Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:22]=[C:21]([C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][C:25]=2[OH:36])[CH:20]=[CH:19][C:7]=1[O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)([OH:3])=[O:2].Cl.[CH2:39](O)[CH3:40]>C(Cl)Cl>[CH:31]1([O:30][C:27]2[CH:28]=[CH:29][C:24]([C:23]([C:21]3[CH:20]=[CH:19][C:7]([O:8][CH2:9][C:10]4[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=4)=[C:6]([CH2:5][CH2:4][C:1]([O:3][CH2:39][CH3:40])=[O:2])[CH:22]=3)=[O:37])=[C:25]([OH:36])[CH:26]=2)[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=C(O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc(C(=O)O)cc1
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
3.32 g of 4-({2-(2-carboxyethyl)-4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}-methyl)benzoic acid was suspended in 3.3 mL of methylene chloride, to which 3.3 mL of 4M hydrogen chloride-ethanol was added, and this mixture was stirred for 7 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and then the resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=10:1] to yield 1.76 g of 4-{[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-ethoxy-3-oxopropyl)phenoxy]methyl} benzoic acid as white solid.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[F:14][C:15]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:26]=[C:27]2[CH:33]=[C:32]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41](O)([CH3:43])[CH3:42])[CH2:36][CH2:35]3)[O:31][C:28]2=[CH:29][N:30]=1>ClCCl.CO>[F:14][C:15]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:26]=[C:27]2[CH:33]=[C:32]([CH:34]3[CH2:35][CH2:36][N:37]([CH2:40][C:41]([F:11])([CH3:43])[CH3:42])[CH2:38][CH2:39]3)[O:31][C:28]2=[CH:29][N:30]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(O)CN1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(F)CN1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bis(2-methoxyethyl)aminosulfur trifluoride (50% in toluene; 0.27 mL) is added to a solution of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-[1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl]-furo[2,3-c]pyridine (0.19 g) in dichloromethane (3 mL) chilled in an ice bath. The solution is stirred at room temperature overnight. The solution is diluted with dichloromethane and little methanol and washed with aqueous NaHCO3 solution. The solution is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→1:2) to give the title compound. LC (method 4): tR=1.09 min; Mass spectrum (ESI+): m/z=449 [M+H]+.
Reaction SMILES: [P:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[C:37]2[C:36](O)=[C:35](O)[CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:18])([CH3:17])[CH3:16].[C:40](=[O:43])([O-])[O-].[K+].[K+].CI.C[C:49](C)=[O:50]>>[P:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[C:37]2[C:36]([O:50][CH3:49])=[C:35]([O:43][CH3:40])[CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccccc1-n1c2ccccc2c2ccc(O)c(O)c21
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Agent: [K+]
Agent: c1ccc2c(c1)ccc1pcccc12
Solvent: CI
Product: COc1ccc2c3ccccc3n(-c3ccccc3C(C)(C)C)c2c1OC

Procedure:
In a 250 ml two-neck flask, N-(t-butylphenyl)dihydroxy carbazole phosphaphenanthrene (Compound I, 4.12 g), potassium carbonate (21 g), and acetone (100 ml) were mixed and stirred. Methyliodide (17.4 g) was added thereto, followed by refluxing and stirring for 1 hour. The reaction solution was filtered, and the filtrate was concentrated and dissolved in ethylacetate. The resultant was washed with distilled water, and the organic layer was dried over anhydrous magnesium sulfate. The dried organic layer was concentrated by distillation under reduced pressure and purified using a column chromatography, thereby obtaining 2 g of N-(t-butylphenyl)dimethoxy carbazole phosphaphenanthrene (Compound 201).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[N:13]=[CH:14][N:15]4[C:20](=[O:21])[N:19]([CH2:22][C:23]#[CH:24])[N:18]=[N:17][C:16]=34)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH3:27][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[C:12]1[N:13]=[CH:14][N:15]2[C:20](=[O:21])[N:19]([CH2:22][C:23]#[CH:24])[N:18]=[N:17][C:16]=12
Reactant: C#CCn1nnc2c(-c3nc(-c4ccccc4)c[nH]3)ncn2c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCn1nnc2c(-c3nc(-c4ccccc4)cn3C)ncn2c1=O
Reaction time: 0.17 h
Yield: 8.5 %

