Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)=[C:4]([CH3:15])[CH:3]=1.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1.BrC1C=CC(NC(=O)CC(N(C2CCCCC2)C(NC2CCCCC2)=O)=O)=C(C)C=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(Br)ccc1NC(=O)CC(=O)O
Reactant: Sc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1cc(Br)ccc1NC(=O)CC(=O)N(C(=O)NC1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1NC(=O)CC(=O)Sc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred mixture of 5.44 grams (0.02 mole) of 3-[(4-bromo-2-emthylphenyl)amino]-3-oxopropanoic acid prepared in Example V (Compound No. 97) and 2.31 grams (0.02 mole) of thiophenol in approximately 100 milliliters of dry tetrahydrofuran in an oven-dried reaction flask was fed a solution of 4.13 grams (0.02 mole) of 1,3-dicyclohexylcarbodiimide in about 25 milliliters of dry tetrahydrofuran, while cooling the reaction mixture in an ice-water bath. On completing the feed the ice bath was removed and the mixture stirred for about one hour following which the precipitated 1,3-dicyclohexylurea by-product (2.5 grams) was removed by filtration. Vacuum stripping the filtrate gave a solid which was recrystallized from acetone to give a compound, melting point 184° C.-187° C., which proved to be 1-(3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoyl)-1,3-dicyclohexylurea. The filtrate from this was concentrated and flash chromatographed (7:3 hexane:ethylacetate, silica column) to give 2.83 grams (0.008 mole) of S-phenyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanethioate having a melting point of 133° C.-135° C.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30](O)([C:38]1[C:39]([OH:47])=[CH:40][C:41]3[O:45][CH2:44][CH2:43][C:42]=3[CH:46]=1)[C:31](=[O:37])[NH:32]2>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:38]1[C:39]([OH:47])=[CH:40][C:41]3[O:45][CH2:44][CH2:43][C:42]=3[CH:46]=1)[C:31](=[O:37])[NH:32]2
Reactant: O=C1Nc2cccc(Br)c2C1(O)c1cc2c(cc1O)OCC2
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: O=C1Nc2cccc(Br)c2C1c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 4-bromo-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (62%) as a white solid: MS (ES+) m/z 346.5 (M+1), 348.5 (M+1).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].ClC(OCC)=O.[NH3:21]>C1COCC1>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C@H:11]1[C:12](=[O:14])[NH2:21])=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
TEA (10.4 mL, 74.5 mmol) was added to a 0° C. solution of Boc-L-azetidine-2-carboxylic acid (7.50 g, 37.3 mmol) in THF (85 mL) and the resulting mixture was stirred at 0° C. for 20 min, before ethyl chloroformate (3.82 mL, 39.1 mmol) was added (exotherm). The rxn mixture was stirred at 0° C. for 20 min, then 25% aq. NH3 (62.7 mL, 447 mmol) in THF (25 mL) was added and the resulting mixture was allowed to reach rt and stirring was continued at rt for 45 min. The mixture was concentrated in vacuo to remove the solvent, the residue was taken up in DCM and water, the org. layer was separated and the inorg. layer was extracted with DCM (2×). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo to yield the title compound C-1 as a white solid which was used further without purification. LC-MS A: tR=0.52 min; [M+H]+=201.27.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][C:11]([CH3:16])=[CH:12][C:13](Cl)=[O:14].O>C1COCC1>[CH3:10][C:11]([CH3:16])=[CH:12][C:13]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:14]
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 47 %

