Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])C1C=CC=CC=1.C1(SC)C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)S(O)(=O)=O>[Cl:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COc1cc2c(Cl)ccnc2cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
7-(Benzyloxy)-4-chloro-6-methoxyquinoline (100 mg), thioanisole (300 μl), and methanesulfonic acid (25 μl) were dissolved in trifluoromethanesulfonic acid (1 ml). The solution was stirred at room temperature for 30 min. The solvent was removed by distillation under the reduced pressure. The residue was made neutral by the addition of an aqueous sodium hydroxide solution, and hexane was added thereto to prepare a suspension. The crystal was collected by suction filtration to give 53 mg (yield 75%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]([O:14][CH3:15])[CH2:10][N:11]=[C:12]=[O:13])[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:21][CH:20]=1>C1C=CC=CC=1.O1CCCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]([O:14][CH3:15])[CH2:10][NH:11][C:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:21][CH:20]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: COC(CN=C=O)c1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COC(CNC(=O)Oc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(C(F)(F)F)c1

Procedure:
A solution containing 1.5 g of the compound prepared in stage A in 10 ml of benzene is added to a solution containing 1.4 g of 5-[(4-hydroxyphenyl)methyl]-2,4-thiazolidinedione in 5 ml of tetrahydrofuran.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:11][C:8]1[CH:9]=[CH:10][N:6]2[C:7]=1[C:2]([Cl:1])=[N:3][CH:4]=[N:5]2
Reactant: Cc1ccn2ncnc(Cl)c12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncnn2ccc(CBr)c12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
A mixture of 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (2.0 g, 11.93 mmol, WO 03/042172) and AIBN (195 mg, 1.19 mmol) in CCl4 (80 mL) under N2 was heated to 100° C. for 5 min, NBS (2.55 g, 14.3 mmol) was added. The reaction mixture was stirred for 10 min, then cooled to rt, filtered. The CCl4 layer was washed with dilute NaHCO3 aqueous solution, dried (MgSO4), filtered and concentrated to give the desired product (2.70 g, 92%).
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:7][CH2:6][CH:5]([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1([F:13])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC(F)(F)CC1
Temperature: 1 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Ethyl 4,4-difluorocyclohexanecarboxylate (10 g, 52.03 mmol) was dissolved in THF (100 mL) and cooled to 1° C. under nitrogen atmosphere. LAH (57.2 mL, 57.23 mmol) was added dropwise to the solution at a rate to keep the temperature below 10° C. The resulting mixture was allowed to reach 20° C. and stirred at that temperature for approximately 1 h. The reaction mixture was then cooled to 10° C. and quenched carefully by the sequential slow addition of 2.2 mL of water, 2.2 mL of 15 w/v % aqueous NaOH and 6.6 mL of water and stirred for 30 minutes at 20° C. The solids were removed by filtration and washed with THF. The reaction solution was dried over MgSO4 and evaporated in vacuo to give crude (4,4-difluoro-cyclohexyl)methanol (7.22 g, 92%). 1H NMR (400 MHz, cdcl3) δ 1.21-1.38 (m, 2H), 1.44 (s, 1H), 1.51-1.90 (m, 5H), 2.04-2.18 (m, 2H), 3.52 (d, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=2)=[O:7])[CH3:4].Br[CH2:23][C:24]#[N:25]>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:23][C:24]#[N:25])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC#N)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 60% NaH in mineral oil (115 mg, 2.9 mmol) and 1H-indole-2,6-dicarboxylic acid diethyl ester (500 mg, 1.9 mmol) in DMF (3 mL) was stirred at room temperature for 0.5 h. Then bromo-acetonitrile in DMF (1 mL) was added and the reaction was warmed to 77° C. and kept at this temperature overnight. The reaction was cooled and quenched with ice water. A large amount of precipitate formed which was filtered and rinsed with water, followed by cold ether. The wet cake was dried in the vacuum oven (50° C.) to give 585 mg of 1-cyanomethyl-1H-indole-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].O>O1CCCC1.CCCCCC>[CH2:8]([O:7][C:1](=[O:6])[CH:2]=[C:3]([O:4][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH3:5])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: C[Si](C)(C)Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C=C(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.4 %

