Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:13]Br>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:12][C:1]1[CH:2]=[CH:3][C:4]([C:7]2([C:10]#[N:11])[CH2:8][CH2:9]2)=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: Cc1ccc(C2(C#N)CC2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC1(c2ccc(CBr)cc2)CC1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
3.0 Grams (0.02 mole) of 1-p-tolylcyclopropane-1-carbonitrile and 0.1 g (0.0004 mole) of benzoyl peroxide were dissolved in 50 ml of carbon tetrachloride, and 3.2 g of bromine was added dropwise over 30 minutes under reflux. After completion of the addition, reaction was continued for further 30 minutes. After cooling the reaction solution, carbon tetrachloride was removed by evaporation to obtain 4.4 g of 1-(4-bromomethylphenyl)cyclopropane-1-carbonitrile.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=2)[O:16][CH2:15][C:14]1([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=1)[CH3:27])=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=2)[O:16][CH2:15][C:14]1([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:32][CH:33]=1)[CH3:27]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCOCCCCN=[N+]=[N-])cc1
Agent: [Pd]
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCOCCCCN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 183.5 %

Procedure:
The (3RS,4RS)-4-(9-azido-5-oxanonyl)-7-methoxymethoxy-3-(4-(methoxymethoxy)phenyl)-3-methylchroman (250 mg, 0.19 mmol) was dissolved in methanoltetrahydofura (1.8/0.2 mL). Palladium charchol (75 mg, 0.05 mmol) was added, and resulting mixture was stirred at rt under hydrogen for 2 h. The mixture solution was concentrated and filtered through silica gel to give 170 mg of crude product as a colorless oil.
Reaction SMILES: C1(C(=[N:14][C:15]2[N:20]=[CH:19][C:18]([CH:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])=O.[NH4+]>CO>[NH2:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]2[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N=C(c3ccccc3)c3ccccc3)nc2)C1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)nc2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(6-(diphenylmethyleneamino)pyridin-3-yl)morpholine-4-carboxylate (370 mg) in methanol (20 ml) was added ammonium formate (789 mg). The reaction mixture was degassed by bubbling argon into the mixture for several minutes. 10% Palladium on activated charcoal (44 mg) was then added and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was then filtered through celite and the filtrate was concentrated in vacuo. The residue was taken up in EtOAc and the mixture was washed sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: heptane/dichloromethane/MeOH) to afford tert-butyl (RS)-2-(6-aminopyridin-3-yl)morpholine-4-carboxylate (171 mg, 73%) as a light yellow oil. MS (ISP): 280.2 ([M+H]+).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].Cl>CC(O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCC(=O)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCC(O)c1ccc(CC(C)C)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 4'-isobutylvalerophenone in 2-propanol was added sodium borohydride, and the mixture was stirred at 50° C. for 5 hours. The reaction mixture was poured into ice water, acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to give the object compound.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:5]=1[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:25][CH3:26])=[C:14]([O:17]CC3C=CC=CC=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH3:27])([O-])=O.C(O)C.[ClH:39]>CO.[Pd]>[ClH:39].[ClH:39].[NH2:1][C:4]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:5]=1[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:25][CH3:26])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH3:27]
Reactant: COc1cc(CC2c3cc(OCc4ccccc4)c(OC)cc3CCN2C)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COc1cc2c(cc1O)C(Cc1cc(OC)c(OC)cc1N)N(C)CC2
Yield: 81 %

Procedure:
A mixture of 1-(2'-nitro-4',5'-dimethoxy-benzyl)-2-methyl-6-methoxy-7-benzyloxy-1,2,3,4-tetrahydroisoquinoline (1.50 g) in absolute methanol (100 ml) containing palladium-charcoal catalyst (5%, 0.45 g) was stirred under hydrogen until absorption ceased. The catalyst was filtered, washed with methanol and the filtrate evaporated to give an oil. Absolute ethanol (10 ml) was added followed by absolute ethanol saturated with hydrochloric acid gas (10 ml) to give 1-(2'-amino-4',5'-dimethoxybenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride (4g) as a white solid (1.18 g, 81%), mp 177°-178°. An analytical sample was evaporated by recrystallization from ethanol, mp 177°-179°.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][C:15]1[N:16]=[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:14][C:15]2[N:16]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: ClCc1nc(-c2ccccc2)oc1-c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2)oc1-c1ccccc1

Procedure:
A solution of potassium phthalimide (10 g, 54 mmoles) and 4-chloromethyl-2,5-diphenyloxazole (10.4 g, 40 mmoles) in 80 cc of dimethylformamide was heated at 100° C. for 2 hours. When the solution was cooled to room temperature 300 cc of water was added. The solution was extracted with chloroform several times. The combined chloroform solution was washed with 20-30 ml of 0.2N sodium hydroxide and finally with water. After drying over sodium sulfate the chloroform was concentrated. The product precipitated out.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32].[CH:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][C:42]=1[CH:51]=O.C(OCC)(=O)C>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32])=[CH:51]/[C:42]1[CH:43]=[CH:44][C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:41]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccc2ccccc2c1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 78.7 %

