Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:13].C(N(CC)CC)C.[CH:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[C:24]1([S:27]([NH:1][C@@H:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][CH2:5][CH2:4][C@H:3]2[OH:13])(=[O:29])=[O:28])[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@@H]1c2ccccc2CCC[C@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@@H]1c2ccccc2CCC[C@H]1O)c1ccccc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
To an ice-cold solution of trans-5-amino-6,7,8,9-tetrahydro-5H-benzocyclo hepten-6-ol (0.056 g, 0.32 mmol; example 15 a) in methylene chloride (10 ml) and triethylamine (1 ml) was added 4-benzene sulfonyl chloride (0.056 g, 0.32 mmol). The reaction mixture was stirred at 0° C. then allowed to come to room temperature for 72 hours. The reaction mixture was diluted with methylene chloride, then washed with 10% hydrochloric acid, saturated potassium hydrogen carbonate solution, dried over MgSO4, filtered and evaporated. Recrystallization from ethyl acetate/n-heptane yielded trans-5-(N-phenylsulfonylamino)-6,7,8,9-tetrahydro-5H-benzocyclo hepten-6-ol as white crystals (0.071 g, 71% yield), m.p. 128.0-128.2° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Li+].[OH-]>CO.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Temperature: 100 °C

Procedure:
Methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate (˜1 g, ˜4.41 mmol) was dissolved in MeOH/H2O (4:1, 50 mL) and then LiOH (0.36 g, 15 mmol) was added. The mixture was heated at reflux for 2 h at 100° C. The analytical HPLC indicated the starting material was consumed, the mixture was cooled to 0° C. and 2 M HCl solution was added bring the pH ˜4. MeOH was removed in vacuo and the acid was precipitated. The acid was collected by filtration and dried in vacuo and used without further purification. ESI-MS (m/z): 217 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 12.87 (br s, 1H), 7.82 (s, 1H), 7.51 (s, 1H), 7.39-7.27 (m, 3H), 3.85 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[C:11]1([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na].Cl>C1COCC1>[OH:23][C@H:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: Cl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](O)c1ccccc1
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
A solution of 1.70 g (11.3 mmol) of L-(+)-tartaric acid in 35 ml of THF was cooled in a cryostat at -20° C., and a solution of 0.5 g (2.8 mmol) of ethyl phenylglyoxylate in THF (5 ml) was added. To the resulting solution, there was further added 0.43 g (11.3 mmol) of sodium borohyride, all at once and with stirring, and the mixture was stirred for 24 hours. The reaction mixture was cooled in an ice bath, 20 ml of 1N HCl was added, and stirring was continued for 15 minutes. After distilling off THF under reduced pressure, the aqueous layer was extracted twice with ethyl acetate (30 ml and 20 ml), and the combined extract was washed first with 20 ml of a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure from the dried solution, and the residue was purified by silica gel column chromatography, giving 0.43 g of ethyl (R)-(-)-2-hydroxy-2-phenylacetate as an ethyl acetate:n-hexane fraction(1:5). Its specific rotation [α]D16 was -108.4° (cl. 12, CHCl3). The synthesis yield was 85% and the optical yield was 85% e.e (see Reference 7).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.C([Si](C)(C)[O:15][CH2:16][C:17]#[CH:18])(C)(C)C.C(N(CC)CC)C>CN1C(=O)CCC1.O.[Cu]I.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>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([C:18]#[C:17][CH2:16][OH:15])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Reactant: OCc1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: OCC#Cc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Copper (I) iodide (0.037 g) and tetrakis(triphenylphosphine)palladium (0) (0.075 g) were added to a solution of (3-iodophenyl)methanol (2.27 g), tert-butyldimethyl(prop-2-ynyloxy)silane (1.1 g) and triethylamine (2.7 mL) in NMP (20 mL) and the mixture stirred at ambient temperature under nitrogen for 18 hours. The mixture was diluted with water and extracted into ethyl acetate (×3). The combined extracts were washed successively with 10% brine, 30% brine and saturated brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash silica chromatography, elution gradient 10, 15 and 20% ethyl acetate in isohexane. Appropriate fractions were evaporated to dryness to give a mixture of product and starting material. The mixture was purified by preparative HPLC (XBridge™, Gradient: 65-99% acetonitrile in 0.2% aqueous TFA) to afford the subtitled compound as a pale yellow oil. Yield 0.44 g.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:3]=1[C:4](OC1C=CC=CC=1)=O.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:26]=1.CO>C1(C)C(C)=CC=CC=1>[CH3:30][O:29][C:27]([C:25]1[N:26]=[C:22]([NH:21][CH2:4][C:3]2[CH:13]=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:2]=2[OH:1])[S:23][CH:24]=1)=[O:28]