Procedure:
182.21 g (1.4 mol) of ethyl acetoacetate and 169.98 g (1.4 mol) of triethylamine were dissolved in a mixed solvent of 182 mL of tetrahydrofuran and 1.64 L of hexane under nitrogen atmosphere. To this solution, 167.3 g (1.54 mol) of trimethylsilyl chloride was added dropwise at a temperature of 21 to 45° C., and then the solution was stirred at 25° C. for 3 hours. The reaction mixture was cooled to 10° C., the reaction was ceased by adding 547 mL of water thereto and an organic layer was separated. The organic layer was washed two times with 273 mL of water, dried over 54.7 g of anhydrous magnesium sulfate, and then filtered. The solvent was evaporated to obtain 301.3 g (crude yield 106.4%) of 3-(trimethylsilyloxy) but-2-enoic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][C:17]([OH:19])=[O:18].O.C(O)C>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][C:17]([OH:19])=[O:18])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: NCC(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 77.5 %

Procedure:
A solution of 4-nitrophthalic anhydride (9.66 g, 50 mmol) and glycine (3.75 g, 50 mmol) in N,N-dimethylformamide was stirred for 30 minutes at 140° C. The reaction mixture was poured into water (150 mL). Resulting precipitate was collected by filtration and washed with water, which was collected by filtration and washed with water, which was recrystallized from ethanol to give 9.69 g (yield 77%) of the titled compound, m.p. 195.5°-196.5° C. (ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:8][CH:7]=1)[OH:5].[K+].[Br-].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:10][CH:11]=1)=[O:5]
Reactant: COC(=O)C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To [4-(3,4-dichlorobenzyloxy)phenyl]-hydroxy-acetic acid methyl ester (750 g) in ethyl acetate (10 L) was added 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) (10.15 g), KBr (26.25 g), and solid NaHCO3 (185.25 g) in a 22-liter round-bottom flask fitted with an overhead stirrer, thermocouple, and a dropping funnel. The reaction mixture was cooled to 0-5° C. using water/ice. To the cooled reaction mixture, bleach (3375 mL, CLOROX) was added dropwise at such a rate so as to maintain the internal temperature at 0-5° C. After addition of the bleach, the reaction mixture was allowed to reach room temperature and was stirred for 2 hours. LC-MS analysis showed that little of the starting material remained at this point. The reaction mixture was diluted with ethyl acetate (12 L) and the layers were separated. The aqueous layer was washed with ethyl acetate (4 L), and the two volumes of ethyl acetate were combined. The combined ethyl acetate layers were washed with water (10 L) and brine (10 L), dried over anhydrous sodium sulfate, concentrated, and filtered. The resulting solid was washed with hexanes (5 L) and dried at 40° C. under vacuum for 4 hours to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1

Procedure:
Prepared from 2,5-dibromopyridine and 1-t-butyloxycarbonylpiperidin-4-ol by the method of Example 10 (b).
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[CH:20]N(C)C)[CH:18]=O)=[CH:13][CH:12]=1.C(O)(=O)C>CO.O>[C:4]([C:6]1[C:7](=[O:8])[NH:9][CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:20]=1)#[N:5]
Reactant: N#CCC(N)=O
Reactant: CN(C)C=C(C=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: N#Cc1cc(-c2ccc(Cl)cc2)c[nH]c1=O
Temperature: 25 °C

Procedure:
To solution of sodium methoxide (7.52 g) in methanol (130 ml) was added cyanoacetamide (5.84 g) followed by 2-(4-chlorophenyl)-3-dimethylaminopropenal and the resulting suspension was refluxed overnight. During this time a yellow solid was formed. The mixture was cooled to room temperature and glacial acetic acid (50 ml) was added followed by water (100 ml). The resulting yellow orange solid was filtered off, washed several times with water and dried to yield 8.1 g of 3-cyano-5-(4-chlorophenyl)-2-pyridinone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>[Cu](I)I.CN1C(=O)N(C)CCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:20]2[C:21]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: I[Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: CN1CCCN(C)C1=O
Product: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 180 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
First, 56 g (240 mmol) of p-dibromobenzene, 31 g (180 mmol) of carbazole, 4.6 g (24 mmol) of copper iodide, 66 g (480 mmol) of potassium carbonate, and 2.1 g (8 mmol) of 18-crown-6-ether were put in a 300-mL three-neck flask, and nitrogen was substituted for air in the flask. Then, 8 mL of N,N′-dimethylpropyleneurea (abbreviation: DMPU) was added therein, and the mixture was stirred at 180° C. for 6 hours. After the reaction mixture was cooled to room temperature, a precipitate was removed by suction filtration. The filtrate was washed with dilute hydrochloric acid, a saturated sodium hydrogen-carbonate aqueous solution, and a saturated saline solution in this order and dried with magnesium sulfate. After being dried, the solution was filtered naturally and concentrated, and an obtained oily substance was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) and recrystallized with chloroform and hexane; thus, 21 g of a light brown plate-shaped crystal of 9-(4-bromophenyl)carbazole that was an object was obtained (yield: 35%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]>O1CCCC1>[CH2:10]1[C:11]2[CH2:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CC1=C2CCCC1
Yield: 74.2 %