Procedure:
In a 100 mL round bottom flask was placed NaH (1.93 g, 0.05 mol). After washing with dry hexane (2×10 mL dry THF (15 mL) was added), to this tan solid. Then, the resulting suspension was added to a solution of aniline (Compound 36, 4.89 mL, 0.054 mol) in dry THF (7 mL) at 0° C. After stirring for 30 min, 3,3-dimethylacryloyl chloride (Compound 35, 6.56 mL, 0.059 mol) was added dropwise to the above solution. The reaction mixture was stirred under N2 for overnight followed by a slow addition of water. The mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with NH4Cl (sat.) and NaCl (sat.), dried over MgSO4 and concentrated to give the title compound as a tan solid (4.45 g, 51%). 1H NMR d 1.87 (s, 3H), 2.21 (s, 3H), 5.72 (s, 1H), 7.29-7.56 (m, 5H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:20]([C:27](O)=[O:28])[CH2:21][O:22][C:23]([CH3:26])([CH3:25])[CH3:24].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O>CN(C)C=O>[NH:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:20]([C:27]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:28])[CH2:21][O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(N)=O
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 8.90 g of H-Asn-Leu-OMe and 11.0 g of Z-Ser(tBu)-OH in 100 ml of freshly distilled dimethylformamide is cooled to 0° C. and mixed with 3.90 g of N-hydroxysuccinimide and 8.70 g of dicyclohexyl carbodiimide. After allowing the batch to stand for 30 minutes at 0° C. and then for 18 hours at 25° C. the precipitated dicyclohexylurea is suctioned off and the filtrate poured into 800 ml of ice water. The resulting crystalline precipitate is dried under vacuum at 40° C. and then recrystallized from aqueous methanol. The resulting analytically pure product - Z-Ser(tBu)-Asn-Leu-OMe -melts at 202°-205° C. Optical rotation [α]D20 =18° (c=1.05 in glacial acetic acid).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1.NN.CCCCCC>C(O)COCCO>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2ncccc21
Agent: NN
Solvent: CCCCCC
Solvent: OCCOCCO
Product: c1ccc2c(c1)Cc1cccnc1-2

Procedure:
Following the procedure described in Example 608, Part C, 3.45 g (19 mmole), of 4-azafluoren-9-one, 6.8 g (0.213 mole) of hydrazine in 50 ml of diethyleneglycol were combined and heated to 205° over a 30-minute period. TLC showed no remaining starting material. Identical workup yielded 2.33 g of pure 4-azafluorene, Rf-0.46 (hexane ethylacetatetriethylamine, 29.75:69.46:0.79).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=O)[C:8]3[C:13]([C:2]=12)=[CH:12][CH:11]=[CH:10][CH:9]=3.O.NN>C(O)COCCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[C:13]([C:2]=12)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1c2ccccc2-c2ncccc21
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: c1ccc2c(c1)Cc1cccnc1-2
Temperature: 170 °C
Yield: 80.7 %

Procedure:
A mixture of 18.1 g (100 mmol) of 5H-indeno[1,2-b]pyridin-5-one, 27 ml (400 mmol) of hydrazine monohydrate, and 500 ml diethylene glycol was degassed and placed under nitrogen, and then heated at 170° C. for 12 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed to give product 13.5 g (81%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[OH:5][CH:6]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1>C1(C)C=CC=CC=1.O1CCOCC1.N1C(C)=CC=CC=1C>[CH:18]([N:17]1[CH2:16][CH:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[O:5][C:1]1=[O:2])([CH3:20])[CH3:19]
Reactant: Cc1ccc(OCC(O)CNC(C)C)cn1
Reactant: O=C(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1ccc(OCC2CN(C(C)C)C(=O)O2)cn1

Procedure:
A solution of 10 g of phosgene in 40 ml of toluene is added dropwise at 5°-10° C. to 15.6 g of 3-(2'-hydroxy-3'-isopropylamino-propoxy)-6-methyl-pyridine, dissolved in 75 ml of dioxane, in the presence of 8 ml of 2,6-lutidine, whilst stirring. The reaction mixture is stirred overnight at room temperature and is then evaporated in vacuo. The evaporation residue is rendered alkaline with a little concentrated sodium hydroxide solution and is extracted with 200 ml of ethyl acetate. The organic phase is evaporated, initially at approx. 20 mm Hg and then at 0.01 mm Hg/60° C. bath temperature. Approx. 50 ml of ether are added to the residue which remains, giving crystalline 3-isopropyl-5-[(6-methylpyridin-3-yloxy)methyl]-oxazolidin-2-one of melting point 86°-88° C.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[ClH:18]>CC(C)=O>[ClH:18].[CH3:16][N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(N2CCN(C)CC2)cc1
Agent: Cl
Solvent: CC(C)=O
Product: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 2 °C

