Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@@:5]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])([C@H:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)(=O)C.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>ClCCl>[CH2:26]([NH:30][S:14]([C:12](=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)[CH3:13])(=[O:15])=[O:16])[CH2:27][CH2:28][CH3:29]
Reactant: CC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S(=O)(=O)Cl
Reactant: CCCCN
Solvent: ClCCl
Product: CCCCNS(=O)(=O)C(C)=C(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.33 h
Yield: 8.6 %

Procedure:
In dichloromethane (4 ml) was dissolved (2R,3R)-3-chlorosulfonyl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butyl acetate (125 mg). To the solution was added, under ice-cooling, n-butylamine (23 mg). The reaction mixture was stirred for 20 minutes under ice-cooling, which was concentrated. The concentrate was subjected to a silica gel chromatography (eluent: hexane/ethyl acetate=1/2→ethyl acetate) for purification to give, as the first eluate, N-butyl-3- (2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl) -2-butene-2-sulfonamide (isomer B, Compound 33, 10 mg) as a colorless oily substance, and, as the second eluate, N-butyl-3-(2,4-difluorophenyl)-4-(1H-1, 2,4-triazol-1-yl) -2-butene-2-sulfonamide (isomer A, Compound 32, 45 mg) as a colorless solid substance.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CN(C1C=CC=CN=1)C.Br[CH2:28][C:29](=[CH2:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[CH2:1]([O:17][CH2:35][C:29](=[CH2:28])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: C=C(CBr)C(=O)OCC
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=C(COCCCCCCCCCCCCCCCC)C(=O)OCC
Reaction time: 18 h
Yield: 261.3 %

Procedure:
To a stirred solution of 1.9 g of hexadecanol in 40 ml of methylene chloride containing 700 mg of dimethylaminopyridine is added 500 mg of ethyl 2-bromomethyl-2-propenoate followed by continued stirring for 18 hours. The solvent is evaporated to give 2.4 g of the desired product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:15][C:16]1[N:17]=[C:18]([NH2:22])[S:19][C:20]=1[CH3:21]>>[BrH:1].[O:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:17]3[C:16]([CH3:15])=[C:20]([CH3:21])[S:19][C:18]3=[NH:22])[C:14]=2[O:13][CH2:12][CH2:11]1
Reactant: BrCCOc1cccc2c1OCCO2
Reactant: Cc1nc(N)sc1C
Product: Br
Product: Cc1sc(=N)n(CCOc2cccc3c2OCCO3)c1C
Temperature: 85 °C
Yield: 11.9 %

Procedure:
A mixture of 5-(2-bromoethoxy)-2,3-dihydro-benzo[1,4]dioxine (1.2 g, 4.7 mmol) and 4,5-dimethyl-thiazol-2-ylamine (0.50 g, 3.9 mmol) was heated at 85° C. for 7 hours. The mixture was cooled to ambient temperature and the residue was recrystallized from ethanol to provide 0.18 g (13%) of the title compound.
Reaction SMILES: Br[CH:2]=[CH:3]Br.[Li]CCCC.[CH3:10][O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C@@H:21]([CH2:22][C:23](=[O:31])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3>C1COCC1.C(Cl)Cl>[C:2]([C@@:23]1([OH:31])[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:21]([CH2:20][CH2:19][C@@H:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:13]2([CH3:14])[C@H:15]3[CH2:16][CH2:17][C@@H:12]2[O:11][CH3:10])[CH2:22]1)#[CH:3]
Reactant: BrC=CBr
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
A solution of 1,2-dibromoethylene (1.6 mL, 3.7 g, 19.71 mmol) in dry THF (10 mL) was treated with n-BuLi (16.4 mL, 2.4M in THF, 39.4 mmol) at -75° C. After stirring the mixture at -78° C. for 0.25 hr, a solution of 17β-methoxy-5β-androstan-3-one (2 g, 6.57 mmol) in THF (20 mL) was added and the mixture was stirred at -78° C. for 15 min. The cooling bath was then removed and the mixture was quenched with NH4Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-ethynyl-3α-hydroxy-17β-methoxy-5β-androstane (1.70 g) as a colorless solid; mp 62-65° C.; TLC Rf (toluene:acetone 95:5)=0.23.
Reaction SMILES: [H-].[Na+].[CH2:3](P(=O)(OCC)OCC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH2:22][C:23]([O:29][CH3:30])([CH:26]=[CH:27][CH:28]=1)C=O.[CH3:32]N(C)C=O>>[CH3:18][O:19][C:20]([C:21]1[CH:28]=[C:27]([CH:32]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:26]=[C:23]([O:29][CH3:30])[CH:22]=1)=[O:31]
Reactant: CN(C)C=O
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: COC(=O)C1=CC=CC(C=O)(OC)C1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(C=Cc2ccccc2)cc(OC)c1
Reaction time: 1 h

