Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([N:17]2[C:21]([C:22]([F:25])([F:24])[CH3:23])=[N:20][N:19]=[N:18]2)[CH:5]=1.CO.[OH-].[Na+]>C(Cl)Cl>[F:24][C:22]([C:21]1[N:17]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=3)[CH:7]=2)[C:3]([OH:26])=[O:2])[N:18]=[N:19][N:20]=1)([F:25])[CH3:23]
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2nnnc2C(C)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnnc3C(C)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 235.1 %

Procedure:
3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (0.605 g, 0.68 mmol) was added to a mixture of methanol (10 mL), methylene chloride (2 mL) and 3N aqueous NaOH (0.5 mL). The reaction mixture was stirred at room temperature for 18 hours, then solvent was removed under reduced pressure. The liquid residue was diluted with water and acidified to pH 5 by addition of 1N aqueous HCl. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give 0.552 g of 3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoic acid.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:7][C:8]([CH3:11])=[CH:9][CH:10]=1)(=[O:5])[CH3:4].CC([O-])=O.[Na+]>O>[Br:1][C:9]1[CH:10]=[C:6]([C:3](=[O:5])[CH3:4])[S:7][C:8]=1[CH3:11]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc(Br)c(C)s1

Procedure:
Bromine (9.7 ml) is added to a solution of 2-acetyl-5-methylthiophene (26.6 g) and NaOAc (17.2 g) in water (100 ml) at room temperature. After 12 hours at room temperature the reaction is quenched with a 1M aqueous solution of sodium thiosulfate (100 ml) and extracted three times with ethyl acetate (250 ml). The organic phases are combined, washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo to yield 1-(4-bromo-5-methyl-thiophen-2-yl)-ethanone (41.8 g) as a brown oil. The crude product is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9](O)=[O:10]>>[CH:9]([NH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: Nc1cccc(O)c1
Reactant: O=CO
Product: O=CNc1cccc(O)c1
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
A mixture of 100 g m-aminophenol and 150 g formic acid was refluxed for 1.5 h and then evaporated to dryness under reduced pressure (90°-95° C., 10-15 mm Hg). Solid material was dried at 100° C., 10 mm Hg, for 1.5 h. 117 g of the title compound were isolated, melting point 112° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:31]([NH:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:32])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (2.2 mmol) in pyridine (4 mL) was treated with phenyl isocyanate (2.4 mmol) and stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo and purification of the residue by flash chromatography (80-100% ethyl acetate/hexanes) provided the title product as a white powder (50%). ESMS [M+H]+: 423.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=[O:12].[OH-].[K+:17]>CO>[K+:17].[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:11](=[O:12])[C:10]([O-:15])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a mixture of 3-Bromobenzaldehyde (22.0 mL, 189.0 mmol) and pyruvic acid (15.8 mL, 227.0 mmol) in methanol (100.0 mL), was slowly added a solution of potassium hydroxide (19.0 g, 340.0 mmol) in methanol (100.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 hours and then filtered. The resulting solid was washed with diethyl ether to give 47.0 g of the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([Si:31]([CH3:38])([CH3:37])[O:32][CH:33]1[CH2:36][NH:35][CH2:34]1)([CH3:30])([CH3:29])[CH3:28].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[N:35]1[CH2:34][CH:33]([O:32][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:37])[CH3:38])[CH2:36]1
Reactant: CC(C)(C)[Si](C)(C)OC1CNC1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CN(c2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)C1
Temperature: 95 °C
Yield: 72 %

Procedure:
Use 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (prepared essentially as described in Preparation 1)(979 mg, 2.3 mmol), 3-(tert-butyldimethyl-silanyloxy)-azetidine (880 mg, 4.7 mmol), palladium (II) acetate (51.6 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (211 mg, 0.23 mmol), BINAP (racemic, 215 mg, 0.345 mmol), cesium carbonate (1.1 g, 3.45 mmol), anhydrous toluene (50 mL) and degas and fill with nitrogen (3 times). Seal the system with septum and tighten it with copper wire when necessary. Heat the mixture at 95° C. for 8 h. Dilute with EtOAc, wash with saturated aqueous sodium bicarbonate solution, brine, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 EtOAc:hexanes) to give the title compound (763 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[CH3:17][N:18]([CH3:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([N:18]([CH3:17])[CH3:28])[CH:20]=2)[CH2:15][CH:16]=1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)c1cccc(C(=O)N2CC=C(c3c[nH]c4ccc(Cl)cc34)CC2)c1
Yield: 95 %