Procedure:
4-(4-Methyl-piperazin-1-yl)-benzoic acid methyl ester (8.5 mmol) is dissolved in 4N HCl (15 ml) and heated under reflux for 8 hours. The mixture is cooled in an ice bath to 0-4° C., diluted with 5 ml acetone and the solid material formed is filtered off, washed with acetone and dried (vacuum). A white powder with mp. >270° C., Rf=0.11 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([F:12])[CH:14]=2)[N:3]=1
Reactant: Nc1cccc(F)c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Product: Fc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1

Procedure:
This compound was prepared in a similar manner as described in example 2, by reaction of 2,6-dichloropurine with 3-fluoroaniline. The reaction mixture was then evaporated on a rotary vacuum evaporator and the residue was partitioned between ethyl acetate and 0.5 M HCl. The organic layer was washed with water, dried with MgSO4, and evaporated to give a yellow solid (3.72 g). The crude product was purified by flash chromatography. Yield: 2.20 g yellow crystalline powder. TLC (chloroform-methanol; 85:15): homogenous. HPLC purity: 98+%
Reaction SMILES: O[CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)[OH:4].C1OC(C(O)CO)[C@@H](O)C1O>>[CH2:11]1[O:12][C@@H:5]2[C@@H:3]([OH:4])[CH2:2][O:8][C@@H:7]2[C@@H:9]1[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: OCC(O)C1OCC(O)[C@@H]1O
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O

Procedure:
According to a preferable embodiment of the present invention, after converting hexitol as the hydrogenated sugar to anhydrosugar alcohol, the two-stage distillation of the resulting liquid of the converting step in the order of wiped-film distillation; and short-path distillation can provide highly pure anhydrosugar alcohol having purity of 98% or higher, a content of sorbitol and sorbitan isomer as impurities of less than 0.1% (more preferably, less than 0.05%) and improved color of pale yellow, with a distillation yield of 94% or higher (more preferably, 95% or higher), and subsequently conducting crystallization, decolorization by adsorbent and ion purification procedures, etc. can provide white isosorbide.
Reaction SMILES: Br[C:2]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:5]2=[CH:6][N:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([OH:10])=[C:4]2[C:3]=1Br>C(O)C.[Pd]>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:16]2[C:5]3=[CH:6][N:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([OH:10])=[C:4]3[CH:3]=[CH:2]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Reaction time: 23 h
Yield: 98 %

Procedure:
A suspension of ethyl 2,3-dibromo-1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (52.0 g, 0.110 mol) and 10% Pd/C (0.5 g) in ethanol (2.0 L) was shaken in a Parr shaker under hydrogen (39 psi) for 23 h. The catalyst was removed by filtration. On concentration of the filtrate, the product precipitated out. It was collected by filtration and dried under vacuum to provide the title compound. (34 g, 98% yield) 1H NMR (DMSO-d6) δ ppm. 11.66 (s, 1H), 8.89 (s, 1H), 8.14 (d, J=3.0 Hz, 1H) 7.37 (d, J=5.7 Hz, 2H), 7.19 (d, J=6.6 Hz, 2H), 7.11 (d, J=3.0 Hz, 1H), 5.71 (s, 2H), 4.45 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H). LC/MS (API-ES, M+H+): 315.1.
Reaction SMILES: [K+].[CH2:2]([N:9]([CH3:14])[CH2:10][C:11]([O-:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:15][CH2:16][CH2:17]O.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1>ClCCl>[Br:15][CH2:16][CH2:17][O:12][C:11](=[O:13])[CH2:10][N:9]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:14]
Reactant: CN(CC(=O)[O-])Cc1ccccc1
Reactant: OCCBr
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CC(=O)OCCBr)Cc1ccccc1
Temperature: 25 °C

