Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:14][CH2:15][O:16][C:17](C)=[O:18]>>[O:13]([C:2]1[S:3][CH:4]=[C:5]([C:17]([O:16][CH2:15][CH3:14])=[O:18])[N:6]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1nccs1
Reactant: Oc1ccccc1
Reactant: CCOC(C)=O
Product: CCOC(=O)c1csc(Oc2ccccc2)n1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
A mixture of the bromothiazole (1.03 g, 4.36 mmol) and phenol (10.0 g, 106 mmol) was stirred at 180° C. for 1 h, cooled to RT, diluted with 100 mL of EtOAc, washed with 1N NaOH (40×3), H2O, and brine, then dried over MgSO4, and concentrated in vacuo to yield a light yellow residue. Purification over silica gel (gradient, 5% to 10% EtOAc/hexanes) provided the title compound. MS m/z: 250 (M+H)++.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][NH:4][C:5](=[O:14])[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13].S(=O)(=O)(O)O.[CH3:20][N:21]([CH3:37])[C:22](=[O:36])[S:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.O>ClCCl>[CH3:20][N:21]([CH3:37])[C:22](=[O:36])[S:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([CH:3]([NH:4][C:5](=[O:14])[C:6]3[C:7]([F:13])=[CH:8][CH:9]=[CH:10][C:11]=3[F:12])[CH2:2][Cl:1])=[CH:34][CH:35]=2)=[CH:26][CH:25]=1
Reactant: O=C(NC=CCl)c1c(F)cccc1F
Reactant: CN(C)C(=O)Sc1ccc(-c2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)Sc1ccc(-c2ccc(C(CCl)NC(=O)c3c(F)cccc3F)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A solution of 1 g (4.59 mmol) N-(chloroethenyl)-2,6-difluorobenzamide in 2 mL of dichloromethane was added to 4 mL of concentrated sulfuric acid at 0° C. A portion of 1 g (3.89 mmol) of S-[1,1'-biphenyl]-4-yl dimethylcarbamothioate was added to the mixture and the mixture was stirred at 0° C. for 2 h. The mixture was stored in the refrigerator overnight. The mixture was poured into water (100 mL) and the mixture was filtered. The solid was washed with water (100 mL) and was dried overnight in vacuo at 70° C. to give the crude product 1.52 g (84% yield) as solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][NH:15][CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1.[CH:19](=O)[CH3:20].[BH4-].[Na+].Cl>CO.CCOCC.O1CCOCC1>[ClH:2].[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1
Reactant: CC=O
Reactant: CCc1cc(Cl)c2c(c1)[C@H]1CNC[C@@H]1NC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: CCc1cc(Cl)c2c(c1)[C@H]1CN(CC)C[C@@H]1NC2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 126.9 %

