Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[O:14][C:13]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27])([CH2:19][CH2:20]2)[CH2:17][CH2:16]3)=[N:12][N:11]=1.[BH4-].[Na+].C(OCC)(=O)C.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[O:14][C:13]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23][CH2:24][CH2:25][CH:26]([OH:28])[CH3:27])([CH2:19][CH2:20]2)[CH2:17][CH2:16]3)=[N:12][N:11]=1
Reactant: COc1ccc(-c2nnc(C34CCC(CCCC(C)=O)(CC3)CC4)o2)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nnc(C34CCC(CCCC(C)O)(CC3)CC4)o2)c(Cl)c1
Temperature: 25 °C

Procedure:
5-{4-[5-(2-Chloro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-one (5-H) (0.150 g, 0.373 mmol) was stirred in methanol (5 mL) at 0° C. Sodium borohydride (0.0169 g, 0.448 mmol) was added. The reaction was allowed to stir to room temperature. The mixture was then layered with ethyl acetate (20 mL) and water (20 mL). The ethyl acetate layer was extracted and dried (MgSO4). Solvent was removed in vacuo to afford 5-{4-[5-(2-chloro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-ol (5-I).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(CO)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH:35]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCC1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCC4CCCCCC4)cc3)c2cc1OC
Yield: 84.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cycloheptylmethanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (64 mg, yield 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11](N(CC)CC)C.[C:18]([O:21][CH2:22][CH3:23])(=[O:20])C.O>O1CCCC1.ClC(OC(C)C)=O>[C:18](=[O:20])([O:21][CH:22]([CH3:23])[CH3:11])[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)OC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
Into a solution of 3.00 g of 4-nitrophenol and 3.31 mL of triethylamine in 30 mL of tetrahydrofuran, 2.46 mL of isopropyl chloroformate was dropped under cooling on ice. To the reaction mixture, after stirred at the same temperature for 10 min, ethyl acetate and water were added. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, followed by solvent removal by evaporation under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed with a 5% potassium carbonate aqueous solution and a saturated sodium chloride aqueous solution successively and dried over anhydrous magnesium sulfate. After removing the solvent by evaporation under reduced pressure, 3.00 g of 4-nitrophenyl isopropyl carbonate was obtained as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])=[CH:8][CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:13]2=[O:23])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-n2c(=O)c3ccccc3n(CC(=O)OC(C)(C)C)c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-acetic acid ethyl ester (Intermediate H) (9.5 g, 29.3 mmol) and K2CO3 (2.5 eq, 10.31 g, 73.3 mmol) in a round bottom flask is treated with dry DMF. tert-Butyl bromoacetate (1.02 eq, 4.2 ml, 30 mmol) is added dropwise via syringe under argon. The reaction suspension is stirred at RT for 1 hour. The reaction mixture is diluted with distilled water and extracted with EtOAc (3×). The separated organic layer is dried over MgSO4, filtered and the solvent is concentrated in vacuo. The title compound is obtained as a brown viscous oil, crystallizing on standing.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]([O:17]C)=[O:16])=[CH:9]2)=[CH:3][CH:2]=1.C1COCC1.[OH-].[Na+]>CO>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]([OH:17])=[O:16])=[CH:9]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(=O)n(Cc2ccc(-c3ccccc3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(=O)n(Cc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a solution of methyl 1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylate (4.5 g) in methanol (50 ml)/THF (50 ml) was added dropwise 1N aqueous sodium hydroxide (28 ml) at room temperature. The reaction mixture was stirred at room temperature for 3 hr and concentrated. The residue was diluted with 1 N hydrochloric acid (30 ml) and extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. Diisopropylether was added to the residue and the resulting crystals were collected by filtration to obtain the titled compound (4.2 g).
Reaction SMILES: [NH2:1][C:2]12[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:3]1([OH:22])[O:4][C:5]1[C:10]2=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1.C(N([CH2:28][CH3:29])CC)C.[C:30](Cl)(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[CH:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:2]1([NH:1][C:30](=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:20](=[O:21])[C:19]3[C:14]([C:3]1([O:22][C:3](=[O:4])[CH2:2][CH2:10][CH2:9][CH2:8][CH2:7][CH2:28][CH3:29])[O:4]2)=[CH:15][CH:16]=[CH:17][CH:18]=3)([CH3:13])[CH3:12]
Reactant: CCCCCCCC(=O)Cl
Reactant: CC(C)c1ccc2c(c1)OC1(O)c3ccccc3C(=O)C21N
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)NC12C(=O)c3ccccc3C1(OC(=O)CCCCCCC)Oc1cc(C(C)C)ccc12
Reaction time: 28 h
Yield: 30 %

