Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N:7]1[C:16]1[N:17]=[C:18](N)[CH:19]=[C:20]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[C:21]=12.N([O-])=[O:37].[Na+].N>O>[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N:7]1[C:16]1[N:17]=[C:18]([OH:37])[CH:19]=[C:20]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[C:21]=12
Reactant: O=N[O-]
Reactant: Cc1c(C)n(Cc2cccc(F)c2)c2c(N3CCc4ccccc4C3)nc(N)cc12
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1c(C)n(Cc2cccc(F)c2)c2c(N3CCc4ccccc4C3)nc(O)cc12
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
The compound prepared in Example 847 was treated with a saturated sodium bicarbonate solution to obtain 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-amine. Concentrated sulfuric acid (1 ml) and water (5 ml) were added to 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-amine (50 mg, 0.13 mmol) and then sodium nitrite (43.1 mg, 0.63 mmol) was added thereto. The reaction mixture was stirred for 5 minutes at 100° C. under heating and then excess ammonia solution was added thereto. The reaction mixture was stirred for 2 minutes under heating at the same temperature and then filtered to discard insoluble materials. A potassium hydroxide solution was added to the reaction mixture, which was then filtered to discard insoluble materials. The reaction mixture was extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 28.4 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: c1cncc(C2CCCCN2)c1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCCCC2c2cccnc2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 3-piperidin-2-ylpyridine (11 mg, 0.045 mmol, 1.0 eq), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H21N3O2: 347.1634, found 347.1644.
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[CH2:5]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[OH:18])[C:11](=[N:13][OH:14])[NH2:12])[CH:6]=[CH2:7]>N1C=CC=CC=1>[CH2:5]([C:8]1[CH:9]=[C:10]([C:11]2[N:12]=[C:1]([CH3:2])[O:14][N:13]=2)[CH:15]=[CH:16][C:17]=1[OH:18])[CH:6]=[CH2:7]
Reactant: C=CCc1cc(C(N)=NO)ccc1O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: C=CCc1cc(-c2noc(C)n2)ccc1O
Temperature: 25 °C

Procedure:
Acetyl chloride (2.28 ml) was added dropwise to a solution of 3-allyl-4-hydroxybenzamidoxime (5.4 g) in pyridine (48 ml). The solution was heated at reflux for 16 hours, cooled to ambient temperature and evaporated. The residue was dissolved in ethyl acetate and the solution was washed with saturated aqueous sodium carbonate solution, dried (MgSO4) and evaporated, to give 2-allyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenol as a low-melting solid (3.8 g), m/z 217 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][NH:5][CH:6]=1.C1C(=O)N([I:20])C(=O)C1>CN(C)C=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Cl:1][C:2]1[C:3]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][NH:5][C:6]=1[I:20]
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1c[nH]nc1C1CCOCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1c(C2CCOCC2)n[nH]c1I
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of 4-chloro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (compound 294.3, 3.00 g, 16.1 mmol) in N,N-dimethylformamide (20 mL) was added NIS (7.26 g, 32.3 mmol). The reaction mixture was stirred overnight at 80° C. The reaction mixture was diluted with 50 mL Na2S2O3 (sat.). The aqueous phase was extracted with 3×100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/8-1/5) as the eluent to furnish 4.05 g (81%) of the title compound as a white solid.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.Cl.[CH3:21][O:22][C:23](=[O:26])[CH2:24][NH2:25].C([O-])(=O)C.[Na+]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH3:21][O:22][C:23]([CH2:24][N:25]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])=[O:26]
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CN
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)[O-]
Agent: Cl
Product: COC(=O)Cn1c(C)ccc1CN1C(=O)c2ccccc2C1=O

Procedure:
18.1 g (0.07 mol) of 6-phthalimido-2,5-hexanedione, 10.0 g (0.08 mol) of glycine methyl ester hydrochloride and 6.6 g (0.08 mol) of sodium acetate are stirred in 300 ml of acetic at 80° C. for 3 hours. After the mixture has been concentrated, the residue is taken up in aqueous sodium bicarbonate solution, the mixture is extracted with methylene chloride, the extract is dried and concentrated and the residue is recrystallised from methanol.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:13]=2)[CH:5]=1.COC(=O)C1C=CC=C(/C=C/C2N=C(Cl)C=C(C)N=2)C=1.[Cl-].[Cl-].[Ca+2].[BH4-].[Na+]>CO.C1COCC1>[CH3:18][C:16]1[CH:15]=[C:14]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[N:13]=[C:12](/[CH:11]=[CH:10]/[C:6]2[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][CH:7]=2)[N:17]=1
Reactant: COC(=O)c1cccc(/C=C/c2nc(C)cc(N3CCCC3)n2)c1
Agent: COC(=O)c1cccc(/C=C/c2nc(C)cc(Cl)n2)c1
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(N2CCCC2)nc(/C=C/c2cccc(CO)c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.2 %