Procedure:
To a solution of (3aR,9bS)-6-chloro-8-ethyl-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-one hydrochloride (Example 29) (10 mg, 0.035 mmol) in 2 mL of methanol was added acetaldehyde (0.006 mL, 0.10 mmol) followed by sodium borohydride (7 mg, 0.17 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction was concentrated and the residue was purified (ISCO, elution with 0-15% methanol/methylene chloride) to afford the free base. To the free base in 1 mL of ether was added 4N HCl in dioxane (0.05 mL). The mixture was concentrated in vacuo, triturated with ether, and dried in vacuo to afford 7 mg (64%) of the title compound of Example 65 as an off-white solid. 1H NMR (CD3OD): 7.27 (s, 1H), 6.95 and 6.91 (s, 1H), 4.30-4.25 and 3.93-3.85 (m, 2H), 3.70-52 (overlapping m, 3H), 3.42-3.27 (overlapping m, 3H), 2.61 (q, 2H), 1.33 (q, 3H), 1.16 (t, 3H). LRMS (ESI): 279.2/281.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.[H-].[Na+].[N+](C1C=CC([O:19][C:20]([N:22]2[CH2:25][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[F:39])=[CH:29][N:28]=3)[CH2:23]2)=O)=CC=1)([O-])=O>CN(C=O)C>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:20]([N:22]2[CH2:23][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[F:39])=[CH:29][N:28]=3)[CH2:25]2)=[O:19])=[CH:3][N:2]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Reactant: Nc1ccnnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccnnc1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a solution of Pyridazin-4-ylamine (30 mg, 0.31 mmol, [Cas. No. 20744-39-2]) in DMF (3 mL) at 0° C. was added sodium hydride (20 mg, 0.5 mmol, 60% disp. in mineral oil). After stirring at 0° C. for 15 min. a solution of 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid 4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was added dropwise. After stirring for 16 hrs at ambient temperature the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed sequentially with sat. aqueous sodium hydrogen carbonate solution (2×50 mL) then sat. sodium chloride solution (50 mL). Mixture dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo and the residue was purified by preparative HPLC to give the title compound (15 mg, 16%)
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1.[C:11](OC=C)(=[O:13])[CH3:12]>O>[C:11]([O:10][CH2:9][C@H:8]1[O:1][CH:2]=[CH:3][C@@H:4]([OH:5])[C@H:6]1[OH:7])(=[O:13])[CH3:12]
Reactant: C=COC(C)=O
Reactant: OC[C@H]1OC=C[C@@H](O)[C@H]1O
Solvent: O
Product: CC(=O)OC[C@H]1OC=C[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.0 g (6.85 mmol) of galactal is dissolved in about 1 ml of water, and 1-4 g of crushed molecular sieves, 25-75 ml of vinyl acetate and 800 mg of lipase from Candida cylindracea (Sigma) are added. The mixture is stirred at room temperature for about 45 min. Drying, filtration, concentration in vacuo and chromatography on silica gel (ethyl acetate/hexane 1:1) or crystallization (from ethyl acetate/hexane) yields 1.090 to 1.160 (85-90%) of the desired 6-O-acetylgalactal.
Reaction SMILES: O[CH:2]([CH3:5])[CH2:3][NH2:4].[Cl-].ClC(C)C[NH3+].[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[NH:4][CH2:3][CH:2]([CH3:5])[S:24]1
Reactant: CC(O)CN
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: CC(Cl)C[NH3+]
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NCC(C)S1

Procedure:
2-Hydroxypropylamine was converted to 2-chloropropylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-chloropropylammonium chloride according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-5-methyl-1,3-thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to afford 2-(2-methyl-4-nitrophenylimino)-3-(2-methylprop-2-en-1-yl)-5-methyl-1,3-thiazolidine HBr salt.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][OH:22].C(N(CC)CC)C.O>O1CCCC1>[OH:22][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:7]([C:5]1[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:8]
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Reactant: Nc1ccccc1CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C(=O)Nc2ccccc2CO)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.6 %

Procedure:
A solution of 34.5 g (0.16 mols) 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride in 50 ml tetrahydrofuran is added dropwise at room temperature to a solution of 20.0 g (0.16 mols) 2-aminophenylmethanol and 36 ml (0.26 mols) triethylamine in 250 ml tetrahydrofuran. After the exotherm has subsided, the reaction is refluxed for 6 hours, then stirred at room temperature for another 48 hours. The reaction mixture is added to about 250 ml water, extracted with ethyl acetate, washed with 2 N hydrochloric acid gewaschen, dried over magnesium sulfate and concentrated tinder vacuum. Column chromatography (gradient cyclohexane/ethyl acetate) yielded 33.8 g (69% theoretical yield) of N-[2-(hydroxymethyl)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide [logP (pH 2.3)=1.55].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:11]3[C:10]([I:25])=[N:9]2)=[N:6][CH:7]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:30](C)=O.[Na+]>C1COCC1>[I:25][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH3:30])=[CH:7][N:6]=2)[N:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(I)nn2-c1ccc(N)cn1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1ccc(-n2nc(I)c3c(NC(=O)OC(C)(C)C)ncnc32)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
To a solution of tert-butyl 1-(5-aminopyridin-2-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (63) (1.1 g, 2.4 mmol) in dry THF (15 mL) was added HCHO (38% aqueous, 3.4 g, 3.6 mmol). The mixture was stirred at room temperature overnight and NaBH(OAc)3 (612 mg, 2.88 mmol) was introduced in several portions. The reaction mixture was stirred at room temperature for 5 h and then quenched with water (10 mL). The solvent was removed in vacuo. The residue was purified by column chromatography (silca gel, 0 to 10% ethyl acetate in dichloromethane) to provide tert-butyl 3-iodo-1-(5-(methylamino)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (64) (200 mg, 18%) as a yellow solid. LC-MS (ESI): m/z (M+1) 468.
Reaction SMILES: C(=O)([O-])[O-].[NH4+:5].[NH4+].[CH3:7][O:8][C:9](=[O:26])[CH:10]([CH:24]=O)[N:11]([CH:22]=O)[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>C1(C)C(C)=CC=CC=1>[CH3:7][O:8][C:9]([C:10]1[N:11]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:22]=[N:5][CH:24]=1)=[O:26]
Reactant: [NH4+]
Reactant: COC(=O)C(C=O)N(C=O)C1CCCc2ccccc21
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cncn1C1CCCc2ccccc21
Temperature: 70 °C