Procedure:
A solution of 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one (0.20 g, 0.67 mmol) in anhydrous methylene chloride (10 ml) was added triethylamine (0.20 g, 2.01 mmol) and octanoyl chloride (0.27 g, 1.67 mmol) and then stirred for 28 hrs. The reaction mixture was concented and extracted with ethylacetate. The concentrated organic layer was purified using silica gel column chromatography (ethylacetate:hexane=1:6 to 1:4) to afford the title compound as a syrup (55 mg, 15%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[B:10]([O:19]C(C)C)([O:15]C(C)C)[O:11]C(C)C>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([O:11][B:10]([OH:19])[OH:15])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(OB(O)O)cc1
Yield: 69 %

Procedure:
4-Methoxyphenylboric acid was prepared in the same manner as described in Example 33B from 4-bromoanisole and triisopropyl borate in 69% yield. This was used in the next step without any further purification.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:18])=[O:2])=[N:12][CH:13]=1
Reactant: COC(=O)c1cccc(Sc2ccc(Cl)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Sc2ccc(Cl)cn2)c1
Yield: 78 %

Procedure:
A solution of 3-(5-chloro-pyridin-2-ylsulfanyl)-benzoic acid methyl ester (780 g, 2.8 mmol) and NaOH (500 mg, 12 mmol) in methanol:THF:water (1:1:1, 6 mL) was stirred at room temperature for 8 h. Solvents were evaporated. Crude mass was taken in water (40 mL), acidified to pH 4.0 and extracted with ethyl acetate. Evaporation of ethyl acetate provided 3-(5-chloro-pyridin-2-ylsulfanyl)-benzoic acid (580 mg).
Reaction SMILES: C([NH:3][C:4]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=O.O.[ClH:19]>O1CCOCC1>[ClH:19].[NH2:3][C:4]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: CCOC(=O)c1ccc(C(C)(C)NC=O)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(N)c1ccc(C(=O)O)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-(1-formylamino-1-methyl-ethyl)-benzoate (2.97 g, 12.6 mmol) is added to a mixture of water (30 mL), dioxane (15 mL) and concentrated hydrochloric acid (3.01 mL, 36.1 mmol) and the mixture is heated to 100° C. for 12 h. The reaction mixture is evaporated and the residue is crystallized from ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:13]1([C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)O)[OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:14][C:13]3[CH:15]=[CH:17][CH:18]=[CH:19][C:20]=3[O:12]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Oc1ccccc1O
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CCC2(CC1)Oc1ccccc1O2

Procedure:
A mixture of 1-ethoxycarbonyl-4-piperidinone (17 g), pyrocatechol (13 g) and p-toluenesulfonic acid (2.5 g) in 250 ml of dry toluene was refluxed with continuous removal of water. After 3 h the reaction mixture was concentrated in vacuo, 2% NaOH (200 ml) was added followed by extraction with dichloromethane. After drying over magnesium sulfate and removal of solvent in vacuo, the remaining red oil was applied to a silica gel column (eluent:ethyl acetate/heptane=1:1) giving 22 g of a slightly yellow oil, 1'-ethoxycarbonyl-spiro[1,3-benzodioxole-2,4'-piperidine]. The oil was dissolved in ethanol (250 ml), NaOH (10 g) and water (20 ml) were added and the mixture refluxed for 20 h. Removal of the solvents in vacuo addition of salt water followed by extraction with dichloromethane gave, after drying the organic phase over magnesium sulfate and removal of the solvent in vacuo, a red oil which was applied to a silica gel column (eluent:ethyl acetate/methanol/triethylamine =4:5:1 ) yielding 10 g of colorless crystals, spiro[1,3-benzodioxole-2,4'-piperidine], mp: 108°-10° C. The title compound, 25a, prepared from 4-phenyl-1-butyl methanesulfonate (2.3 g) and spiro[1,3-benzodioxole-2,4'-piperidine] (1.9 g) according to the method described in EXAMPLE 2, crystallized as the maleate salt from acetone by addition of maleic acid. Yield: 1.6 g, mp: 156°-57° C.
Reaction SMILES: [OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8](O)=[O:9].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:9]
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C(=O)O)cc(OCC(O)CO)c2Oc2cccc(OC)c2)cc1
Reactant: Nc1ccccc1
Product: COc1ccc(S(=O)(=O)Nc2cc(C(=O)Nc3ccccc3)cc(OCC(O)CO)c2Oc2cccc(OC)c2)cc1