Reactant: COc1cc(O)c(C(=O)Oc2ccccc2)cc1OC
Reactant: COC(=O)c1csc(N)n1
Solvent: Cc1ccccc1C
Solvent: CO
Product: COC(=O)c1csc(NCc2cc(OC)c(OC)cc2O)n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
In 250 mg of xylene were suspended 250 mg of phenyl 2-hydroxy-4,5-dimethoxybenzoate (3a) and 144 mg of methyl 2-amino-1,3-thiazole-4-carboxylate (4a) in a stream of argon, which was then heated to reflux (at 140° C.) for 7 hours. The reaction was not completed. After cooling, methanol was added, followed by stirring for one hour. The precipitated crystal was collected by filtration and dried under reduced pressure at 60° C. to provide 170 mg of the same compound (5a) as that of Example 4 at a yield of 55%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[BH4-].[Na+].C(OC(=O)C)(=O)C.Cl>CO.N1C=CC=CC=1.C(OCC)(=O)C.[Pd].CC(C)=O>[F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH3:7])[CH:9]=1
Reactant: COc1cc(C)c(F)cc1C=O
Agent: [Pd]
Agent: Cl
Agent: [BH4-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(C)c(F)cc1C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
17.5 g of 5-fluoro-2-methoxy-4-methylbenzaldehyde was dissolved in 100 ml of methanol, 4.7 g of sodium borohydride was added to the suspension at 0° C. and the resulting mixture was stirred for 30 minutes. Acetone was added to the reaction mixture to decompose excess reagent. The resulting reaction mixture was evaporated and extracted with 150 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the resulting mixture was evaporated to give white crystals. These crystals were dissolved in 50 ml of pyridine, followed by the addition of 19.6 ml of acetic anhydride. The resulting mixture was stirred at room temperature for 4 hours and poured into chilled dilute hydrochloric acid. The resulting mixture was stirred for 30 minutes, followed by the addition of ethyl acetate. The organic layer was separated, washed with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the resulting mixture was evaporated to give a solid. This solid was dissolved in 100 ml of ethyl acetate, followed by the addition of 3 g of 10% palladium/carbon (containing 50% of water). The resulting mixture was subjected to catalytic hydrogenation at ordinary temperature under normal pressure for 3 hours, and the resulting reaction mixture was filtered through Celite. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography to give 9.7 g of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH:12]1([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[CH:17]=[CH:16][C:15]([CH:12]4[CH2:14][CH2:13]4)=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: c1cc(N2CCNCC2)ncc1C1CC1
Product: O=C(c1ccc(Br)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Yield: 85.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-fluorobenzoic acid (1.2 g) and 1-(5-cyclopropylpyridin-2-yl)piperazine (1.02 g) described in Preparation Example 187, the title compound (1.73 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][CH:34](O)[CH3:35].C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[CH3:35][CH:34]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)[CH2:33][C:32]([CH3:38])([CH3:37])[CH3:31]
Reactant: Oc1cccc2cccnc12
Reactant: CC(O)CC(C)(C)C
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CC(C)(C)C)Oc1cccc2cccnc12
Temperature: 25 °C

Procedure:
A 250 mL round bottom flask equipped with a pressure equalizing dropping funnel, stirring bar and N2 outlet was charged with 4.00 g (27.6 mmol) of 8-hydroxyquinoline, 21.7 g (3 equiv) of PPh3 and 80 mL of anhydr. THF. After stirring for 5 min, 4.91 mL (1.25 equiv) of 4,4-dimethyl-2-pentanol was added. The reaction mixture was then cooled in an ice bath and a solution of 9.52 g (1.5 equiv) of DBAD in 50 mL of anhydr. THF was added dropwise over 30 minutes. The reaction was allowed to slowly warm to room temperature, and stirring was maintained for an additional 6 h. Then, an additional 2.46 mL (0.62 equiv) of the alcohol was added, the reaction mixture was cooled in an ice bath and a solution of 4.76 g (0.75 equiv) of DBAD in 25 mL of anhydr. THF was added dropwise over 15 minutes. The reaction was allowed to slowly warm to room temperature, and stirring was maintained for an additional 12 h. An additional 10.9 g (1.5 equiv) of PPh3 was added, followed by 2.46 mL (0.62 equiv) of the alcohol. The reaction mixture was cooled in an ice bath and a solution of 4.76 g (0.75 equiv) of DBAD in 25 mL of anhydr. THF was added dropwise over 15 minutes. The reaction was allowed to slowly warm to room temperature, and stirring was maintained for an additional 6 h. The reaction mixture was then evaporated in vacuo and the resulting residue dissolved in 150 mL of EtOAc. The solution was washed with 2 N HCl (3×400 mL). The aqueous layers were combined and basified with 10 N NaOH to pH 14. The resulting solution was extracted with EtOAc (3×150 mL), the organic layers were combined, dried over anhydr. Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel column chromatography (10% EtOAc/hexanes+2% TEA) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.95 (dd, 1H), 8.10 (dd, 1H), 7.40 (m, 3H), 7.09 (br d, 1H), 4.79 (m, 1H), 2.20 (dd, 1H), 1.57 (m, 1H), 1.46 (d, 3H), 0.98 (s, 9H); MS (DCI/NH3) m/z 244 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([S:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:19](Br)[C:20]#[CH:21]>>[CH2:21]([O:15][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([S:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])=[CH:18][CH:17]=1)[C:20]#[CH:19]
Reactant: C#CCBr
Reactant: CC(C)CCCC(C)Sc1ccc(C(=O)O)cc1
Product: C#CCOC(=O)c1ccc(SC(C)CCCC(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,5-dimethylhexyl)thio]benzoic acid and propargyl bromide, there is obtained p-[(1,5-dimethylhexyl)thio]benzoic acid propargyl ester M.P. 130°-131°C/0.03 mmHg.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=2[N:7]=1.[NH2:34][C:35]1[CH:44]=[CH:43][C:38]([C:39]([NH:41][CH3:42])=[O:40])=[CH:37][C:36]=1[O:45][CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:46][O:45][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:35]=1[NH:34][C:2]1[N:3]=[C:4]([O:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH3:26])[C:6]=2[N:7]=1)[C:39]([NH:41][CH3:42])=[O:40]
Reactant: COc1cc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCOCC4)c23)ccn1
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Nc2nc(OC3CCOCC3)c3c(-c4ccnc(OC)c4)cn(COCC[Si](C)(C)C)c3n2)c(OC)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a degassed mixture of 2-chloro-5-(2-methoxypyridin-4-yl)-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 4-amino-3-methoxy-N-methylbenzamide (1.1 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.175 M) was added palladium acetate (0.3 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.6 equiv). The reaction was stirred at 100° C. for 2 h. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered and concentrated to afford the crude product (95% yield, crude) as a brown solid which was used in the next step without further purification. MS (ESI) m/z 635.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][NH:12][CH2:13]2.C(N(CC)CC)C.[C:28](Cl)(=[O:32])[CH2:29][CH2:30][CH3:31]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][N:12]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH2:13]2
Reactant: CCCC(=O)Cl
Reactant: O=[N+]([O-])c1cc2c(c(-c3ccccc3Cl)c1)CCNC2
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCCC(=O)N1CCc2c(cc([N+](=O)[O-])cc2-c2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47 %

Procedure:
5-(2-chlorophenyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.065 g, 0.2 mmoles) was dissolved in anhydrous dimethylacetamide (1 ml) followed by the addition of triethylamine (0.068 mls) and butyryl chloride (0.0253 mls, 0.24 mmoles) followed finally by N,N-dimethylamino pyridine (catalytic amount). The reaction was left stirring at room temperature for 2.5 hours and the solution purified by automated C18 HPLC purification (0.0336 g, 47% yield, 100% pure, CO-AAW00017).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]([CH3:15])=O.S(Cl)(Cl)=O>CN(C1C=CN=CC=1)C.COCCOC>[OH:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:13]([CH3:15])([CH3:12])[O:1][C:2]=2[CH:10]=1
Reactant: CC(C)=O
Reactant: O=C(O)c1ccc(O)cc1O
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Product: CC1(C)OC(=O)c2ccc(O)cc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a cold mixture of 2,4-dihydroxybenzoic acid (25.9 g, 168.1 mmol), acetone (12.7 g, 218.5 mmol) and DMAP (1.03 g, 8.4 mmol) in 1,2-dimethoxyethane (DME) (96 mL) in an ice bath was added thionyl chloride (26.0 g, 218.5 mml) slowly. Resulting mixture was stirred at 0° C. for 1 h and then at rt for 23 h. Reaction mixture was quenched at 0° C. with saturated NaHCO3 solution (slowly with caution). After 200 mL of saturated NaHCO3 solution was added, NaHCO3 solid was added in small portion to the mixture until pH reaches 7-8. It was diluted with water (200 mL) and extracted with EtOAc (2×200 mL). Organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated. Crude residue was triturated with CH2Cl2 (100 mL). Solid was collected and dried to provide the title compound (10.4 g). 1H NMR (200 MHz, DMSO-d6): δ (ppm)=7.66 (d, J=7.8 Hz, 1H), 6.59 (d, J=7.8 Hz, 1H), 6.36 (s, 1H), 1.65 (s, 6H).