Procedure:
33.0 g of ammonium carbonate are added at room temperature to a solution of 15.5 g of N,α-bis-formyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)glycine methyl ester in 300 ml of xylene. The mixture is heated to 70° C. for 1 hour then the temperature is raised to 120° C. for 3 hours. After concentration the 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-5-imidazolecarboxylic acid methyl ester precipitates from the solution, having a melting point of 63° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[N:10].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1>[C:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[F:11])#[N:10]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1nn(C)c(N)c1C#N
Solvent: c1ccncc1
Product: Cc1nn(C)c(NC(=O)c2ccccc2F)c1C#N
Yield: 50 %

Procedure:
5-Amino-1,3-dimethyl-1H-pyrazole-4-carbonitrile (10 g, 73.4 mmole) was suspended in pyridine (90 ml) and 2-fluorobenzoyl chloride was added dropwise while cooling reaction mixture on an ice bath. Stirred reaction mixture overnight at room temperature. Removed most of the pyridine and added 100 ml cold water to precipitate the product. Isolated product by filtration, washed with cold water, small amount of cold ethanol and dried under vacuum to obtain 9.15 g product (yield: 50%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13]([OH:15])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.O[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=N1.Cl.C(N=C=NCCCN(C)C)C.C1(N)C=CC=CC=1N>CN(C)C=O.C(OCC)(=O)C>[NH2:29][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH:31][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][N:18]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC(=O)c1ccnc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54 %

Procedure:
A solution of 2-benzamidoisonicotinic acid (0.50 g, 2.06 mmol), N,N-diisopropylethylamine (1.10 mL, 6.32 mmol), 1-hydroxybenzotriazole (0.418 g, 3.09 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.59 g, 3.09 mmol) in N,N-dimethylformamide (25 mL) was stirred for 15 minutes at ambient temperature and 1,2-phenylenediamine (0.22 g, 2.06 mmol) was added. The resulting solution was stirred for 20 hours at ambient temperature, diluted with ethyl acetate (75 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to give N-(2-aminophenyl)-2-benzamidoisonicotinamide as an off-white solid (0.37 g, 53%): MS (ES+) m/z 333.5 (M+1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]([C:27]1[CH:31]=[CH:30][S:29][C:28]=1[CH:32]=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:32][C:28]2[S:29][CH:30]=[CH:31][C:27]=2[O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1sccc1Oc1ccccc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2sccc2Oc2ccccc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 76.3 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.25 g, 0.98 mmol) was reacted with 3-phenoxythiophene-2-carboxaldehyde (0.300 g, 1.47 mmol) in 4 mL of 4% KOH in EtOH for 3 hours at room temperature to afford 0.331 g (76%) of the title compound as an off-white solid, mp 135-137° C.: APCI-MS m/e 443.5 (M+ +1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[O:7][CH2:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@H:20]([CH3:28])[CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:15]([N+:29]([O-])=O)[CH:14]=1.C(N(CC)CC)C.C1C=CC(O[C:52](OC2C=CC=CC=2)=[N:53][C:54]#[N:55])=CC=1>O1CCCC1.C(O)(C)C.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[O:7][CH2:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@H:20]([CH3:28])[CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)/[C:52](=[N:53]/[C:54]#[N:55])/[NH:29][C:15]=2[CH:14]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: C[C@H](CN1CCOCC1)Nc1ccc(/C=C2\c3ccc(F)cc3COc3cc(F)ccc32)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C[C@H](CN1CCOCC1)n1/c(=N/C#N)[nH]c2cc(/C=C3\c4ccc(F)cc4COc4cc(F)ccc43)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.9 %

