Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[CH3:19]OC(OC)OC.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:9]=[CH:19][NH:8][C:6]=2[CH:7]=1
Reactant: COC(OC)OC
Reactant: Nc1cc(Cl)c(Oc2ccccc2)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Clc1cc2[nH]cnc2cc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 5-chloro-2-nitro-4-phenoxyphenylamine (0.810 g, 3.06 mmol) in DMF (12 mL) was added trimethylorthoformate (12 mL) followed by sodium dithionite (2.66 g, 15.3 mmol), and glacial acetic acid (1.5 mL). The reaction mixture was heated in a sealed tube at 100° C. for 14 h. Additional sodium dithionite (0.5 g) and acetic acid (1 mL) were added and heating was continued at 120° C. for an additional 3 h. The reaction flask was cooled in ice, added cautiously to half-saturated sodium bicarbonate solution (300 mL) and extracted with EtOAc. Combined organic layers were washed with 5% NaHCO3, brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (hexanes:EtOAc, 0% to 5% over 20 minutes) to yield the titled compound as a yellow amorphous solid (0.57 g, 76%) as a mixture of tautomers. MS (ESI/CI): mass calcd. for C13H9ClN2O, 244; m/z found, 245 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.55 (s, 1H), 8.06 (s, 1H), 8.0-7.2 (m, 2H), 7.32 (t, J=7.9 Hz, 2H), 7.09 (t, J=7.3 Hz, 1H), 6.96 (d, J=8.3 Hz, 2H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:12]N)[CH:4]=1.O=[C:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]1>C(O)(=O)C.CCOC(C)=O>[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]2[C:4]=1[C:20]1[CH2:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][C:15]=1[NH:12]2
Reactant: NNc1cc(Br)ccc1C(=O)O
Reactant: CCOC(=O)C1CCCC(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)ccc(Br)c23)C1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
Step 2 A stirred suspension of 4-bromo-2-hydrazinylbenzoic acid hydrochloric acid salt (16.35 g, 58.1 mmol) in acetic acid (171 mL) was treated with ethyl 3-oxocyclohexanecarboxylate (9.88 g, 58.1 mmol) at rt. The mixture was stirred at reflux for 2.5 h, then was cooled to rt and concentrated to afford a brown solid. This was suspended in EtOAc (20 mL) and the precipitate was collected by filtration, washed with EtOAc and air dried to provide 5-bromo-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (11.46 g). The filtrate was concentrated and the residue was resuspended in EtOAc, the precipitate collected by filtration and dried to provide additional product (0.82 g) for a total of 12.28 g (58%). 1H NMR (400 MHz, DMSO-d6) δ 13.10 (br. s., 1H) 11.06 (s, 1H) 7.50 (d, J=8.13 Hz, 1H) 7.19 (d, J=8.13 Hz, 1H) 4.07-4.15 (m, 2H) 3.08-3.19 (m, 1H) 2.99-3.08 (m, 1H) 2.89-2.99 (m, 2H) 2.79-2.89 (m, 1H) 2.09-2.22 (m, 1H) 1.75-1.89 (m, 1H) 1.20 (t, J=7.14 Hz, 3H). Mass spectrum m/z 366.0, 368.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SC1C=CC2C(=CC=CC=2)C=1.BrCC1[C:44]2[C:39](=[CH:40][CH:41]=[C:42](C3C=CC=CC=3OC)[CH:43]=2)[NH:38]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].C1C2C(=CC=CC=2)C=CC=1S>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21][NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSc1ccc3ccccc3c1)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: Sc1ccc2ccccc2c1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-(naphthalen-2-ylsulfanylmethyl)-1,2-dihydroquinoline 100 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80 mg of potassium carbonate, and 42 mg of 2-naphthalenethiol reacted to give 8 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14](#[N:17])[CH:15]=[CH2:16]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:16][CH2:15][C:14]#[N:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=CC#N