Procedure:
1,1,3,3-Tetramethylguanidine (50.5 μL, 0.40 mmol) was added to a solution of rac.-N-[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 130; 106.4 mg, 0.20 mmol) in tetrahydrofuran (1 mL) at −20° C. After 5 min, a solution of naphthalene-2-carboxaldehyde (31.4 mg, 0.20 mmol) in tetrahydrofuran (0.5 mL) was added. The solution was stirred at −20° C. for 1 h and then was stirred at room temperature for 4 h. Ethyl acetate (15 mL) was added and the solution was washed with 1N hydrochloric acid solution (10 mL) and brine (10 mL). The dried (MgSO4) organic phase was filtered, evaporated and the resulting residue was triturated with petroleum ether to furnish (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(naphthalen-2-yl)propenoic acid methyl ester (88 mg, 78% yield) as a yellow solid.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].[CH:9](OCC)=[S:10].[C-]#N.[Na+]>C(O)C>[CH2:7]([O:6][C:4]([C:3]1[N:1]=[CH:2][S:10][CH:9]=1)=[O:5])[CH3:8]
Reactant: CCOC=S
Reactant: [C-]#[N+]CC(=O)OCC
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cscn1
Temperature: 50 °C
Yield: 92 %

Procedure:
A solution of 4.52 g. (0.04 m) of ethyl isocyanoacetate and 3.60 g. (0.04 m) of ethyl thioformate in 15 ml. of absolute ethanol is added dropwise with vigorous stirring to a suspension of 0.25 g. of sodium cyanide in 10 ml. ethanol at 15° C. An exotherm developes during the addition and is moderated with ice-bath cooling. The reaction mixture is warmed at 50° C. for 30 minutes. The solvent is then removed in vacuo and the resulting residue extracted with several portions of hot hexane to give a 92% yield of 4-ethoxycarbonyl thiazole.
Reaction SMILES: B.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[CH3:23][C:24]([O:27][C:28](=[O:43])[NH:29][CH2:30][CH2:31][CH2:32][C:33]([C:35]1[C:36]([O:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:34])([CH3:26])[CH3:25].CO>O1CCCC1>[CH3:26][C:24]([O:27][C:28](=[O:43])[NH:29][CH2:30][CH2:31][CH2:32][CH:33]([OH:34])[C:35]1[C:36]([O:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=1)([CH3:23])[CH3:25]
Reactant: COc1ncccc1C(=O)CCCNC(=O)OC(C)(C)C
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: CO
Product: COc1ncccc1C(O)CCCNC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 14 h

Procedure:
Borane (0.7 ml, 1M in tetrahydrofuran) was added to a solution of (3aR)-tetrahydro-1-methyl-3,3-diphenyl-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (0.05 ml, 1M in toluene) in tetrahydrofuran (2 ml) at 0° C. A solution of the product from step (a) above (0.304 g) in tetrahydrofuran (3 ml) was added over 20 minutes and then stirred at 0° C. for 4hand at 20° C. for 14 h. Methanol was added and the solution was evaporated and the residue azeotroped with methanol. Purification by chromatography on silica eluting with petrol-ether gave the sub-title compound as a colourless oil (0.255 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:32][CH2:31][CH:27]([C:28]([NH2:30])=[O:29])[CH2:26][CH2:25]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([CH2:22][N:24]4[CH2:32][CH2:31][CH:27]([C:28]([NH2:30])=[O:29])[CH2:26][CH2:25]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC(=O)C1CCNCC1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: NC(=O)C1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 58.9 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 1.58 mmol), isonipecotamide (434 mg, 3.03 mmol), absolute ethanol (20 ml), activated 3 Å molecular sieves (500 mg), titanium (IV) isopropoxide (2.31 ml, 7.88 mmol) and STAB (2.84 g, 13.6 mmol) were reacted in accordance with the general procedure D. The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (97:2:1) to give the title compound as a colorless solid (400 mg, 59%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.85 (d, 2H), 5.45 (br s, 2H), 4.01 (t, 2H), 3.79-3.69 (m, 2H), 3.57-3.46 (m, 2H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.35 (s, 2H), 2.31 (br s, 1H), 2.14-1.72 (m, 14H), 1.67-1.51 (m, 4H).
Reaction SMILES: [Cl-].[Ti+4:2].[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4:7].[Cl-].[Cl-].[Cl-].N.C([OH:14])C>>[OH-:14].[Ti+4:2].[OH-:14].[OH-:14].[OH-:14].[OH-:14].[Zr+4:7].[OH-:14].[OH-:14].[OH-:14]
Reactant: CCO
Agent: [Ti+4]
Agent: [Zr+4]
Agent: N
Product: [OH-]