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@@H:44]([CH2:54][S:55][C:56]6[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=6)[CH2:45][CH2:46][N:47]6[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]6)=[C:39]([S:62]([C:65]([F:68])([F:67])[F:66])(=[O:64])=[O:63])[CH:38]=5)(=[O:36])=[O:35])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[C:5]([C:69]([OH:71])=[O:70])=[C:4]1[CH3:72].O[CH2:74][CH2:75][P:76](=[O:81])([O:79]C)[O:77]C>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:3]([CH2:2][CH3:1])[C:4]([CH3:72])=[C:5]([C:69]([O:71][CH2:74][CH2:75][P:76](=[O:77])([OH:81])[OH:79])=[O:70])[C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@H:44]([CH2:45][CH2:46][N:47]6[CH2:48][CH2:49][CH:50]([OH:53])[CH2:51][CH2:52]6)[CH2:54][S:55][C:56]6[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=6)=[C:39]([S:62]([C:65]([F:66])([F:67])[F:68])(=[O:63])=[O:64])[CH:38]=5)(=[O:36])=[O:35])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: CCn1c(C)c(C(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Reactant: COP(=O)(CCO)OC
Product: CCn1c(C)c(C(=O)OCCP(=O)(O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1

Procedure:
9 was prepared from BM-957 and dimethyl (2-hydroxyethyl)phosphonate according general procedure V. MS (ESI): m/z 1173.42 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.[Br-].[Li+].N1CCNCC1.C(=O)([O-])O.[Na+].Cl>CN(C)C=O>[Br:10][C:6]1[CH:5]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:14]2=3)=[O:12])[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(C)cc32)cc1Br
Agent: C1CNCCN1
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)N(C(=O)c1cc(Br)c(O)c(Br)c1)CCO2
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
In a 5 ml flask, (3,5-dibromo-4-methoxy-phenyl)-(7-methyl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone (100 mg, 0.23 mmol), lithium bromide (39 mg, 0.45 mmol), piperazine (30 mg, 0.35 mmol) and N,N-dimethyl formamide (1 ml) were added and then stirred at 100□ for 30 minutes. Lithium bromide (39 mg, 0.45 mmol) was further added thereto and then stirred at 1000 for 1 hour. Lithium bromide (39 mg, 0.45 mmol) was further added thereto and then stirred for 1 hour. After neutralizing with saturated solution of sodium hydrogen carbonate to pH 8 to 9, the mixture was adjusted to pH 6 again by using 1N hydrochloric acid. The formed solid was filtered. The resulting solid was purified by column chromatography on silica eluting with a solvent of methanol:dichloromethane=1:30. The fractions containing the product were collected and evaporated to obtain the target compound 27-2 as white solid (74 mg, 76%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:13](C)=[N:14][N:15]=[C:8]1[CH:7]=[C:6]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23].I([O-])(=O)(=O)=[O:27].[Na+]>[Ru](=O)=O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:6](=[O:27])[C:5]1[CH:4]=[C:3]([C:2]([F:25])([F:24])[F:1])[CH:12]=[CH:11][C:10]=1[N:9]1[CH:13]=[N:14][N:15]=[C:8]1[CH3:7]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnc2cc(-c3ccccc3Cl)c3cc(C(F)(F)F)ccc3n12
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 7-(trifluoromethyl)-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 2'-chloro-5-(trifluoromethyl)-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)([CH3:14])[CH3:13].C(OC(N1CCC2C=CC(N)=CC=2CC1)=O)(C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CC(C)Oc1ccccc1B(O)O
Agent: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)Oc1ccccc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-isopropoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-isopropoxyphenylboronic acid in a manner analogous to Example 2c (0.24 g, 40%). MS=288 (MH)+. 302b) 7-[8-(2-Isopropoxy-phenyl]-[1,2,4]triazolo[1,5a]pyridine-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-isopropxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine and 7-amino-1,2,4,5-tetrahydro-3-benzazepin-3-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.35 g, 82%). MP=112-114° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.73 (d, 1H), 7.60 (m, 2H), 7.48 (s, 1H), 7.38 (m, 2H), 7.17 (m, 1H), 7.05 (m, 3H), 4.57 (m, 1H), 3.44 (m, 4H), 2.80 (m, 4H), 1.41 (s, 9H), 1.15 (m, 6H). MS=514 (MH)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:10][N:11]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]1=[O:17]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:13]2[CH2:14][C:15](=[O:16])[N:11]([CH3:10])[C:12]2=[O:17])=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN1C(=O)C=CC1=O
Solvent: CC(=O)O
Product: CN1C(=O)CC(c2c[nH]c3ccccc23)C1=O
Temperature: 105 °C
Reaction time: 16 h

Procedure:
A mixture of indole (3.14 g) and N-methylmaleimide (6.2 g, 3 equiv.) in acetic acid is heated at 105° C. for 16 hr, cooled to room temperature, held for 16 hr and filtered. The filtercake is washed with acetic acid and dried to afford the title product, 5.5 g, identified by HPLC and mass spectral analyses.