Reactant: COc1ccc(CCN)cc1OC
Solvent: CO
Product: COc1ccc(CCNCCC#N)cc1OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
54.5 gm of 2-(3,4-dimethoxy-phenyl)-ethylamine were dissolved in 100 ml of methanol, a solution of 16.2 gm of acrylonitrile in 50 ml of methanol was added dropwise at 50° C, and the mixture was stirred for 1 hour at 50° C. After evaporation of the methanol, the raw reaction product thus obtained was used without further purification in the next step.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[C:13]1([CH:19]2[NH:24][CH2:23][CH2:22][NH:21][C:20]2=[O:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[O:25]=[C:20]1[NH:21][CH2:22][CH2:23][N:24]([C:7]([Cl:10])=[O:6])[CH:19]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1NCCNC1c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C1NCCN(C(=O)Cl)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
To a stirred solution of triphosgene (0.558 g) in DCM (10 ml) pyridine (0.46 mL) was added at 0° C. and, after 10 min, 3-phenyl-piperazine-2-one (1 g). The ice bath was removed and the mixture was stirred at room temperature overnight. The mixture was concentrated and the product was purified by flash chromatography (CH/AcOEt 1:1) to give the title compound (0.253 g) as a foam.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1.[CH2:11]([N:13]([CH2:18][CH3:19])[C:14](=[O:17])[CH2:15][OH:16])[CH3:12].[OH-].[K+].C(O)(C)C>O>[CH2:11]([N:13]([CH2:18][CH3:19])[C:14](=[O:17])[CH2:15][O:16][C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1)[CH3:12]
Reactant: CCN(CC)C(=O)CO
Reactant: FC(F)(F)c1nsc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCN(CC)C(=O)COc1nc(C(F)(F)F)ns1
Temperature: -10 °C
Reaction time: 10 h
Yield: 47.1 %

Procedure:
5.6 g (0.03 mol) of 5-chloro-3-trifluoromethyl-1,2,4-thiadiazole are added to a mixture which comprises 4 g (0.03 mol) of hydroxyacetic acid diethylamide, 1.9 g (0.03 mol) of potassium hydroxide powder and 80 ml of isopropanol and has been cooled to -10° C. The reaction mixture is stirred for 10 hours at -10° C. and poured into water, and the product is filtered off under suction. 4 g (47% of theory) of (3-trifluoromethyl-1,2,4-thiadiazol-5-yl)-oxyacetic acid diethylamide are obtained in the form of white crystals of melting point 60° C.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH:18]1([C:24]2[S:25][C:26]([C:30](O)=[O:31])=[C:27]([CH3:29])[N:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>O>[CH:18]1([C:24]2[S:25][C:26]([C:30]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:15])[F:16])=[O:31])=[C:27]([CH3:29])[N:28]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: Cc1nc(C2CCCCC2)sc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1sc(C2CCCCC2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To 7 ml of N,N-dimethylformamide were dissolved 0.50 g (2.5 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 0.56 g (2.5 mmol) of 2-cyclohexyl-4-methylthiazole-5-carboxylic acid, followed by the addition of 0.42 g (5.0 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 0.64 g (yield: 78%) of 4,4-difluoro-3-methyl-3-butenyl 2-cyclohexyl-4-methylthiazole-5-carboxylate.