Procedure:
8-(4-Phenyl-1H-imidazol-2-yl)-3-(prop-2-ynyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (1.07 mmol) was dissolved in dry DMF (35 mL) and cooled in ice under a nitrogen atmosphere. A 60% suspension of sodium hydride in mineral oil (1.18 mmol) was added in one portion and the reaction stirred on ice for 10 minutes. Methyl iodide (2.14 mmol) was then added dropwise to the reaction and the mixture stirred at room temperature for 48 hours. The mixture was poured onto ice water (140 mL) and the precipitate was filtered, washed with water, ethyl acetate, and diethyl ether, and purified by column chromatography (hexane:ethyl acetate 4:3) to give the title compound (0.030 g; 89%). δH (DMSO-d6) 8.97 (1H, s), 7.90 (1H, s), 7.83 (2H, d, J=7.2), 7.40 (2H, t, J=7.6), 7.25 (1H, t, J=7.2), 5.13 (2H, d, J=2.0), 3.99 (3H, s), 3.52 (1H, J=2.0).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[N:7]([O-:9])=O.[Na+].[C:11](O)(=O)C.[OH-].[Na+].S(OC)(OC)(=O)=O>O>[C:1]([C:3](=[N:7][O:9][CH3:11])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: N#CCC(N)=O
Reactant: O=N[O-]
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CON=C(C#N)C(N)=O
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
To a stirred mixture of α-cyanoacetamide (252 g, 3 mole) and sodium nitrite (414 g, 6 mole) in water (600 ml) was added acetic acid (371 ml, 10 mole) at 5°-10° C. over 1.5 hours. The mixture was allowed to stir for another 1.5 hours and adjusted to pH 8.5 with 6N NaOH. To the mixture was added dimethyl sulfate (568 ml, 6 mole) at 15°-20° C. and the mixture was stirred at 45° C. for 1.5 hours. The reaction mixture was adjusted to pH 8.5 with 6N NaOH and allowed to stand at 5° C. overnight to separate the precipitate, which was collected by filtration, washed with cold water and air-dried to give 292 g (77%) of the title compound as brown needles melting at 170°-172° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:11][CH2:12][CH3:13])(=O)C.[OH2:14]>>[OH:14][C:2]1[CH:3]=[CH:4][C:5]([CH2:7][C:1]2[C:6]([CH3:5])=[CH:13][C:12]([OH:11])=[C:3]([CH3:4])[CH:2]=2)=[CH:6][C:1]=1[CH3:7]
Reactant: Cc1ccccc1
Reactant: CCOC(C)=O
Reactant: O
Product: Cc1cc(Cc2cc(C)c(O)cc2C)ccc1O
Temperature: 20 °C

Procedure:
Into a 1 liter of four-necked flask were charged 4.76 g of para-toluenesulfonic acid, 54.07 g of ortho-cresol and 108.14 g of methanol. Further, keeping the temperature at 30° C., 38.05 g of 4-hydroxymethyl-2,5-dimethylphenol obtained above was added in ten portions over 1 hour. The mixture was stirred at the same temperature for 2 more hours. After completion of the reaction, 200 g of toluene and 200 gof ethyl acetate was added. Thereafter, 200 g of deionized water was added and the resulting mixture was stirred and a phase separation was carried out. Then, metal content was removed by adding 200 g of 1% aqueous oxalic acid solution, followed by stirring the mixture and by carrying out a phase separation. Thereafter, washing with 200 g of deionized water was repeated four times, and the oil phase was concentrated. To the concentrated mass, 200 g of toluene was added and the resulting solution was cooled to 20° C. and filtered. The filter cake was rinsed with 200 g of toluene and dissolved in 200 g of ethyl acetate. After adding 200g of toluene thereto, the resulting mixture was concentrated. To the concentrated mass, 200 g of toluene was added and the resulting mass was cooled to 20° C. and filtered. The filter cake was rinsed with 200 g of toluene and dried a whole day and night under reduced pressure at 45° C. to obtain 20.12 g of 4-(4-hydroxy-3-methylbenzyl)-2,5-dimethylphenol.
Reaction SMILES: C(C(CC=C)C[O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)C=C.C([O-])([O-])=O.[K+].[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>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.C1(C)C=CC=CC=1>[CH2:13]([Si:7]([CH2:12][CH:11]=[CH2:10])([OH:6])[C:8]1[CH:9]=[CH:10][C:11]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:12][CH:13]=1)[CH:8]=[CH2:9]
Reactant: COc1ccc(B(O)O)cc1
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CC[Si](O)(CC=C)c1ccc(-c2ccc(OC)cc2)cc1
Yield: 54 %