Procedure:
A solution of 60 mg of (E)-3-[2-(4-methyl-6-pyrrolidin-1-yl-pyrimidin-2-yl)-vinyl]-benzoic acid methyl ester, product of example 40, in MeOH/THF (each 2 ml) was treated at RT with 41 mg (0.37 mmol) CaCl2 followed by 28 mg (0.74 mmol) NaBH4 and then stirred for 18 h at RT until completion of the reaction according to TLC analysis. The reaction mixture was partitioned between diluted aqueous HCl and EtOAc. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was applied to a short silica gel column with CH2Cl2/MeOH (95/%) as eluent. Combination of the purified fractions and concentration in vacuo gave 10 mg (18%) of the desired (E){3-[2-(4-methyl-6-pyrrolidin-1-yl-pyrimidin-2-yl)-vinyl]-phenyl}-methanol as a white solid. ISP mass spectrum, m/e: 296.4 (M+1 calculated for C18H21ClN3O: 296).
Reaction SMILES: C([O:5][NH:6][C:7](=[O:32])[CH2:8][N:9]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)(C)(C)C.C(O)C>C(Cl)Cl>[OH:5][NH:6][C:7](=[O:32])[CH2:8][N:9]([S:21]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)NOC(C)(C)C)Cc2ccc3ccccc3n2)cc1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(CC(=O)NO)Cc2ccc3ccccc3n2)cc1
Reaction time: 8 h

Procedure:
N-(t-Butyloxy)-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide (1.15 g, 2.42 mmol) is dissolved in methylene chloride (30.0 mL) and ethanol (0.20 mL) in a glass sealed tube. Hydrochloric acid gas (from a lecture bottle) is bubbled through the solution for 20 minutes, and then the tube is sealed and stands at room temperature overnight. The next day, additional hydrochloric acid gas is bubbled through the solution for 20 minutes, more ethanol (0.20 mL) is added, and then the tube is sealed and stands at room temperature for two days. After that time, the solvent is removed. The product is purified by silica gel chromatography (5% to 15% methanol/methylene chloride with ~1% ammonium hydroxide) to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide, m.p. 177°-178° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]/[N:16]=[C:17](\[CH3:25])/[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:26]I.Cl>CN(C)C=O.O>[CH3:26][O:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]/[N:16]=[C:17](\[CH3:25])/[C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(O)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.4 %

Procedure:
60% oily sodium hydride (0.20 g, 5.0 mmol) was added to a solution of methyl (E)-α-hydroxy-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetate (1.59 g, 4.6 mmol) and methyl iodide (1.95 g, 13.7 mmol) in N,N-dimethylformamide (15 ml) with stirring at 0° C. After 45 minutes, water was added, and the mixture was adjusted to pH 1 with 1N hydrochloric acid, extracted with ether, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/methylene chloride=9/1) to give the desired compound methyl (E)-α-methoxy-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetate (1.19 g, 72%) as an oil.
Reaction SMILES: CC(=NO)C(C)=NO.[BH4-].[Na+].[CH:11]1([CH2:17][O:18][C:19]2[CH:32]=[CH:31][C:22]([CH:23]=[C:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(=O)C>O.[OH-].[Na+].C1COCC1.CN(C=O)C>[CH:11]1([CH2:17][O:18][C:19]2[CH:32]=[CH:31][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCC3CCCCC3)cc2)S1
Agent: CC(=NO)C(C)=NO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCC3CCCCC3)cc2)S1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To the suspension containing CoCl2.6H2O (4.4 mg, 0.016 mmol) and dimethylglyoxime (73.1 mg, 0.58 mmol) in 10 ml of water, 4 drops of 1.0N NaOH and NaBH4 (409.3 mg, 10.6 mmol) were subsequently added. The mixture was cooled to 0° C., and 5-(4-(cyclohexylmethoxy)benzylidene)thiazolidine-2,4-dione (1 g, 3.13 mmol) in 15 ml of THF-DMF (2:1) was added thereto over 20 minutes. The mixture was stirred at room temperature for 18 hours, to which acetic acid was then added until the pH thereof reached about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on silica gel to afford 5-(4-(cyclohexylmethoxy)benzyl)thiazolidine-2,4-dione (Derivative 114 of the above formula) as white solid (0.8 g, yield: 79%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[N:16]=3)=[C:9]([F:30])[CH:8]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO.C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([CH:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[OH:23])[N:16]=3)=[C:9]([F:30])[CH:8]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridine-5-yl)(phenyl)methanone (718.0 mg, 1708 μmol) in methanol (12.0 mL) and THF (4.8 mL) was added sodium borohydride (64.6 mg, 1708 μmol), and the resulting solution was stirred at 25° C. for 10 min. Saturated aqueous NH4Cl (10 mL) was then added, and MeOH and THF were removed in vacuo. The resulting suspension was partitioned between ethyl acetate and water). The organic layer was separated and washed with brine, and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridine-5-yl)(phenyl)methanol as a yellow solid. MS (ESI) m/z: Calculated: 422.1; Observed: 423.0 (M++1).
Reaction SMILES: [C:1](Cl)(=O)[O:2]C(Cl)(Cl)Cl.[NH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:11]=1[C:12]([OH:14])=[O:13].C(OCC)C>O1CCOCC1>[CH3:19][C:15]1[C:11]2[C:12](=[O:14])[O:13][C:1](=[O:2])[NH:9][C:10]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cccc2[nH]c(=O)oc(=O)c12
Yield: 56 %