Procedure:
A mixture of 5-chloro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.53 g, 2.3 mmol) (Eur. J. Med. Chem., 1987, 22, 33-43) and 3-(dimethylamino)benzoyl chloride (0.5 g, 2.3 mmol) (Chem. Pharm. Bull., 1980, 28, 2045-2051) in tetrahydrofuran was stirred and treated with triethylamine (0.64 mL, 2 eq). The mixture was stirred for 2 h, treated with aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate. The organic phase was washed with brine and dried (Na2SO4) to give the title compound (0.83 g).
Reaction SMILES: C1C=CC=CC=1.[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=[CH2:9].[C:14]([O-:17])(=[O:16])[CH3:15].[Na+].C(CC(=O)C)(=O)C.O=O.C(OCC)(=O)C=CC1C=CC=CC=1.C1(C(C2C=CC=CC=2)=CC(OCC)=O)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[C:14]([O:17][CH:9]=[CH:8][C:7]([O:11][CH2:12][CH3:13])=[O:10])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CCOC(=O)C=C(c1ccccc1)c1ccccc1
Agent: CCOC(=O)C=Cc1ccccc1
Solvent: CC(=O)O
Solvent: CC(=O)CC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)C=COC(C)=O

Procedure:
In a flask, 15 mmol of benzene, 1.5 mmol of ethyl acrylate, 0.1 mmol of palladium(II) acetate, 0.02 mmol of H7PMo8V4O40, 0.08 mmol of sodium acetate, 0.1 mmol of acetylacetone, and 5 ml of acetic acid were placed and were stirred at a constant temperature of 90° C. in an atmosphere of oxygen gas at 1 atm (0.1 MPa) for 6 hours. The resulting reaction mixture was analyzed by gas chromatography to find that ethyl cinnamate, ethyl 3,3-diphenylacrylate, and ethyl 3-acetoxyacrylate were produced in yields of 63%, 5%, and 12%, respectively.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([Cl:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:28][C:25]([F:26])([F:27])[C:22]1[N:20]2[N:21]=[C:16]([N:12]3[CH2:11][CH2:10][N:9]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])[CH2:14][CH2:13]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Reactant: CC(c1ccccc1)N1CCNCC1
Product: CC(c1ccccc1)N1CCN(c2ccc3nnc(C(F)(F)Cl)n3n2)CC1
Yield: 64 %

Procedure:
A mixture of 1-(1-phenylethyl)piperazine and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 339 to give 3-[chloro(difluoro)methyl]-6-[4-(1-phenylethyl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 64% yield.
Reaction SMILES: [CH3:1][C:2]1(C)OC(=O)[CH:5]([C:9](=[O:20])[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[C:4](=[O:21])[O:3]1>C(O)C>[CH2:2]([O:3][C:4](=[O:21])[CH2:5][C:9](=[O:20])[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[F:19])[CH3:1]
Reactant: CC1(C)OC(=O)C(C(=O)Cc2cc(F)c(F)cc2F)C(=O)O1
Solvent: CCO
Product: CCOC(=O)CC(=O)Cc1cc(F)c(F)cc1F
Temperature: 70 °C
Yield: 93 %