Procedure:
In analogy to Example 121, by coupling 3-(2,3-dihydroxy-propoxy)-5-(4-methoxy-benzenesulphonylamino)-4-(3-methoxy-phenoxy)-benzoic acid with aniline there was obtained 3-(2,3-dihydroxy-propoxy)-5-(4-methoxy-benzenesulphonylamino)-4-(3-methoxy-phenoxy)-N-phenyl-benzamide as a foam.
Reaction SMILES: [O-2].[Mg+2:2].[OH-].[Mg+2].[OH-].[N+:6]([O-:9])([OH:8])=[O:7].[C:10]([OH:13])(=[O:12])[CH3:11]>O>[C:10]([O-:13])(=[O:12])[CH3:11].[Mg+2:2].[C:10]([O-:13])(=[O:12])[CH3:11].[N+:6]([O-:9])([O-:8])=[O:7].[Mg+2:2].[N+:6]([O-:9])([O-:8])=[O:7]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])O
Agent: [Mg+2]
Agent: [O-2]
Agent: [OH-]
Solvent: O
Product: CC(=O)[O-]
Product: O=[N+]([O-])[O-]

Procedure:
As for the light magnesium oxide used for preparing said slurry of magnesium salt and said slurry of magnesium hydroxide in said step 1), the specific surface area is ≧100 m2/g, and the content of MgO≧95% (at weight); the monoprotonic acid used for preparing the slurry of magnesium salt is acetic acid and/or nitric acid; the dosage of acetic acid and/or nitric acid is determined according to the mole ratio for its sufficient reaction with MgO; the solid content of the slurry of magnesium salt and the slurry of magnesium hydroxide is 10%-14% (at weight). To prepare said slurry of magnesium salt, said light magnesium oxide is at first stirred with water evenly and then glacial acetic acid and/or nitric acid is added to magnesia for sufficient reaction, so as to produce magnesium acetate and/or magnesium nitrate; when said glacial acetic acid and/or nitric acid is reacting with magnesia, the stirring rate reaches 300-600 revolutions per minute. The ferric iron salt used in step 1) is preferably ferric nitrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:21][OH:22].[OH-].[Na+].CO>O>[F:1][C:2]1[CH:3]=[C:4]([C:8](=[N:21][OH:22])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: ON=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(F)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A reaction vessel was charged with 1-(3-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone (2 g, 7 mmol), hydroxylamine (2.2 g, 32 mmol), 10% NaOH aqueous solution (11 ml, 27 mmol) and methanol (24 ml). The reaction mixture was heated to 70° C. and stirred at 70° C. for 3 hrs. It was then cooled to room temperature and water (12 ml) was added. The mixture was stirred at 0° C. for 1 hr. The solids were collected on a filter, washed with water, and dried under vacuum at 50° C. overnight to provide 1.9 g (91%) of the title compound as a solid with purity 99% AUC by HPLC (Phenomenex Luna 3μ cyano, 100 mm×4.6 mm. Flow rate: 1 ml/min. UV detection: 220 nm. Eluent: 75% A, 25% B. A: 80/20/0.05 water/acetonitrile/TFA. B: 20/80/0.05 water/acetonitrile/TFA).
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([C:16]([O:18]CC)=[O:17])=[N:12][C:13]=2[O:14]C)OC1.[Cl:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>CO.[Cu-]=O>[ClH:22].[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:9]2[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[NH:12][C:13](=[O:14])[CH:8]=2)[CH:27]=1
Reactant: Clc1c[nH]cn1
Reactant: CCOC(=O)c1ccc(B2OCC(C)(C)CO2)c(OC)n1
Agent: O=[Cu-]
Solvent: CO
Product: Cl
Product: O=C(O)c1cc(-n2cnc(Cl)c2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Synthesis of ethyl 4-(4-chloro-1H-imidazol-1-yl)-6-methoxypyridine-2-carboxylate (C34). 1,1-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (49.8 mg, 0.068 mmol) was added to a solution of ethyl 5-bromo-6-methoxypyridine-2-carboxylate (prepared in analogous fashion to methyl 5-bromo-6-methoxypyridine-2-carboxylate (C30) in Preparation 10; 254 mg, 0.97 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (264 mg, 1.17 mmol), and potassium acetate (293 mg, 2.92 mmol) in 1,4-dioxane (8 mL). The reaction was stirred at 85° C. for 6 hours, whereupon it was allowed to cool to room temperature. Dichloromethane was added, and the resulting mixture was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo to afford intermediate ethyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxypyridine-2-carboxylate. To a solution of ethyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxypyridine-2-carboxylate (crude) in methanol (50 mL) was added 4-chloro-1H-imidazole (C33) (100 mg, 0.97 mmol) and copper(I) oxide (14 mg, 0.098 mmol) and the reaction was stirred at ambient temperature overnight. The mixture was heated to 50° C. for 2 hours, and additional copper(I) oxide (14 mg, 0.098 mmol) was added. The reaction was heated to reflux for 2 hours and was then filtered through Celite. The Celite pad was washed with methanol, and the combined filtrate and washings were concentrated in vacuo. Purification was carried out twice via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane, then 0% to 40% ethyl acetate in heptane), affording the title compound as a white solid. Yield: 29.3 mg, 0.104 mmol, 11%. LCMS m/z 282.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.44 (t, J=7.1 Hz, 3H), 4.14 (s, 3H), 4.46 (q, J=7.1 Hz, 2H), 7.24 (d, J=1.6 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.82-7.83 (m, 1H), 7.84 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([O:9][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)[nH]cc2Cl)CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
A 500 mL round bottom flask was charged with 5-chloro-4-hydroxypyridin-2(1H)-one (10 g, 68.7 mmol), t-butyl 4-hydroxypiperidine-1-carboxylate (16.59 g, 82 mmol), triphenylphosphine (27.0 g, 103 mmol) and DMF (200 ml). This mixture was stirred for 40 minutes to form a clear and homogeneous solution. The solution was then cooled to 0° C. and diisopropyl azodicarboxylate (16.23 mL, 82 mmol) was added drop-wise while maintaining the temperature below 20° C. during the addition. After the addition, the reaction mixture was allowed to warm to room temperature overnight. The reaction was then heated to 60° C. for 0.5 hours. After cooling the reaction mixture to room temperature, the DMF was distilled from the reaction under vacuum at 50° C. to yield brownish, viscous oil. The oil was dissolved in 300 mL of chloroform and then was washed with dilute sodium bicarbonate (pH 8-10) (3×50 mL). The chloroform layer was directly concentrated to afford a light yellow viscous oil, which was partitioned between 250 mL of diethyl ether and 70 mL of 1 N NaOH. The aqueous phase was extracted thoroughly with diethyl ether until LC/MS showed no triphenylphosphine oxide or other impurities in the aqueous layer. The aqueous layer was purged with nitrogen to remove residual ether and then acidified slowly with 1 N HCl (˜70 mL) to pH 5 followed by cooling to 0° C. for 2 hours. The precipitates were collected by filtration, washed with ice water (2×20 mL), and air dried overnight. The light yellow solid was further vacuum dried at 40° C. to a constant weight to yield t-butyl 4-(5-chloro-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (13.2 g, 40.1 mmol, 58.4% yield) as a light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 12.5 (br, s, 1H), 7.19 (s, 1H), 5.75 (s, 1H), 4.34-4.41 (m, 1H), 3.40-3.48 (m, 2H), 3.26-3.37 (m, 2H), 1.71-1.83 (m, 2H), 1.60-1.71 (m, 2H), 1.32 (s, 9H); MS m/e 329 (M+H+), 273 (M+H+-t-butyl).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[C:8]2[CH2:15]O.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.C(OCC)C>[Cl:19][CH2:15][C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:11]=[N:10][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cncc(CO)c2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc2cncc(CCl)c2c1