Procedure:
Trichloromethyl carbonochloridate (2.04 mL, 16.9 mmol) was added to 2-amino-6-methylbenzoic acid (2.13 g, 14.1 mmol) in anhydrous dioxane (32 mL) under nitrogen, then refluxed for 30 minutes. Diethyl ether (100 mL) was added, and the precipitated solid was collected by filtration to give 5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (1.4 g, 56%) which was used without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([C:23](=[O:34])[C@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[CH3:25])[CH2:20]2)[C:16]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])([OH:35])[CH2:15]1.C(N(CC)CC)C>ClCCl>[CH3:43][O:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C@:16]1([OH:35])[CH2:15][C@H:14]([CH2:13][O:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:22][C@@H:21]2[C@H:17]1[CH2:18][N:19]([C:23](=[O:34])[C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH3:25])[CH2:20]2
Reactant: COc1ccccc1[C@H](C)C(=O)N1CC2CC(CO)CC(O)(c3ccccc3OC)C2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Temperature: 20 °C
Reaction time: 48 h
Yield: 20.7 %

Procedure:
20.1 g of p-toluenesulphonyl chloride are added to a solution of 23.2 g of 6-hydroxymethyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol (mixture of the 2 diastereoisomers, 3aR,4R,6S,7aS,S and 3aS,4S,6R,7aR,S) and 14.9 cm3 of triethylamine in 300 cm3 of dichloromethane. After stirring at 20° C. for 48 hours, the reaction mixture is washed with 150 cm3 of water, then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.20 mm, diameter 8.0 cm, height 45 cm), eluting under a pressure of 0.8 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and collecting fractions of 500 cm3. Fractions 14 to 17 are concentrated to dryness under reduced pressure. The residue obtained is subsequently chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 7.5 cm, height 60 cm), eluting under a pressure of 0.8 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60:40 then 50:50 by volume) and collecting fractions of 500 cm3. Evaporation to dryness of fractions 22 to 26 gives 6.5 g of the (3aS,4S,6R,7aR)-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]-6-tosyloxymethyl perhydroisoindol-4-ol diastereoisomer in the form of a thick white foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[Br:13]Br>C(O)(=O)C.O>[Br:13][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:12]
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2c1ccc(O)c2Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 75.1 %

Procedure:
To a solution of 4.3 g of 6-hydroxy-1-teralone in 0 ml of acetic acid and 6 ml of water with stirring under ice cooling is added dropwise a solution of 5.1 g of bromine in acetic acid for 8 minutes. After addition, the mixture is stirred unde ice cooling for 5 minutes and at room temperature for 30 minutes. To the reaction mixture is added 170 ml of ice-cold water. The insoluble substance is collected by filtration, dried and recrystallized from a mixture of hexane, ethyl acetate and ethanol to give 4.8 g of 5-bromo-6-hydroxy-3,4-dihydro-1(2H)-naphthalenone, melting at 183°-186° C.
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:20][C:19]1[CH:21]=[CH:22][C:16]([C:15]([F:14])([F:23])[F:24])=[CH:17][CH:18]=1)#[CH:3]
Reactant: O=C([O-])OCC=Cc1ccccc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: C#CC(Nc1ccc(C(F)(F)F)cc1)c1ccccc1
Reaction time: 12 h
Yield: 72.7 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.094 g, 0.490 mmol) and p-trifluoromethylaniline (0.100 g, 0.62 mmol). The reaction was conducted at room temperature for 12 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 94/6. The mixture was purified by flash column chromatography on silica gel (1% ethyl acetate in hexanes) to give the title compound (0.098 g, 72%). HPLC analysis indicated the enantiomeric excess of the product was 96% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99.75/0.25; flow rate=0.6 mL/min; detection wavelength=254 nm; TR=29.8 (major), 34.9 (minor) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.50-7.35 (m, 7H), 6.64 (d, J=8.4 Hz, 2H), 6.08 (ddd, J=16.8, 10.4, 6.0 Hz, 1H), 5.33 (dt, J=7.2, 1.2 Hz, 1H), 5.30 (d, J=1.2 Hz, 1H), 5.02 (t, J=5.6 Hz, 1H), 4.40 (d, J=4.8 Hz, 1H). 13C NMR (100.59 MHz, CDCl3) δ 149.50, 140.88, 138.01, 128.88, 127.76, 127.08, 126.43 (q, J=3.8 Hz), 123.56, 119.03 (q, J=32.5 Hz), 116.58, 112.64, 60.34. Anal. Calcd for C16H14NF3: C, 69.31; H, 5.09; N, 5.05; F, 20.55. Found: C, 69.46; H, 5.12; N, 5.09; F, 20.37.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:4][C:3]=1[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-])=O)[CH:15]=1>C(OCC)(=O)C.[Pd].[C]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:9][CH2:10][CH2:11][O:12]2)[CH:5]=[CH:4][C:3]=1[O:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:18])=[CH:19][CH:20]=1
Reactant: Nc1ccc(Oc2ccc(C3OCCO3)cc2Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(C3OCCO3)cc2Cl)cc1N
Reaction time: 24 h