Procedure:
2,2-Dimethyl-5-[2-(2,4,5-trifluoro-phenyl)-acetyl]-[1,3]dioxane-4,6-dione 1b (15.72 g, 49.6 mmol) was dissolved in 280 mL of ethanol under stirring, then the reaction mixture was heated to 70° C. in an oil bath overnight. After cooling, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 3-oxo-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1c (12 g, yield 88%) as a yellow oil.
Reaction SMILES: [N:1]1[CH:5]=[CH:4][N:3]2[CH2:6][CH2:7][CH:8]([OH:9])[C:2]=12>C(Cl)Cl.O=[Mn]=O>[N:1]1[CH:5]=[CH:4][N:3]2[CH2:6][CH2:7][C:8](=[O:9])[C:2]=12
Reactant: OC1CCn2ccnc21
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C1CCn2ccnc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.8 %

Procedure:
To a solution of 5H,6H,7H-pyrrolo[1,2-a]imidazol-7-ol (7.1 g, 57.2 mmol) in DCM (70 mL) was added MnO2 (34.8 g, 400.3 mmol) portion wise. The reaction mixture was stirred vigorously at RT for 3 days under N2. The reaction mixture was filtered through Celite and washed with DCM (200 mL) and EtOAc (200 mL). The filtrate was concentrated in vacuo to give the title compound as a yellow solid (4.04 g, 58% yield); 1H NMR (500 MHz, CDCl3) delta 3.08-3.23 (2H, m), 4.39 (2H, t, J=5.83 Hz), 7.26 (1H, s), 7.56 (1H, s); LC-MS: m/z=+122.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]2)[CH:10]=[C:9]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[N:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=1>CCCCC.O1CCOCC1>[C:3]([C:7]1[N:8]=[C:9]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[CH:10]=[C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][O:22][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=3)[CH2:17][CH2:18]2)[N:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CSc1nccc(Cl)n1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCO)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCC
Product: CSc1nccc(OCCCN2CCN(c3cc(C4CCC4)nc(C(C)(C)C)n3)CC2)n1
Yield: 85.2 %

Procedure:
0.36 g of sodium hydride (9 mmol, 60% in paraffin) were washed oil-free with pentane before 1.5 g of 3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-propan-1-ol (4.5 mmol) dissolved in 20 ml of dioxane were added. The reaction was heated to reflux for 1 h. After cooling, 0.75 g of 4-chloro-2-methylsulfanyl-pyrimidine (4.67 mmol) dissolved in 10 ml of dioxane were added. The reaction mixture was stirred under reflux for 2 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted with 5% aqueous citric acid, the pH of the aqueous phase was adjusted to basic pH with 2 N sodium hydroxide solution. The aqueous layer was re-extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated to yield 1.75 g of the title compound as a yellowish oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[N+:13]([O-])([O-:15])=[O:14].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:13]([C:12]1[CH:11]=[CH:10][C:4]([CH:5]=[CH:6][C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[OH:1])([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)C=Cc1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)C=Cc1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 26.1 %

Procedure:
3-Hydroxycinnamic acid (3.00 g, 18.3 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.70 g, 26.1 mmol). The addition of sulfuric acid (25 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.0 g, 26%). 1H NMR (CD3COCD3): d 8.07 (d, 1H), 7.69 (d, 1H), 7.51 (s, 1H), 7.46 (d, 2H), 6.75 (d,1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].COS(=O)(=O)OC.[C-:19]#[N:20].[K+].C(Cl)(Cl)Cl>C(O)C.O.O.CCCCCC>[C:19]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[CH:7][N:8]=1)#[N:20]
Reactant: CC(C)(C)c1cc[n+]([O-])cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccnc(C#N)c1
Reaction time: 3 h
Yield: 23.6 %