Procedure:
An equimolar solutions of titanium chloride (TiCl4) and zirconium chloride (ZrCl4) in anhydrous ethanol are mixed and treated with excess aqueous ammonia solution to obtain a co-precipitate of titanium hydroxide and zirconium hydroxide. After working up said co-precipitate in a manner similar in example 1 it is calcined at 500° C. to obtain a support which is then impregnated with an appropriate amount of aqueous nickel oxalate solution and dried at 90° C. so as to obtain a supported catalyst which contains 2% by weight of nickel catalyst. The supported catalyst is then divided into four equal portions which are all reduced in reactors with hydrogen at respectively 250° C., 300° C., 400° C. and 500° C. The supported catalysts thus reduced are then tested for their activity in the conversion of benzene under the following conditions:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:21]=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[OH:39].[F-].[Cs+]>COCCOC.CO>[OH:39][C:25]1[CH:26]=[CH:27][C:28]([C:2]2[CH:3]=[CH:4][C:5]3[C:11](=[O:12])[NH:10][C:9]4[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:8]=4[NH:7][C:6]=3[CH:21]=2)=[CH:29][C:24]=1[O:23][CH3:22]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: COC(=O)c1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1ccc2c(c1)NC(=O)c1ccc(-c3ccc(O)c(OC)c3)cc1N2
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A mixture of Example 1B (92 mg, 0.3 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (112 mg, 0.45 mmol), Pd(PCy3)2Cl2 (11 mg, 0.015 mmol), and CsF (144 mg, 0.9 mmol) in DME (20 mL) and methanol (10 mL) was heated to reflux for 16 hours, cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 95 mg (81%) of the desired product. MS (DCI) m/e 391 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.26 (s, 1H), 8.36 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.60 (d, J=2.2 Hz, 1H), 7.55 (dd, J=8.1, 1.9 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.17-7.19 (m, 2H), 7.06-7.09 (m, 2H), 6.87 (d, J=8.1 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Na+].C(=O)([O-])O.[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(NC1CC(C)(C)N([O])C(C)(C)C1)=O.O.C(OCC)(=O)C>[Cl:12][CH2:11][C:10](=[O:13])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CCl)COCc1ccccc1
Agent: CC(=O)NC1CC(C)(C)N([O])C(C)(C)C1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCl)COCc1ccccc1
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To the mixture consisting of 30 mmol (6.0 g) of 1-benzyloxy-3-chloro-2-propanol, 1.5 mmol (320 mg) of 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxyl, 33 mmol (3.4 g) of sodium bromide, 90 mmol (7.50 g) of sodium hydrogencarbonate, 75 ml of ethyl acetate and 35 ml of water was added dropwise 47 mmol (32 g) of sodium hypochlorite aqueous solution (1.5 mmol/g) under cooling with ice. Temperature of the reaction system was about 4° C. and pH was about 8.5. After the dropping was completed, stirring was further continued for 30 minute. Thereto was added 20 ml of a 5% sodium thiosulfate aqueous solution and the organic layer was separated. The organic layer was dried over sodium sulfate, filtered off and concentrated under reduced pressure to obtain a crude product. It was purified with silica gel column to obtain 4 g of 1-chloro-3-benzyloxy-2-propanon. The yield was 67%.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].N12CCCN=C1CCCCC2.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>C(#N)C>[NH2:1][C@@H:2]([CH2:3][CH2:4][O:5][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])[C:6]([OH:8])=[O:7]
Reactant: N[C@@H](CCO)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)OCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of L-Homoserine (1 g, 8.4 mmol) in acetonitrile (10 ml) at 0° C. was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.32 ml, 8.8 mmol). Tert-butyl-dimethyl-silyl chloride (1.33 g, 8.8 mmol) was then added portionwise over 5 minutes and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. A white precipitate had formed which was filtered off and washed with acetonitrile before drying under vacuum. The title compound was isolated as a white solid (1.8 g, 92%). 1H NMR (300 MHz, DMSO), δ: 7.50 (1H, bs), 3.70 (1H, m), 3.35 (4H, bm), 1.95 (1H, m), 1.70 (1H, m), 0.90 (9H, s), 0.10 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:11]3=[CH:20][C:21]([C:23]([O:25]C)=[O:24])=[CH:22][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)C>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:11]3=[CH:20][C:21]([C:23]([OH:25])=[O:24])=[CH:22][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(N3CCOCC3)nc(-c3ccc(N)cc3)nn2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(-c2nc(N3CCOCC3)c3cc(C(=O)O)cn3n2)cc1
Yield: 68.4 %