Procedure:
Dissolve (R)-[4-((E)-3,8-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-(1-methyl-2-morpholin-4-yl-ethyl)-amine (0.017 mol, 9.0 g) in tetrahydrofuran (35 mL) and isopropanol (90 mL). Add triethylamine (0.039 mol, 3.9) and 10% platinum on carbon (1.5 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 2 h. Filter off the catalyst through a plug of diatomaceous earth. Dilute the filtrate with dioxane (35 mL), add diphenyl N-cyanocarbonimidate (0.019 mol, 4.61 g) and stir at room temperature for 48 h. Concentrate the reaction mixture under reduced pressure. Purify on a silica gel column using 0.5% methanol in dichloromethane as eluent to obtain the title compound (6.0 g, 64%) as an off-white solid. LC-MS m/z 528.2 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:24]=[O:25].O>O1CCCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][C:9]1[C:10]([F:16])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:24]=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(C=O)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl-(2,4-difluoro-phenoxy)-dimethyl-silane (36, 5.90 g, 24.1 mmol) in tetrahydrofuran (100 mL), under an atmosphere of nitrogen, cooled in a −78° C. acetone/dry ice bath, was added n-butyllithium (2.50 M in hexane, 10.6 mL, 26.5 mmol) slowly. The reaction was allowed to stir for 1 hour, then N,N-dimethylformamide (2.24 mL, 29.0 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated The compound was isolated by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give a colorless oil (37, 5.0 g, 76.0%). MS(ESI) [M+H+]+=272.2.
Reaction SMILES: C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)O[CH2:3][C:4]1C=C[CH:7]=[CH:6][C:5]=1[N:10]=[N+:11]=[N-:12].[NH2:24][C@@H:25]([CH2:36][S:37][S:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(=O)(O)[O-].[Na+].[C:48]([O:51][CH2:52][CH3:53])(=[O:50])C>O1CCOCC1.O>[CH2:29]([NH:28][C:26](=[O:27])[C@@H:25]([NH:24][C:48](=[O:50])[O:51][CH2:52][C:53]1[CH:7]=[CH:6][C:5]([N:10]=[N+:11]=[N-:12])=[CH:4][CH:3]=1)[CH2:36][S:37][S:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)SSC[C@H](N)C(=O)NCc1ccccc1
Reactant: [N-]=[N+]=Nc1ccccc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)SSC[C@H](NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)NCc1ccccc1
Reaction time: 15.5 h
Yield: 65 %

Procedure:
2-Azidobenzyl (4-nitrophenyl) carbonate (168 mg, 0.534 mmol) was added to a suspension of (R)-2-amino-N-benzyl-3-(tert-butyldisulfanyl)propanamide (Compound tk93) (145 mg, 0.486 mmol) and sodium bicarbonate (102 mg, 1.215 mmol) in 1,4-dioxane (2 mL) at room temperature. The reaction mixture was stirred at the same temperature for 15.5 hours, followed by addition of ethyl acetate and water. The resulting mixture was extracted with ethyl acetate, and the organic phase was washed with water (5 mL×2) and brine (5 mL) and dried over sodium sulfate. Following concentration under reduced pressure, the resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) and then purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic-acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (R)-4-azidobenzyl (1-(benzylamino)-3-(tert-butyldisulfanyl)-1-oxopropan-2-yl)carbamate (Compound tk95) (148.9 mg, 65%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(OCC)(=O)C>[CH2:21]([O:20][C:18]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCC1CCCCN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCCCC1CCO
Reaction time: 2 h