Procedure:
4-{[2-Chloro-4-(1,3-dioxolan-2-yl)phenyl]oxy}-2-nitroaniline (1.41 g) was dissolved in 100 mL of ethyl acetate and hydrogenated over 100 mg of 10% Pd/carbon (wet, Degussa type) under balloon of H2 gas. After 24 hours, the reaction was filtered through Celite and concentrated to give 4-{[2-chloro-4-(1,3-dioxolan-2-yl)phenyl]oxy}-1,2-benzenediamine which was used without further purification. (M+1) 306.9, 1.57 min (LC/MS method B)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[N:21]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:23][C:24]=2[C:25]([F:28])([F:27])[F:26])=[O:19])=[CH:13][N:12]=1)[C:5]([OH:7])=O.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]1[N:12]=[CH:13][C:14]([NH:17][C:18]([C:20]2[N:21]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:23][C:24]=2[C:25]([F:27])([F:28])[F:26])=[O:19])=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)c(Cl)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
According to the procedures described in Tetrahedron Lett. 1998, 39, 5891 and Org. Proc. Res. Dev. 2004, 8, 952, 3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid (30 mg, 0.06 mmol), methanesulfonamide (7 mg, 0.07 mmol), 4-dimethylaminopyridine (2 mg, 0.02 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14 mg, 0.07 mmol) were suspended in 3 mL of dichloromethane and the mixture was refluxed for 3 h. The reaction mixture was cooled down to room temperature and filtered. The white precipitates were washed with ethyl acetate. The combined filtrate was stirred with 150 mg of Amberlyst-15 at room temperature for 2 h. The reaction was filtered to remove the resin, and the filtrate was concentrated and purified by flash chromatography (eluting with ethyl acetate and hexanes) to afford 12 mg of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-chloro-4-methanesulfonylaminocarbonyl-phenyl)-pyridin-3-yl]-amide as a light yellow solid. LCMS calcd for C24H16ClF3N4O5S (m/e) 564, obsd 565 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[C:14]([NH:19][CH2:20][CH2:21][CH2:22][OH:23])=[N:15][CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]>N1C=CC=CC=1.C1C=CC=CC=1>[C:1]([O:23][CH2:22][CH2:21][CH2:20][NH:19][C:14]1[C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=[CH:16][N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1cccnc1NCCCO
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(OCCCNc1ncccc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
70 ml of benzoyl chloride are introduced dropwise into a solution of 77.8 g (0.04 mol) of 3-[(3-nitro-2-pyridyl)amino]propanol (M. ISRAEL, N. TIROSH, J. Med. Chem. 1973, 16, 520) in 48.5 ml of pyridine and 800 ml of benzene. The mixture is stirred for 2 h at ambient temperature and the precipitate is filtered. The filtrate is washed with 1N hydrochloric acid and then with water. Drying, filtering and evaporation are carried out. A crystallized product is obtained.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([NH2:21])[C:14]=2[N:22]=1)[CH3:8]>ClCCl.C(Cl)(Cl)Cl>[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:23][CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH2:29][CH2:30]2)[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([NH2:21])[C:14]=2[N:22]=1)[CH3:8]
Reactant: CC(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)C(C)C)CC1
Reaction time: 8 h
Yield: 50.2 %

Procedure:
Isobutyryl chloride (96 μL, 0.917 mmol) was added drop wise to a chilled (0° C.) solution of 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine (304 mg, 0.917 mmol) in dichloromethane (10 mL). The reaction mixture was allowed to stir overnight then it was diluted with chloroform and washed with 5% sodium hydroxide, water and brine. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from acetonitrile to provide 185 mg of 2-(ethoxymethyl)-1-[2-(1-isobutyrylpiperidin-4-yl)ethyl]-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine as a yellowish solid, m.p. 167.5-169.2° C.