182 mg) was obtained.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:13]=[C:12]([O:14]C)[C:11]([CH:16]([CH3:18])[CH3:17])=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].[CH3:19]O>O>[OH:14][C:12]1[C:11]([CH:16]([CH3:18])[CH3:17])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:3][CH3:19])[CH:13]=1
Reactant: COC(=O)c1cc(C(C)C)c(OC)cc1O
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc(O)c(C(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 85 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 0.5 ml) was added to a suspension of methyl 2-hydroxy-5-isopropyl-4-methoxybenzoate (418 mg, 1.87 mmol) in methanol (4 ml) and water (2 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford 4-hydroxy-5-isopropyl-2-methoxybenzoic acid (332 mg, 85%) as an off-white solid. 1H NMR (DMSO-d6) 11.88 (1H, br s), 10.11 (1H, s), 7.54 (1H, s), 6.51 (1H, s), 3.75 (3H, s), 3.11 (1H, m), 1.13 (6H, d). MS: [M+Na]+ 233.
Reaction SMILES: BrC1N=C2CCCN(CCCCCCC([O-])=O)C2=NC=1Cl.[Br:22][C:23]1[N:24]=[C:25]2[CH2:33][CH2:32][C:31](=O)[N:30]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:26]2=[N:27][C:28]=1[Cl:29].CO>C1COCC1>[Br:22][C:23]1[N:24]=[C:25]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:26]2=[N:27][C:28]=1[Cl:29]
Reactant: CCOC(=O)CCCCCCN1C(=O)CCc2nc(Br)c(Cl)nc21
Agent: O=C([O-])CCCCCCN1CCCc2nc(Br)c(Cl)nc21
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCN1CCCc2nc(Br)c(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-(2-bromo-3-chloro-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate A cooled (0° C.) solution of ethyl 7-(2-bromo-3-chloro-6-oxo-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1)(1.0 g, 2.388 mmol) in THF (10 ml) under a nitrogen atmosphere was treated with borane-methyl sulfide complex over 30 mins. The resulting mixture was stirred at 0° C. for 2 h 30 minutes and stored in a fridge overnight. The mixture was cooled in an ice bath and cautiously treated with MeOH (5 ml). The yellow solution was stirred at 0° C. for 1 hour and concentrated under reduced pressure. The crude material was purified by chromatography on silica eluting with 0-100% EtOAc in iso-hexane to afford ethyl 7-(2-bromo-3-chloro-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:11]=2[C:12]#[N:13])[CH:5]=[N:6][C:7]=1[F:8].[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[C:12]([C:11]1[CH:14]=[C:15]([CH:16]=[CH:17][C:10]=1[O:9][C:4]1[CH:5]=[N:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH2:18][O:19][C:23]1[CH:24]=[C:25]2[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1)#[N:13]
Reactant: N#Cc1cc(CO)ccc1Oc1cnc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cnc(F)c(F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 2-((5,6-difluoropyridin-3-yl)oxy)-5-(hydroxymethyl)benzonitrile, NaH and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:19]([OH:27])[CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](=[O:27])[CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCCCO2)cc2cccnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CC1CCCCO1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-2-yl)-ethanol (2.5 g, 6.5 mmol) in dichloromethane (100 mL) at 25° C. was added Dess-Martin periodinane (9.6 g, 23 mmol). The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with dichloromethane (50 mL), washed with a saturated aqueous sodium bicarbonate solution (3×100 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-2-yl)-ethanone (2.1 g, 84%) as a light yellow solid: LC/MS m/e calcd for C20H20N2O4S [M+H]+ 385.46, observed 385.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18](=[O:24])[CH:19]([CH3:23])[CH2:20][CH:21]=[O:22])[C:5]2=[O:25].[OH:26]OS([O-])=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18](=[O:24])[CH:19]([CH3:23])[CH2:20][C:21]([OH:26])=[O:22])[C:5]2=[O:25]
Reactant: CC(CC=O)C(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(CC(=O)O)C(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixture of 4-(6-chloro-2-hydroxy-4-oxo-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-3-yl)-3-methyl-4-oxobutanal (0.1 g, 0.3 mmol) in 2 mL DMF was stirred at room temperature and treated with oxone (0.2 mL, 0.3 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with 20 mL H2O, and the pH was adjusted to pH=5 with concentrated HCl. The precipitate that formed was collected by filtration and washed with 20 mL water. The product was dried under high vacuum to give 0.1 g of the product as an off-white solid. MS m/z 379 (M+H)+. Calculated for C19H19ClO6: 378.