Procedure:
A mixture of 8.00 g (53 mmol) of 4-t-butylpyridine N-oxide and 6.7 g (53 mmol) of dimethylsulfuric acid was stirred at 70° to 80° C. for 3 hours. After cooling, the mixture was dissolved in 60 ml of an ethanol-water mixture. While the mixture was stirred at 10° C. or lower, a solution of 6.9 g (0.11 mol) of potassium cyanide in 20 ml of water was dropwise added, followed further by stirring at the same temperature for one hour and at room temperature for 1.5 hours. After an addition of 200 ml of water, the mixture was stirred with chloroform, dried over anhydrous sodium sulfate, and then concentrated under a reduced pressure. Separation by silica gel column chromatography (ethyl acetate:hexane=1:4 for the first time, 1:9 for the second time) gave 2.00 g of an oily product (yield 23.6%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][C:4]1[NH:15][C:7]2=[N:8][CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:6]2[CH:5]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CO>[CH3:16][N:2]([CH2:3][C:4]1[NH:15][C:7]2=[N:8][CH:9]=[C:10]([NH2:12])[CH:11]=[C:6]2[CH:5]=1)[CH3:1]
Reactant: CN(C)Cc1cc2cc([N+](=O)[O-])cnc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)Cc1cc2cc(N)cnc2[nH]1
Temperature: 75 °C
Yield: 54.6 %

Procedure:
SnCl2 dihydrate (0.11 g, 0.463 mmol) was added to a solution of N,N-dimethyl-1-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)methanamine (0.017 g, 0.077 mmol) in ethyl acetate (0.8 mL) and methanol (0.2 mL). The mixture was heated at 75° C. for 2 hours, after which saturated aqueous sodium bicarbonate was added. The salts were filtered off, and then the layers were separated. The organic layers were dried over sodium sulfate, filtered, and evaporated to afford 2-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (0.008 g, 50%).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[O:18]1[CH2:20][C@H:19]1[C:21]([O:23][CH3:24])=[O:22].[Si:25]([O:32][CH2:33][C@H:34]([OH:36])[CH3:35])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[Si:25]([O:32][CH2:33][C@H:34]([O:36][CH2:20][C@H:19]([OH:18])[C:21]([O:23][CH3:24])=[O:22])[CH3:35])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)[C@@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Product: COC(=O)[C@@H](O)CO[C@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
Magnesium trifluoromethanesulfonate (1.165 g, 3.61 mmol) was added in one portion to (S)-methyl oxirane-2-carboxylate (1.475 g, 14.45 mmol) and (R)-1-(tert-butyldimethylsilyloxy)propan-2-ol (CAS no. 136918-07-5) (2.75 g, 14.45 mmol) cooled to 10° C. The resulting suspension was stirred at 10° C. for 10 minutes and then warmed to 45° C. and stirred for 2 days. The crude product was purified by flash silica chromatography, eluting with 0 to 30% EtOAc in isohexane to afford the product (1.680 g, 39.8%). 1H NMR (400 MHz, DMSO) δ0.00 (s, 6H), 0.83 (s, 9H), 0.98 (d, 3H), 3.35-3.45 (m, 2H), 3.47-3.65 (m, 3H), 3.66 (s, 3H), 4.09-4.15 (m, 1H), 5.37 (d, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14](P(OCC)(OCC)=O)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:27]([C:29]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:32]=[CH:31][C:30]=1[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=O>C1COCC1>[CH2:3]([O:10][C:11]([NH:13]/[C:14](=[CH:27]\[C:29]1[C:30]([NH:41][C:42]([O:43][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:48])=[CH:31][N:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=1)/[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOP(=O)(OCC)C(NC(=O)OCc1ccccc1)C(=O)OC
Reactant: CC(C)(C)OC(=O)Nc1cnc(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 41.7 %

Procedure:
To a slurry of 60% of sodium hydride (228 mg, 5.7 mmol) in THF (17 mL) at 0° C. was added 1A (1.88 g, 5.24 mmol) in several portions over 10 min. The reaction mixture was then brought to RT for 20 min, then cooled again at 0° C. A suspension of 3C (1.42 g, 4.76 mmol) in THF (17 mL) was added over 10 min at 0C, then the reaction was warmed up to RT. After stirring for 20 min, the reaction was quenched with water (40 mL). The aqueous layer was extracted with EtOAc (50 mL×2). The combined EtOAc extracts were dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel (110 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as an off-white solid (1 g, 42%). LC/MS (method A): retention time=3.33 min, (M+H)+=504.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[CH2:14]([N:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][NH2:20])[CH3:15]>O1CCOCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:21][CH3:22])[CH2:14][CH3:15])=[O:9]
Reactant: CCN(CC)CCCN
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Solvent: C1COCCO1
Product: CCN(CC)CCCNC(=O)c1cc(Cl)ccc1N