Procedure:
N-Benzyl-N-methyl glycine potassium salt (2.00 g. 11.16 mmol) and 2-Bromo ethanol (2.48 g. 17.86 mmol) was suspended in 20 mL of dichloromethane. To this solution was added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.40 g. 33.5 mmol) and 4-dimethylamino)pyridine. (1.00 g.) and the reaction was stirred at 25° C. The mixture was diluted with 40 mL of dichloromethane, and was washed with water (1×60 mL), saturated sodium bicarbonate solution (2×60 and brine (1×60 mL). The organic phase was then dried over magnesium sulfate, and filtered through a pad of Celite. Evaporation of the solvent in vacuo affordedd an oil, which was purified on silica gel eluting with ethyl acetate to afford N-Benzyl-N-methyl glycine 2-bromoethyl ester as an oil (0.70 g. 27% yeild).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[N+:10]([O-])([OH:12])=[O:11]>ClC(Cl)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1ccc(O)cc1F
Reactant: O=[N+]([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
3-fluoro-4-methylphenol (3.66 g, 29.0 mmol) was dissolved in dichloroethane (32 mL) and tetrabutylammonium bromide (0.935 g, 2.90 mmol) was added. Nitric acid 70% (3.7 mL, 58 mmol) was diluted with water (33 mL) to make a 7% nitric acid solution. This solution was added to the reaction mixture which was then stirred at room temperature for 4 h at which time the reaction was judged complete by TLC. The reaction was poured into water and extracted with dichloromethane (3×). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was absorbed onto silica gel and purified by chromatography on SiO2 to give 5-fluoro-4-methyl-2-nitrophenol as a yellow solid (2.83 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (s, 1 H), 7.89 (d, J=8.1 Hz, 1 H), 6.85 (d, J=11.0 Hz, 1 H), 2.13 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:20])([CH3:19])[C:15](OC)=[O:16])[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:20])([CH3:19])[CH2:15][OH:16])[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 85.5 g of methyl 3-[3-tert-butoxycarbonyl-2,2-dimethyl-1,3-oxazolidine-4(S)-yl]-2,2-dimethyl-propionate in 300 ml of tetrahydrofuran is added to a suspension of 22 g of lithium aluminium hydride in 700 ml of tetrahydrofuran at -10° C. and the mixture is then stirred at 0° C. for 30 min. Thereafter, 22 ml of water, 22 ml of a 5N sodium hydroxide solution and 66 ml of water are added dropwise in succession at 0° C. and the mixture is subsequently stirred for 30 min. The suspension is filtered over Hyflo® and evaporated. After drying with sodium sulfate in methylene chloride, the title compound is obtained in the pure form: white crystals; mp. 45°-6° C.; Rf (A)=0.53, Rf (D)=0.18; [α]D =+52.8 (c=0.91 in CHCl3); FAB-MS: (M+H)+ =288; anal. calc. for C15H29NO4 : C 62.69%, H 10.17%, N 4.87%; found C 62.88%, H 10.11%, N 4.86%.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:10]=1>C(O)C.[Pd]>[CH3:5][C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:10]=1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cn(-c2ccc(N)cc2)cn1
Temperature: 25 °C
Yield: 90 %