Procedure:
A mixture of the 4-(diallylhydroxysilyl)iodobenzene (151 mg, 0.46 mmol) obtained in Example 17, Pd(PPh3)4 (15.9 mg, 0.014 mmol), K2CO3 (94.8 mg, 0.69 mmol), and 4-methoxyphenyl boronic acid (83.4 mg, 0.55 mmol) was added with dist.toluene (5 mL). Subsequently, the resultant mixture was stirred under a nitrogen atmosphere at 80° C. for 38 hours to obtain a reaction mixture. Thereafter, a salt formed in the reaction mixture was removed by filtering with celite. The solvent was distilled from the organic layer with an evaporator to obtain a crude product. After that, the crude product thus obtained was separated and purified by silica gel column chromatography (hexane/EtOAc=3/1), and thereby 4-(diallylhydroxysilyl)-4′-methoxybiphenyl was obtained (76.1 mg, 54% yield).
Reaction SMILES: [C:1]([CH:4]1[CH:8]2[CH2:9][C:10](=[O:13])[CH:11]=[CH:12][C:7]2([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)OC1=O)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:8]([CH2:4][C:1](=[O:3])[CH3:2])[CH:9]=1
Reactant: CC(=O)C1C(=O)OC2(C#Cc3ccccc3)C=CC(=O)CC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)Cc1cc(O)ccc1C#Cc1ccccc1
Yield: 65 %

Procedure:
3-Acetyl-3a,7a-dihydro-7a-(phenylethynyl)benzofuran-2,5-(3H,4H)-dione, the product of Example 1A, (1.5 g, 5 mmole) was dissolved in MeOH (50 mL) and water (10 mL). Anhydrous potassium carbonate 7.1 g, 50 mmole) was added and the mixture was heated at reflux for 45 min. The reaction was quenched into ice cold 3N hydrochloric acid and extracted with EtOAc (3×50 mL). The combined extracts were washed with water (50 mL) and brine (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel; 3:1::hexane:EtOAc) to give 0.84 g (65%) of the title compound as a light brown crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:14]([O:16]C)=[O:15].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1oc2ccc(OC)cc2c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2oc(C(=O)O)c(OC)c2c1
Temperature: 0 °C
Yield: 96 %

Procedure:
A mixture of 10.6 g (0.045 mole) of 3,5-dimethoxy-2 -benzofurancarboxylic acid, methyl ester in 80 ml of methanol is treated with 75 ml of 1.0 N aqueous sodium hydroxide solution. The new mixture is stirred at reflux for 45 minutes, cooled, and added to 750 g of ice/water. After extraction with dichloromethane, 3×300 ml) the aqueous layer is cooled in ice and acidified with glacial acetic acid to precipitate the crude product. The precipitate is filtered and washed with water to yield 9.6 g (88% crude yield) of 3,5-dimethoxy-2-benzofurancarboxylic acid. A sample recrystallized from ethyl acetate is analytically pure, mp 168° C.-dec.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1.Cl>CO>[F:3][C:4]1[CH:13]=[C:12]2[C:7](=[CH:6][CH:5]=1)[CH2:8][CH:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH:11]2[OH:14]
Reactant: COC(=O)CC1CC(=O)c2cc(F)ccc2C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1Cc2ccc(F)cc2C(O)C1