Procedure:
15 g (90.2 mmol) of fluorene was dissolved in 200 ml of a tetrahydrofuran (THF)/ethylene diamine solution (1:1 ratio). The solution was cooled in a ice bath and with stirring 3.13 g of lithium (451.2 mmol) was added in small portions. After all the lithium had been added the solution was stirred for 2 h with consequent dissolution of the lithium metal. The resulting solution was then poured into a HCl/ice mixture. The solution was then extracted with diethyl ether. The organic washings were combined, washed with water and dried over MgSO4. The solution was filtered and the solvent removed on a rotary evaporator. The crude material was then purified by dissolving in hexane and passing through a silica gel column to give 11.4 g (75 percent yield) of product after solvent removal.
Reaction SMILES: O.[OH-].[Li+].[F:4][CH:5]([F:20])[C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:15]=1)[C:9]([O:11]C)=[O:10]>O.O1CCCC1>[F:4][CH:5]([F:20])[C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][N:17]([CH3:18])[CH3:19])[CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(CN(C)C)cc(C(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cc(C(=O)O)cc(C(F)F)c1
Reaction time: 3.5 h

Procedure:
Lithium hydroxide monohydrate (65.2 mg, 1.55 mmol) in water (0.7 mL) was added to a solution of methyl 3-(difluoromethyl)-5-[(dimethylamino)methyl]benzoate (45 mg, 0.13 mmol, from Step C) in tetrahydrofuran (2 mL). Upon stirring for 3.5 hours, the mixture was treated with 1N HCl to adjust the pH to 7, then THF was removed by rotary evaporation. Acetonitrile was added to make a 1:1 ACN:water mixture, the mixture was filtered, and the filtrate was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product as a white solid. Yield: 0.030 g (100%); LC-MS: 230.1 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 7.95 (s, 2H), 7.50 (s, 1H), 7.05 (t, 1H), 3.44 (s, 2H), 2.15 (s, 6H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: Cc1ccccc1C(=O)c1ccccc1

Procedure:
Methylbenzophenone was prepared from mixtures of toluene and benzoyl chloride using essentially the method described in Example 1, with the following modifications in the distillation scheme.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].[S-:17][C:18]#[N:19].[K+].C1OCCOCCOCCOCCOCCOC1>ClC1C=CC=CC=1>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[CH:15][CH:16]=[C:7]([NH:6][C:18]([NH2:19])=[S:17])[CH:8]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: N#C[S-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Clc1ccccc1
Product: COC(=O)c1cccc(NC(N)=S)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
At −10° C. sulfuric acid (0.46 mL) is added dropwise to a solution of methyl 3-aminobenzoate (17.2 mmol) in chlorobenzene (19 mL). After 15 min potassium thiocyanate (18.2 mmol) is added portionwise over 30 min. The mixture is treated with 18-crown-6 (0.18 mmol), heated to 100° C. for 16 h and allowed to cool to rt. After 4 h the obtained precipitate is filtered off and washed successively with chlorobenzene (33 mL) and hexane (three times 130 mL). The residue is diluted with water (390 mL) and the suspension is stirred for 30 min. After filtration the residue is washed twice with water (130 ml, each), concentrated in vacuo and dried additionally by azeotropic removal of water with toluene. The obtained product is used without further purification. LC-MS: tR=0.66 min; [M+H]+=211.0.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]CC2C=CC=CC=2)=[O:15])=[CH:9][CH:8]=1)=[O:4]>CO>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)COc1ccc(CC(=O)OCc2ccccc2)cc1
Solvent: CO
Product: COC(=O)COc1ccc(CC(=O)O)cc1

Procedure:
7.8 g (0.025 mol) of benzyl 4-methoxycarbonylmethyloxy-phenyl-acetate are hydrogenated exhaustively in 150 ml of methanol in the presence of 8 g of palladium hydroxide-on-charcoal at room temperature under a hydrogen pressure of 50 psi. After removal of the catalyst, the mother liquor is concentrated to dryness under reduced pressure. 4.7 g (89.5% of theory) of a resinous crude product remain.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(C(=O)O)cc1
Product: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 4.5 °C
Reaction time: 0.67 h
Yield: 94.8 %