Reaction SMILES: Cl.[OH:2][NH3+:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:35])[CH2:12][CH2:13][CH:14]2[C:17](=[O:18])[N:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH:15]2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C>C(O)(C)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:35])[CH2:12][CH2:13][CH:14]2[C:17](=[O:18])[N:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]([NH:3][OH:2])=[NH:24])=[CH:21][CH:20]=3)[CH:15]2[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Reactant: [NH3+]O
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C(=N)NO)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
199 mg of hydroxylammonium hydrochloride were added to a solution of 200 mg of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile (8) and 0.45 ml of triethylamin in 15 ml of isopropanol. The mixture was stirred at room temperature for 12 h. The reaction solution was extracted twice with ethyl acetate/water. The organic phases were dried over magnesium sulfate and concentrated. This gave the product of molecular weight 463.51 (C26H26F1N3O4); MS (ESI): 464.19 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.B(F)(F)F>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C@H:7]2[C@H:7]([C:6]3[CH:9]=[CH:10][CH:3]=[CH:4][CH:5]=3)[N:20]2[S:17]([C:14]2[CH:13]=[CH:12][C:11]([CH3:21])=[CH:16][CH:15]=2)(=[O:18])=[O:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: COc1ccc([C@H]2[C@H](c3ccccc3)N2S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
4-Methoxybenzaldehyde (1.22 ml, 10 mmol) and p-toluenesulphonamide (1.71 g, 10 mmol) were refluxed in toluene (70 ml) for 5 minutes using a Dean and Stark apparatus. Reflux was maintained while BF3 (C2 H5)2O (0.05 ml, 0.4 mmol) was added via a syringe. The reaction mixture was maintained at reflux for 12 hours before being allowed to cool to room temperature whereby the title compound precipitated from the toluene. Filtration followed by recrystallisation from dichloromethane-petrol yielded N-(4-methoxybenzylidene)-toluene-p-sulphonamide as a yellow solid (0.478 g; 17%) m.p. 127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Br:14]N1C(=O)CCC1=O>C(#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(C)ccc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)c1cc(CBr)ccc1OC
Temperature: 25 °C
Yield: 44 %

Procedure:
Under a nitrogen atmosphere, methyl 2-methoxy-5-methylbenzoate (901 mg, 5 mmol) was dissolved in acetonitrile, and N-bromosuccinimide (890 mg, 5 mmol) and benzoyl peroxide (24 mg, 0.1 mmol) were added thereto. The mixture was refluxed for one hour. After the completion of the reaction was confirmed by HPLC, the reaction mixture was allowed to cool down to a room temperature, and the solvent was distilled off. Thereafter, the residue was dissolved in ethyl acetate. The organic layer was washed with water 3 times and then with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, and then the resulting residue was purified by flash column chromatography (Yamazen, Hi-Flash column, silica gel, hexane/ethyl acetate (volume ratio)=10:1) to give the title compound (570 mg, 44.0%) as an oily substance.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[CH2:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>C(O)C>[CH2:15]([C:19]1[CH:20]=[CH:21][C:22]([N:23]2[CH:10]=[C:11]([Cl:12])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1]2=[NH:2])=[CH:24][CH:25]=1)[CH2:16][CH2:17][CH3:18]
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CCCCc1ccc(N)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCc1ccc(-n2cc(Cl)cc(C(N)=O)c2=N)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.2 %

Procedure:
To a solution of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.5 g) in ethanol (10 ml) was added 4-butylaniline (0.95 g) (Table 1-2, amine 69), and the mixture was stirred at room temperature for 17 hr. Triethylamine (0.65 g) was added, and the mixture was further stirred at room temperature for 5 hr. The reaction mixture was concentrated and dissolved in a mixture of dimethyl sulfoxide (5 ml)-water (5 ml), and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, the residue was purified by preparative HPLC, and the obtained fraction was treated with PL-HCO3 MP (200 mg cartridge, Polymer Laboratories) to give the title compound (0.15 g). HPLC purity 94%. MS m/z 304 (M+H+).