Procedure:
To a solution of 2-piperidin-2-yl-ethanol (2.04 g in 50 mL methylene chloride) at 0° C. was added 2.64 mL of triethylamine and 5 mg N,N-dimethylaminopyridine. To the stirred solution, 2.45 mL of benzyl chloroformate was added dropwise and the reaction allowed to proceed at room temperature. After 2 hours, the mixture was diluted with ethyl acetate and washed sequentially with 10% aqueous sodium bisulfate, water and brine. The organic portion was dried over magnesium sulfate and purified by flash chromatography on silica gel (hexane:ethyl acetate, 70:30) to give the title compound (2.05 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.O[CH:13]([CH3:20])[C:14](=[CH2:19])[C:15]([O:17][CH3:18])=[O:16].[Cl-].[Na+]>ClCCl.ClC.CCCCCC>[Br:1][CH2:19][C:14](=[CH:13][CH3:20])[C:15]([O:17][CH3:18])=[O:16]
Reactant: C=C(C(=O)OC)C(C)O
Reactant: O=C1CCC(=O)N1Br
Agent: CCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CSC
Solvent: ClCCl
Solvent: CCCCCC
Product: CC=C(CBr)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
8.0 g (46 mmoles) of N-bromosuccinimide were dissolved in 60 ml of dry dichloromethane and were cooled to 0° C. To the mixture were added drop by drop 4 ml (50 mmoles) of dimethyl sulphide dissolved in 40 ml of chloromethane. The mixture was stirred for 10 minutes at 0° C. At the end of that time 5.46 (42 mmoles) of a solution of methyl 3-hydroxy-2-methylidene-butanoate in 40 ml of dichloromethane were slowly added to it. The resulting suspension was stirred for 24 hours at room temperature until a transparent solution was obtained. To this mixture was added n-hexane (100 ml) and it was poured into a separating funnel containing 200 ml of a saturated solution of sodium chloride and ice. The organic phase was washed with 100 ml of a saturated solution of sodium chloride. The aqueous phases were extracted with diethyl ether (2×100 ml), they were washed with water (3×100 ml) and they were dried over anhydrous sodium sulphate. They were vacuum concentrated giving 7.45 g (92% yield) of a syrupy liquid of methyl 2-bromomethyl-2-butanoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC12CC3(C45CC6(C)CC(C)(CC(C(Cl)=O)(C6)C4)C5)CC(C)(CC([C:34](Cl)=[O:35])(C3)C1)C2.[C:37](Cl)(=O)C1C=CC=CC=1.O>CN1CCCC1=O>[O:35]1[C:34]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[N:1]=[CH:37]1
Reactant: CC12CC3(C)CC(C(=O)Cl)(C1)CC(C14CC5(C)CC(C)(CC(C(=O)Cl)(C5)C1)C4)(C2)C3
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc2ocnc2c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
In a 2 L four-neck flask provided with a thermometer, a Dimroth condenser and an agitator, 64.8 g of 4,6-di(3,5-dimethyl-1-adamantyl)-1,3-bis(4-amino-3-hydroxyphenoxy)benzene (0.10 mol) obtained in Synthesis example 2 was dissolved in 800 g of dried N-methyl-2-pyrrolidone under nitrogen flow followed by the addition of 17.4 g of pyridine (0.22 mol). The mixture was heated to 60° C., then 42.8 g of 5,5′,7,7′-tetramethyl-1,1′-biadamantane-3,3′-dicarboxylic acid chloride (0.095 mol) was gradually added and then agitated at 60° C. for three hours. Then, 2.10 g of benzoic acid chloride (0.015 mol) was added with the inner temperature of the flask kept at 5° C. or below in an ice bath. A reaction solution was added to 4 L of distilled water in small droplets followed by collecting and drying precipitate, thus obtaining a benzoxazole resin precursor.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH2:6][CH2:5]2.CN(C)C=O.[Br:24]N1C(=O)CCC1=O>O>[Br:24][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([C@@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH2:8]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C2CCc3cc(O)ccc3C2)COC(=O)N1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1([C@H]2CCc3c(ccc(O)c3Br)C2)COC(=O)N1
Reaction time: 6 h
Yield: 95.8 %

Procedure:
To a mixture of 4-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (100 mg, 0.0004 mol) (pure isomer 2) in N,N-Dimethylformamide (0.5 mL, 0.006 mol) was added N-Bromosuccinimide (72.0 mg, 0.000404 mol) in N,N-Dimethylformamide (0.5 mL, 0.006 mol) and was stirred at for 6 hrs. Water was added, and the mixture was extracted with dichloromethane. The solvent was removed and residue was purified with Isco (12 g silica gel, 0-40% MeOH:DCM) to give a white precipitate (125 mg, 95% yield). 1H NMR showed a single isomer. The solid (10.1 mg) was dissolved in MeOH (3 mL) and the solvent allowed to evaporate slowly to give white needles, which was washed with MeOH and collected (5.0 mg). LCMS 1.23 min 328.21 ([M+2], 100%). X-ray shows (S,S) configuration, see FIG. 2.