Procedure:
The hydrochloride of the compound obtained in Step B (1.09 g; 0.005 mol) is suspended in 50 ml of chloroform. Thionyl chloride (2.80 ml; 0.04 mol) is added and then the reaction mixture is heated at reflux for 24 hours with stirring. After evaporation under reduced pressure, the residue obtained is taken up in ethyl ether. The precipitate formed is suction-filtered off and recrystallised from acetonitrile to yield the title compound in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:27]([O-])=O)=[C:11]([CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-].C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]2[C:10]=1[NH:27][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)Cc1c(C(F)(F)F)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Ti+4]
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCc3ccccc3)c2[nH]1

Procedure:
The reaction was carried out in a manner similar to Reference Example 12 c) except for using 10.9 g (26.7 mmol) of ethyl (3-benzyloxy-6-trifluoromethyl-2-nitrophenyl)pyruvate, 165 g (213 mmol) of 20% titanium chloride aqueous solution and 100 ml of ethanol. Ethyl 7-benzyloxy-4-trifluoromethyl-2-indolecarboxylate was thus obtained in the yield of 8.00 g (82.6%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[Br:16]([O-])(=O)=O.[Na+].[Br-].[Na+]>C(Cl)Cl.O.S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>[Br:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(Br)c1ccc(C(=O)CCCCl)cc1
Temperature: 10 °C
Yield: 281.5 %

Procedure:
Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (74.7 g, 333 mmol) in methylene chloride (250 mL) and add sodium bromate (17.6 g, 117 mmol) in water (75 mL) in a three-necked Morton flask equipped with an overhead stirrer. Cool the solution to 10° C. and irradiate with two 150 W incandescent flood lamps. Add, by dropwise addition, a solution of sodium bromide (24 g, 233 mmol) and stir for 2 hours. Illuminate for another 30 minutes, add sodium dithionate (2.0 g), separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo to give the title compound (100 g, 99%).