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[Br:13]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:13][C:9]1[CH:8]=[CH:7][C:6]([OH:10])=[CH:5][C:4]=1[CH2:3][C:2]([OH:1])([CH3:12])[CH3:11]
Reactant: CC(C)(O)Cc1cccc(O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)Cc1cc(O)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Alcohol 29 (12.3 g, 74.2 mmol) is dissolved in dry DMF and cooled to 0° C. under N2. Solid N-bromosuccinimide (NBS, 14.77 g, 83.0 mmol) is added in small portions (the yellow color is allowed to dissipate between additions) over 1.5 h. After the addition is complete, stirring at 0° C. is continued for 30 min. The mixture is then poured into water and extracted with EtOAc (3×). The organic phase is washed with water (1×) and brine (1×), dried (MgSO4), filtered, and evaporated. The residue is dissolved in EtOAc/CH2Cl2 and diluted with hexane to afford 30 as white crystals, mp 139-141° C. (12.7 g, 70%). Concentration of the mother liquor gives two more crops (1.2 and 1.0 g) of crystals, bringing the total to 14.9 g (82%). 1H NMR (acetone-d6, 2.05 ppm) 8.43 (S,1), 7.34 (d, 1, J=8.7), 7.01 (d, 1, J=2.7), 6.64 (dd, 1, J=8.7, 2.8), 2.89 (s,2), 1.21 (s,6); 13C NMR (acetone-d6, 20.83 ppm) 147.90, 130.98, 124.56, 111.34, 107.05, 106.19, 62.35, 39.59, 20.76; MS (EI, eE=70 eV) m/z 246/244 (M+), 231/229, 201, 188/186, 163, 150, 131, 108, 107, 91, 77, 63, 59 (base peak), 51, 43; Anal. Calcd for C10H13BrO2 (MW=245.1) : C,49.00 H,5.35. Found: C,49.03 H,5.20.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.Cl.[C-:10]#[N:11].[K+]>O>[OH:8][C:5]1([C:10]#[N:11])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(=O)CC1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Product: CN1CCC(O)(C#N)CC1
Temperature: 10 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To freshly distilled 1-methylpiperidin-4-one (81.72 g, 0.72 mole) in water (200 cc), were added about 100 cc HCl 37% to pH 3. The reaction mixture was cooled in an ice bath and potassium cyanide (49 g, 0.75 mole) in water (200 cc) was added at an adequate rate in order to maintain an internal temperature of about 10° C. The reaction was stirred two hours more after the addition and then filtered. After washing with water and drying, the product, 4-hydroxy-4-cyano-1-methylpiperidine, was obtained in 67% yield as a white powder (67 g, 0.48 mole, mp. 135° C.).
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:13]([Si:15](OCC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH3:14]>O1CCCC1>[CH2:13]([Si:15]([NH:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH3:14]
Reactant: NC1CCCCC1
Reactant: CCO[Si](CC)(OCC)OCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCO[Si](CC)(NC1CCCCC1)OCC
Temperature: 70 °C
Yield: 83 %

Procedure:
Following the same general procedure described in Example 1, a 500 ml, four-necked flask fitted with a pressure equalizing funnel was charged with 0.5 mol of isopropylmagnesium chloride in 250 ml of tetrahydrofuran. Cyclohexylamine, 0.55 mol (52 g), was added over 30 minutes via a pressure equalizing funnel. The contents were refluxed for 15 minutes to complete the evolution of gas. Ethyltriethoxysilane, 0.5 mol (96 g) was added via the pressure equalizing funnel. The contents were refluxed at a pot temperature of 70° C. for two hours. Ethyl(cyclohexylamino)diethoxysilane was filtered under nitrogen atmosphere from the magnesium ethoxychloride. The filter cake was washed with ether (2×100 ml) to obtain the residual product. The solvent was removed via rotary evaporation. The residue was distilled under vacuum to yield 102 g of ethyl(cyclohexylamino)diethoxysilane as a colorless oil (purity>98%); bp 68° C./0.5 mm. The total yield was 83% of theoretical.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]([F:13])([F:12])C(O)=O.CN(C=O)C.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([OH:26])[CH:25]=1>O>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH:8]([F:12])[F:13])[CH:25]=1
Reactant: O=C(O)C(F)(F)Cl
Reactant: Oc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1cncc(Br)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Potassium carbonate (7.13 g) and chlorodifluoroacetic acid (1.75 ml) were added to a DMF solution (40 ml) of 3-bromo-5-hydroxypyridine (3.0 g). The temperature of the obtained mixture was heated to 100° C., and the mixture was then stirred for 24 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with diethyl ether. The organic layer was successively washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over magnesium sulfate, followed by filtration. The solvent was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:diethyl ether), so as to obtain the title compound (670 mg).