Procedure:
Ammonium formate (2.202 g, 34.9 mmol) and palladium (10% w/w on carbon, 50% wet, 0.473 g, 4.44 mmol) were added to a solution of 4-methyl-1-(4-nitrophenyl)-1H-imidazole (for a preparation see intermediate 93) (4.73 g, 23.28 mmol) in ethanol (150 mL) and the resulting mixture was refluxed under nitrogen for 1 h then cooled to room temperature. An extra portion of ammonium formate (2.202 g, 34.9 mmol) was then added and the resulting mixture was refluxed for a further hour then cooled to room temperature and filtered through celite. Most of the solvent was removed in vacuo and the residue was loaded on a 50 g SCX column which was eluted with MeOH (5 CV) then with 2N NH3 in MeOH (5 CV). The ammonia fractions were combined and concentrated in vacuo to give 4-(4-methyl-1H-imidazol-1-yl)aniline (3.92 g, 21.06 mmol, 90%) as a yellow solid.
Reaction SMILES: C1C2=C3C(=CC=C2NC1)NC(C(OC)=O)=C3.[C:17]([O:21][C:22]([N:24]1[C:35]2[C:27](=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([C:36]([O:38]C)=[O:37])=[CH:29]3)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[C:35]2[C:27](=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([C:36]([OH:38])=[O:37])=[CH:29]3)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)OC(C)(C)C)CC3
Agent: COC(=O)c1cc2c3c(ccc2[nH]1)NCC3
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 215 %

Procedure:
A solution of 4 (16 mg, 0.015 mmol) and 5 (6.2 mg, 0.02 mmol) in DMF (2 mL) was treated with DIPEA (10 uL). The reaction mixture was stirred for 1 hr at 25° C. The final product was purified by Prep HPLC (SymmetrPrep C18, 7 μm, 19×150 mm column), eluted at 10 ml/min (0.01% TFA in water/acetonitrile) with a gradient: 10% acetonitrile in 5 min, 10% to 50% acetonitrile in 15 min, maintaining 50% acetonitrile in 5 min, 50% to 100% acetonitrile in 5 min, to obtain 6 (13 mg, 75%). MS: calcd for C51H55BrN10O9 (M+H) m/z 1031.33 found 1031.6.
Reaction SMILES: C([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)C.Cl.[Na]>O1CCCC1>[NH2:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][C:4](=[O:3])[CH2:5][CH2:6]2
Reactant: CCOC1=CCc2cccc(N)c2C1
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: Nc1cccc2c1CC(=O)CC2
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of (7-ethoxy-5,8-dihydronaphthalen-1-yl)amine (1.07 g, 5.65 mmol) in tetrahydrofuran (30 mL) was added solution of aqueous 2N HCl (10 mL), and stiired at 40° C. for 1 hour. The mixture was neutralized with addition of sodium bicorbonate, and the product was extracted with ethylacetate. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 8-amino-3,4-dihydronaphthalen-2(1H)-one (0.71 g, 78% yield).
Reaction SMILES: CC([O-])(C)C.[Na+].[C:7]1(Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:7]1([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1ccccc1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.6 %

Procedure:
In the drybox, 20.0 mg (0.087 mmol) of (Me2CH)PH(O)(2,4-(MeO)2C6H3) from Experiment 3, 20.0 mg (0.0218 mmol) of Pd2 (dba)3 and 3.0 mL of dioxane were loaded into a reactor (20 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature for 10 min. Next, 144 mg (1.5 mmol) of NaOtBu was added into the mixture above, followed by syringing 122 μl (1.2 mmol) of PhCl, and 100 μl (1.0 mmol) of piperidine into the reactor. The resulting mixture was refluxed for 8 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 59 mg (37% yield) of 1-phenylpiperidine. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ 7.15 (m, 2H), 6.84 (m, 2H), 6.72 (m, 1H), 3.06 (t, J=5.48 Hz, 4H), 1.61 (m, 4H), 1.48 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ 152.3, 129.0, 119.2, 116.5, 50.7, 25.9, 24.43 ppm. MS: Calcd for C11H15N(M+): 161.3. Found: 162.3 (M+ +H).