Procedure:
A solution containing 4.00 grammes (20.3 mmoles) of 5-chloroisatoic anhydride in 25 ml of dioxane at room temperature is joined by 4.80 ml (30.4 mmoles) of 3-diethylamino- 1-propylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=O)[NH:9]2)=[CH:4][C:3]=1[C:13]#[N:14].O=P(Cl)(Cl)[Cl:17]>O>[Cl:17][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[C:3]([C:13]#[N:14])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2[nH]c(=O)ccc2cc1C#N
Solvent: O
Product: Cc1cc2nc(Cl)ccc2cc1C#N
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 7-Methyl-2-oxo-1,2-dihydroquinoline-6-carbonitrile (10 g, 54 mmol) and POCl3 (30 mL) was stirred at 110° C. for 2 h and then at 20° C. overnight. The mixture was carefully poured into a mixture of water and ice (400 mL) while being stirred vigorously. The product was collected by filtration and dried by co-evaporation with MeCN/Toluene to furnish the title product. LC/MS (IE, m/z): [M+1]+=203.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl>C(Cl)(Cl)Cl.CO>[CH2:1]([S:17][CH2:18][CH:19]([CH2:22][OH:23])[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCSCC(CO)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.4 %

Procedure:
To a solution of 6.0 grams (0.01 mole) of (±)-1-S-hexadecyl-2-O-methyl-3-O-tritylthioglycerol in 100 milliliters of chloroform:methanol (3:1) was added 0.2 gram of p-toleunesulfonic acid and the reaction stirred at room temperature for 24 hours. The reaction mixture was neutralized with 1.0 gram of sodium bicarbonate and then extracted three times with 200 milliliter portions of water. The nonaqueous layer was separated and the solvent removed in vacuo to give the crude product as an oil. Silica gel chromatography (CHCl3 eluent) provided 3.1 grams (89%) of pure product as a semi-waxy solid. 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 28H, (CH2)14 ], 2.58 (m, 2H, --S--CH2), 2.62 (m, 2H, CH--CH2 --S--), 3.40(m, 1H, CH), 3.44(s, 3H, CH3 --O--), 3.75(m, 2H, CH2 --OH).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].OS(C(F)(F)F)(=O)=O.C1C(=O)N([Br:26])C(=O)C1>CC#N>[Br:26][C:7]1[C:8]([OH:10])=[CH:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(O)cc1Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: N#Cc1cc(Br)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.2 %

Procedure:
To a solution of 2-chloro-4-hydroxybenzonitrile (10.0 g, 65.11 mmol, Apollo Scientific) in MeCN (200 mL) was added triflic acid (6.32 mL, 71.62 mmol, Spectrochem) and NBS (13.90 g, 78.13 mmol, Spectrochem) at −30° C. The reaction mixture was allowed to warm to RT and stirred for 15 h. The reaction mixture was quenched with saturated aqueous NaHSO3 solution (500 mL) and extracted with ethyl acetate (2×1000 mL). The combined organic layers were washed with water (500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude compound which was purified by column chromatography (silica gel 100-200 mesh and 0-6% EtOAc in hexane) to obtain 5-bromo-2-chloro-4-hydroxybenzonitrile (7.0 g, 46.2%) as white solid. m/z (ESI) 230.0 (M−H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([CH3:18])[CH:10]=1>>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:14])=[C:11]([CH3:18])[CH:10]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: NC1CCOCC1
Product: Cc1cc(Br)ccc1C(=O)NC1CCOCC1
Yield: 100 %

Procedure:
The title compound was prepared in substantially the same way as intermediate (iv) by coupling of tetrahydropyran-4-yl amine with 4-bromo-2-methylbenzoic acid to give 0.65 g (100% yield) as a thick oil which solidified on standing.