Procedure:
4-Ethylbenzoic acid (20 g, 133 mmol) was ice-cooled and fuming nitric acid (94%, d=1.50, 50 ml) was dropwise added thereto for 40 min. The mixture was stirred at 4-5° C. for 1.25 hr. The resulting yellow suspension was poured into ice-water and the precipitated crystals were collected by filtration. The crystals were dissolved in ethanol, and water was added for recrystallization to give the objective compound (24.6 g, 94.8%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[C:10]1(/[CH:16]=[CH:17]/B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:9][O:8][C:4]1[CH:3]=[C:2](/[CH:17]=[CH:16]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: COc1cc(Br)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1cc(/C=C/c2ccccc2)ccn1
Temperature: 90 °C
Yield: 92.8 %

Procedure:
4-Bromo-2-methoxypyridine (1.85 g, 9.84 mmol), (E)-phenylvinylboronic acid (4.3 g, 30 mmol), K2CO3 (4.0 g, 30 mmol) and PdCl2(dppf) (400 mg, 0.5 mmol) were stirred in DMSO (15 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated to 90° C. for 30 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated, and the residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) to provide the title compound (1.93 g, 93%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=5.2 Hz, 1H), 7.51 (m, 2H), 7.40-7.22 (m, 4H), 7.02-6.94 (m, 2H), 6.78 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [Al](OC(C)C)(OC(C)C)OC(C)C.S(=O)(=O)(O)O.CC(O)C.[CH3:23][C:24](=[CH:27][CH2:28][CH:29]1[CH2:33][CH:32]=[C:31]([CH3:34])[C:30]1([CH3:36])[CH3:35])[CH:25]=[O:26]>CC(C)=O>[CH3:23][C:24](=[CH:27][CH2:28][CH:29]1[CH2:33][CH:32]=[C:31]([CH3:34])[C:30]1([CH3:36])[CH3:35])[CH2:25][OH:26]
Reactant: CC(C=O)=CCC1CC=C(C)C1(C)C
Agent: CC(C)O[Al](OC(C)C)OC(C)C
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(=CCC1CC=C(C)C1(C)C)CO
Temperature: 85 °C
Reaction time: 7 h
Yield: 88 %

Procedure:
10.2 g (50 mmol) of Al(O-i-Pr)3, 0.25g (2.5 mmol) of sulfuric acid and 180 g (3.0 mol) of IPA were fed into a 1000 ml four-necked round bottom flask under atmosphere of nitrogen, and stirred at 85° C., and then 192 g (1.0 mol) of 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-al was added. The reaction was conducted while fraction containing acetone generated at the solution temperature of 85° to 95° C. was removed by distillation. After 7 hours, the reaction solution was analyzed by GLC, 88% of 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol was obtained (corresponding to 92% selectivity for conversion of the aldehyde as the starting material).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[N:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40](O)=[O:41])[CH:38]=3)[N:33]([C:43]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:32]=2)=[CH:27][CH:26]=1.[NH2:62][CH:63]1[CH2:68][CH:67]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:66][N:65]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:64]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:69]1([CH:67]2[CH2:68][CH:63]([NH:62][C:40]([C:37]3[CH:38]=[C:39]4[C:34](=[CH:35][CH:36]=3)[N:33]([C:43]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:32]=[C:31]4[C:28]3[CH:27]=[CH:26][N:25]=[CH:30][CH:29]=3)=[O:41])[CH2:64][N:65]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:66]2)[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)CC(c2ccccc2)C1
Reactant: O=C(O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (44 mg, 0.114 mmol) was added to a suspension of 3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (50 mg, 0.104 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of tert-butyl 3-amino-5-phenyl-piperidine-1-carboxylate (29 mg, 0.104 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][C@H:16]3[NH:27][CH2:26][CH2:25][C@@:22]4([C:23]=2[CH:24]=1)[C@H:17]3[CH2:18][CH2:19][CH2:20][CH2:21]4.C(N(CC)CC)C>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][C@H:16]3[N:27]([C:1](=[O:3])[CH3:2])[CH2:26][CH2:25][C@@:22]4([C:23]=2[CH:24]=1)[C@H:17]3[CH2:18][CH2:19][CH2:20][CH2:21]4
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(C)=O)CC3
Temperature: 60 °C
Yield: 81.9 %

Procedure:
Acetic anhydride (3.14 g, 30.76 mmol) was added to a solution of (+)-3-methoxy-morphinan hydrochloride (1.5 g, 5.1 mmol) in THF (30 ml) and triethylamine (8.7 g, 85.98 mmol) in the presence of nitrogen. The resulting solution was heated at 60° C. for 15 hr. The reaction mixture was cooled to room temperature and evaporated under vacuum. The residue was dissolved in methylene chloride (50 ml), washed with water (40 ml×2) and dried (MgSO4). Evaporation of the dried solution gave a tan viscous oil (1.25 g, 81% yield); ms (ESI+): m/z 300(M+1).