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[C:26]([Br:32])[C:25]=1[Cl:33]>>[Br:23][C:24]1[CH:29]=[C:28]([CH:27]=[C:26]([Br:32])[C:25]=1[Cl:33])[CH2:30][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: Clc1c(Br)cc(CBr)cc1Br
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: Cl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(Br)c(Cl)c(Br)c4)CC3)OC2=O)cc1

Procedure:
The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (100 mg, 0.306 mmol; Example 1, Step 2) and 1,3-dibromo-5-(bromomethyl)-2-chlorobenzene (122 mg, 0.337 mmol) following essentially the same procedure described in Step 1 of Example 7-9. The title compound was obtained as a white solid (175 mg) and was used without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[NH2:4].[CH3:12]OC(OC)OC>C(O)C>[O:1]1[CH:12]=[N:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)=[N:2]1
Reactant: COC(OC)OC
Reactant: NC(=NO)c1ccc(O)cc1
Solvent: CCO
Product: Oc1ccc(-c2ncon2)cc1

Procedure:
N′,4-Dihydroxybenzenecarboximidamide (1.28 g, 8.4 mmol) was suspended in 3 mL ethanol and 3 mL trimethylorthoformate in a 20 mL biotage microwave reaction tube. The mixture was sealed and microwaved at 150° C. for 10 min. The solvent was removed by concentration and the residue was purified by column chromatography eluting with 20% DCM/hexanes to give the desired product as white solid. LRMS calc: 162.0; obs: 163.2 (M+1).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:28])[C@@H:15]([O:24][CH:25]([CH3:27])[CH3:26])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)C1C=CC=CC=1.[OH:29]O.[OH-].[Li+].O>O1CCCC1>[OH:23][C:19]1[CH:18]=[C:17]([CH2:16][C@H:15]([O:24][CH:25]([CH3:26])[CH3:27])[C:14]([OH:28])=[O:29])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)O[C@@H](Cc1cccc(O)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)O[C@@H](Cc1cccc(O)c1)C(=O)O
Reaction time: 8 h

Procedure:
1.535 g of 4 (S)-Benzyl-3-[3-(3-hydroxyphenyl)-2 (S)-isopropoxypropionyl]oxazolidin-2-one was dissolved in 40 ml of tetrahydrofuran, and 3.3 ml of 30% aqueous hydrogen peroxide and 12 ml of 1N aqueous lithium hydroxide were successively added under ice-cooling, and stirring was continued at room temperature overnight. After adding water to the reaction solution, the mixture was extracted with dichloromethane and the aqueous layer was acidified by 1N hydrochloric acid. Following extraction (×3) was conducted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressures, to give 847 mg of 3-(3-hydroxyphenyl)-2(S)-isopropoxypropanoic acid. This product was then dissolved in 10 ml of N,N-dimethylformamide, and 400 mg of potassium hydrogencarbonate and 0.32 ml of ethyl iodide were successively added thereto, and stirring was continued at room temperature for 3 days. The reaction solution was diluted with ethylacetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 567 mg of the title compound as a colorless oil in the 3:1 hexane-ethyl acetate fraction.
Reaction SMILES: C(NC(=O)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3C[CH2:20][N:19]([C:22]([O:24][C:25](C)([CH3:27])C)=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)C.ClC1N=C(N2CCOC[C@@H]2C)C2CN(C(OCC)=O)CC=2N=1.[F:59]C1C=C(B2OC(C)(C)C(C)(C)O2)C=CC=1N>>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:27])=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:8][C:7]=1[F:59]
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: CCOC(=O)N1Cc2nc(-c3ccc(N)c(F)c3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 88 %

Procedure:
Method as described for intermediate 5 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The reaction mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and reduced in vacuo. The residue was purified by flash SCX2 chromatography affording the title compound (130 mg, 0.32 mmol, 88%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>>[Br:9][CH2:10][CH2:11][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCOc1ccc(I)cc1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
A mixture of 4-iodophenol (15.0 g, 68.2 mmol) and 1,2-dibromoethane (50 ml, 580 mmol) and potassium carbonate (14.0 g, 0.1 mol) was stirred and refluxed for 22 h. After cooling to r.t., the mixture was filtered, washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/ethyl acetate 40:1 to 20:1) to afford the title compound (18.7 g, 84%) as a white solid.