Procedure:
Compound 10a (14 mmol) was suspended in 150 mL of ethanol, and 30 mL of 2 M aqueous sodium hydroxide solution was added. The reaction mixture was refluxed to be a clear solution and the reaction was substantially completed. 2 mL of acetic acid was added. Most of the solvent was distilled off under reduced pressure, and the precipitates were filtered to give compound 11a (3.25 g, 68.5%). m.p.>300° C. 1H NMR (300 MHz, DMSO-d6): δ 7.91 (d, J=8.8 Hz, 2H), 7.71 (d, J=1.2 Hz, 1H), 6.99 (d, J=1.2 Hz, 1H), 6.59 (d, J=8.8 Hz, 2H), 5.49 (s, 2H), 4.02 (t, J=4.4 Hz, 4H), 3.77 (t, J=4.4 Hz, 4H). MS (EI) m/e (%): 339 (M+, 100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17]C(=O)C.O.[C:23]1(C)C=CC(S(O)(=O)=O)=C[CH:24]=1.CCOC(C)=O>CCO>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([O:12][CH2:23][CH3:24])[CH3:11])[C:7]([C:13]([F:14])([F:15])[F:16])=[CH:6][C:5]=1[NH2:17]
Reactant: COC(=O)c1cc(C(C)O)c(C(F)(F)F)cc1NC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(C)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 179 %

Procedure:
A solution of 2-acetylamino-5-(1-hydroxy-ethyl)-4-trifluoromethyl-benzoic acid methyl ester (500 mg, 1.64 mmol) in EtOH (5 mL) was treated with p-toluenesulfonic acid monohydrate (100 mg, 0.518 mmol) and stirred at r.t. for 5 d. The reaction mixture was taken into EtOAc and washed with sat. aq NaHCO3. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 5:1 hexanes/EtOAc) to give title product (270 mg, 57%) as colorless crystals. m.p.: 100-103° C., API-ES: m/z 292 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2].[CH:21](B(O)O)=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2]
Reactant: OB(O)C=Cc1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2nc(C(C)(C)C)sc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(C=Cc2ccccc2)c2nc(C(C)(C)C)sc2c1O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere 4-bromo-2-tert-butyl-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (300 mg, 0.835 mmol), styreneboronic acid (185 mg, 1.25 mmol), cesium carbonate (675 mg, 2.08 mmol), and tetrakis(triphenylphosphine)palladium(0)(143 mg, 0.12 mmol) were suspended in 4 mL of anhydrous 1,4 dioxane. The reaction was heated at reflux temperature for 18 h, then cooled to room temperature and diluted with ethyl acetate. The organic mixture was successively washed with water, saturated sodium bicarbonate, and brine solutions. The organic fractions were dried over anhydrous sodium sulfate and concentrated to a crude solid residue, which was then purified by column chromatography, eluting the desired product from silica gel with a gradient of 10-90% ethyl acetate in hexanes: 180 mg of a yellow oil. MS: (+) m/z 382.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][OH:14])=[CH:7][CH:6]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCO)cc1
Solvent: c1ccncc1
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
To a stirred solution of (R)-tert-butoxycarbonylamino-[4-(2-hydroxy-ethoxy)-phenyl]-acetic acid methyl ester (80 mg, 0.25 mmol) in pyridine (1.5 mL) was added methanesulfonyl chloride (0.023 mL, 0.30 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the crude product was purified by chromatography over silica gel eluted with 3:1 v/v hexanes/ethyl acetate to give (R)-tert-butoxycarbonylamino-[4-(2-methanesulfonyloxy-ethoxy)-phenyl]-acetic acid methyl ester (50 mg, 50% yield) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([NH2:13])=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[Br:1][C:2]1[C:11]2[CH2:10][N:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[C:5]2[NH:13][C:15](=[O:19])[C:16](=[O:17])[NH:14][C:4]=2[CH:3]=1
Reactant: O=C(O)C(=O)O
Reactant: CN1CCc2c(N)c(N)cc(Br)c2C1
Agent: Cl
Product: CN1CCc2c(c(Br)cc3[nH]c(=O)c(=O)[nH]c23)C1
Temperature: 25 °C
Yield: 24.1 %

Procedure:
A solution of the product from Example 13 (0.62 g, 2.56 mmol) and oxalic acid (0.23 g, 2.56 mmol) in 25 mL of 3N aqueous HCl solution were heated at reflux for 18 hours. The reaction mixture was cooled to room temperature and the solid which formed was collected by filtration and washed with cold water. The solid was recrystallized from hot water and dried under vacuum (100° C., P2O5) to give the title compound as a tan solid (0.191 g, 20%), mp=315-320° C. (dec.).