Procedure:
To a mixture of 8 g. of sodium borohydride and 150 ml. of methanol, 23.5 g. of 7-fluoro-3-(methoxycarbonylmethyl)-1-tetralone are added. The mixture is diluted with 250 ml. of 2N hydrochloric acid after standing for four hours at 25° C; the aqueous mixture is then extracted with chloroform. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to yield methyl 6-fluoro-4-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetate. The latter compound is dehydrogenated by the process described in Part B of Example 2 to furnish methyl 6-fluoro-4-hydroxy-2-naphthylacetate.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH3:19])[CH:13]=[CH:12][CH:11]=1>FC(F)(F)S(O)(=O)=O>[F:9][C:10]1[C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH3:19])[C:13]([I:1])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cccc(F)c1C(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1c(I)ccc(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Iodosuccinimide (7.47 g, 33.2 mmol) was added dropwise to a stirred solution of 6-fluoro-2-methylbenzoic acid (5.12 g, 33.2 mmol) in trifluoromethanesulfonic acid (50 mL) at room temperature. The mixture was stirred at room temperature overnight, poured into ice/water and stirred for 3 h until solid produced. The precipitate was collected, washed with water, and air dried to give the title compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.P(=O)(O)(O)O.C(OCC)(=O)C>CS(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)cc1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1cc(OCc2ccc3ccccc3n2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a solution of 2-nitro-5-(2-quinolylmethoxy)benzyl alcohol (1.74 g, 5.6 mmol), prepared in step 1, and dicyclohexylcarbodiimide (3.71 g, 18 mmol) in DMSO (25 ml) was added 1M solution of phosphoric acid in DMSO (2.7 ml), and the resulting mixture was stirred at room temperature for 1 hour. Ethyl acetate (100 ml) was then added and the precipitated dicyclohexylurea was filtered off. The filtrate was washed with water, and brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride-ethyl acetate 15:1) to afford 1.25 g of 2-nitro-5-(2-quinolylmethoxy)benzaldehyde.
Reaction SMILES: [O-:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[C:9]1([C:15]2[CH:20]=[C:19](C3C=CC=CC=3)C=C(C3C=CC=CC=3)[O+]=2)[CH:14]=C[CH:12]=[CH:11][CH:10]=1.[CH2:33]([C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(O)C>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[CH2:33]([C:45]1[CH:46]=[CH:47][C:48]([N+:49]2[C:20]([CH3:19])=[CH:15][C:9]([CH3:14])=[CH:10][C:11]=2[CH3:12])=[CH:50][CH:51]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc(-[n+]2c(C)cc(C)cc2C)cc1

Procedure:
A 2.3-g portion (0.005 mole) of 2,4,6-triphenylpyrylium triflate is placed in a 500-ml round-bottom flask. To this, 200 ml of ethanol is added and then 1.3 g (0.005 mole) of p-dodecylaniline is added. The mixture is refluxed for about 20 hours. The ethanol is removed by evaporation to give a yellow waxy substance. This material is washed with ether which causes some yellow crystals to precipitate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:17](=O)[NH2:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:17]#[N:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
3-Carbamoyl-azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (25.4 g; 93.5 mmol) is dissolved in THF (260 ml) and pyridine (19.2 g; 243 mmol) and cooled to 0° C. under stirring. Trifluoroacetic acid anhydride (26.4 ml; 187 mmol) is added dropwise over 10 minutes, the mixture warmed to room temperature and stirred for 30 minutes, poured on water and extracted with TBME three times. The combined organic phases are dried over Na2SO4, filtered, evaporated and purified via chromatography (SiO2; heptane/TBME 6:4) to yield the title compound as light brown oil (22.4 g; 94%).
Reaction SMILES: [N:1]1([C:6]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.O=[C:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.ClC(Cl)C>>[N:7]1[C:6]2[N:1]3[CH:2]=[CH:3][CH:4]=[C:5]3[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Oc1cccnc1-n1cccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Solvent: O
Product: c1cnc2c(c1)OC1(CCNCC1)c1cccn1-2
Temperature: 130 °C
Yield: 93 %

Procedure:
A mixture of 2-pyrrol-1-ylpyridin-3-ol (1.00 g, 6.24 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (1.24 g, 6.24 mmol), 4-methylbenzenesulfonic acid hydrate (119 mg, 0.625 mmol), molecular sieves (442 mg) and dichloroethane (8.9 mL) was heated at 130° C. for 162 hours. The reaction was filtered and washed with dichloroethane. The solid was dissolved in MeOH and filtered through a plug of Celite. The solvent was evaporated under reduced pressure to yield spiro[piperidine-4,6′-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine] (1.4 g, 38%). ESI-MS m/z calc. 241.1, found 242.5 (M+1)+; Retention time: 1.10 minutes (4 min run).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([CH3:34])[C:21](=[O:33])[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[C:31]#[N:32])[C:15]=23)[CH2:9]1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([CH3:34])[C:21](=[O:33])[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[C:31]#[N:32])[C:15]=23)[CH2:9]1
Reactant: Cn1c(=O)n(Cc2ccc(Cl)cc2C#N)c2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccnc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(Cc2ccc(Cl)cc2C#N)c2c(N3CCC[C@@H](N)C3)ccnc21
Yield: 36.2 %

Procedure:
The operation referred to the step (6) described in Example 1. 300 mg (R)-1-[1-(4-chloro-2-cyano-benzyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]piperidin-3-yl carbamic acid tert-butyl ester (0.605 mmol) and 4.15 mL trifluoroacetic acid were charged to afford 112 mg titled product with a yield of 36.2%.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-4](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)C=CC=CC=1.COCCOC>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([O:15][CH2:16][O:17][CH3:18])=[C:2]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=1)[C:11]([CH3:12])=[CH:10]2
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCOc1c(-c2cccc(C(F)(F)F)c2)c(C)cc2cc(OC)ccc12
Yield: 99 %

Procedure:
2-Bromo-6-methoxy-1-(methoxymethoxy)-3-methylnaphthalene (14) (0.5 g, 1.61 mmol), 3-trifluoromethylbenzeneboronic acid (0.61 g, 3.21 mmol), tetrakis(triphenylphosphino)palladium (0) (0.186 g, 0.161 mmol), 2 M sodium carbonate (15 mL) and ethylene glycol dimethyl ether (15 mL) were added in a sealed tube and reacted as described above to give 0.60 g (99%) of the title compound (208) as a white solid. 1H NMR (400 MHz, d-CDCl3): δ 2.21 (s, 3H), 3.01 (s, 3H), 3.93 (s, 3H), 4.76 (s, 2H), 7.09 (m, 1H), 7.12-7.15 (dd, J1=2.5 Hz, J2=9.1 Hz, 1H), 7.45 (s, 1H), 7.55-7.65 (m, 4H), 7.98 (d, J=9.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:14][O:15][C:16](=[O:29])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:14][O:15][C:16](=[O:29])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:26])(=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C=Cc1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C=Cc1ccccc1S(=O)(=O)Nc1ccccc1
Yield: 60.5 %

Procedure:
To a mixture of aniline (0.33 g, 3.53 mmol) and pyridine (1 ml) a solution of 3-(2-chlorosulfonylphenyl)acrylic acid methyl ester (33) (0.45 g, 1.72 mmol) in dichloromethane (3 ml) was added and the resultant solution was stirred at 50° C. for 1 hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCl. The organic layer was washed successively with water, saturated NaCl and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with ethyl acetate-chloroform (1:7, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.33 g, 60%). 1H NMR (CDCl3, HMDSO), δ: 3.86 (3H, s); 6.27 (1H, d, J=16.0 Hz); 6.69 (1H, br s); 6.87–7.67 (8H, m); 7.94–8.13 (1H, m); 8.49 (1H, d, J=16.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.CN1CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In methylene chloride (80 ml) was dissolved (4-chloro-2-methoxyphenyl)methanol (3.69 g). Under ice cooling, molecular sieve 4A (4.57 g), N-methylmorpholine (2.81 g) and tetra-n-propylammonium perruthenate (420 mg) were added to the resulting solution, followed by stirring at room temperature for 2.5 hours. The reaction mixture was distilled under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane:ethyl acetate=9:1), whereby the title compound (3.07 g) was obtained as pale yellow oil.