Procedure:
To a slurry of 1.0 mole of sodium hydride in one liter of N,N-dimethylformamide is added 1.0 mole of diethyl benzylphosphonate. The reaction mixture is stirred for one hour and then a solution of 1.0 mole of 3-methoxyisophthalaldehydic acid methyl ester in a minimal amount of dimethylformamide is added. The reaction mixture is stirred for several hours and is then added to ether-water. The ether extract is washed several times with water, dried over magnesium sulfate and evaporated to a residue. The residue is purified via crystallization from hexane to yield 5-methoxy-3-stilbene carboxylic acid methyl ester. The free acid is obtained by refluxing a solution of 1.0 mole of the methyl ester in one liter of 1 N methanolic sodium hydroxide for 4-5 hours. The reaction mixture is evaporated to a residue which is added to ethyl acetate. The ethyl acetate solution is extracted with several portions of water. The combined aqueous extract is neutralized with 1 N hydrochloric acid and extracted with several portions of ethyl acetate. This organic extract is dried over magnesium sulfate and evaporated to a residue. The residue is purified by crystallization from hexane to yield 5-methoxy-3-stilbene carboxylic acid.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:1]1([CH:7]([NH:8][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=2)[C:9]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)=[N:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: NC(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCCC2)nc1
Temperature: 120 °C
Yield: 85.4 %

Procedure:
A mixture of crude (+/−)-1-cyclohexyl-1-{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methanamine (405 mg, 1.21 mmol), methyl 6-fluoronicotinate (225 mg, 1.45 mmol), and potassium carbonate (501 mg, 3.62 mmol) in N,N-dimethylformamide (4.2 ml) was heated to 120° C. for 12 hours. The reaction mixture was diluted with water to precipitate a crude solid that was collected by filtration. The crude material was purified via ISCO MPLC (SiO2, 0-50% ethyl acetate in heptane) to yield the product (0.486 g, 86%) as a solid. 1H NMR (400 MHz, CDCl3, δ): 8.78 (s, 2H), 8.70 (d, J=1.6 Hz, 1H), 8.55 (d, J=8.2 Hz, 2H), 7.94 (dd, J=8.8, 2.0 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 6.31 (d, J=8.8 Hz, 1H), 5.38 (d, J=7.0 Hz, 1H), 4.76 (t, J=6.9 Hz, 1H), 3.84 (s, 3H), 1.97 (d, J=12.5 Hz, 1H), 1.59-1.88 (m, 5H), 1.04-1.34 (m, 5H). MS (M+1): 471.2.
Reaction SMILES: [H-].[Na+].[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][OH:28])[N:24]=[CH:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:29]1[CH2:31][CH:30]1[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1>CN(C)C=O>[OH:29][CH:30]([C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1)[CH2:31][O:28][CH2:27][C:25]1[N:24]=[CH:23][N:22]([C:3]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:26]=1
Reactant: N#Cc1ccc(C2CO2)cc1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
20.0 mmol of sodium hydride (60% dispersion in paraffin) are added to a solution of 20.0 mmol of (1-trityl-1H-imidazol-4-yl)methanol [33769-07-02] in 120 ml of absolute N,N-dimethylformamide under argon. The mixture is heated at 100° C. for 1 hour and then cooled to 40° C. A solution of 20.0 mmol of 4-oxiranylbenzonitrile [52695-39-3] in 10 ml of absolute N,N-dimethylformamide is added dropwise at 35-40° C., and the reaction mixture is stirred at 40° C. for 15 minutes. The reaction mixture is cooled to room temperature, poured into ice-water and extracted with ethyl acetate. The combined organic phases are washed with water and brine, dried over sodium sulphate and evaporated. The title compound is obtained as a white solid from the residue by flash chromatography (SiO2 60F). Rf=0.29 (dichloromethane-methanol 95:5); Rt=4.26 (gradient I).
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=O.[C:39]([BH3-])#[N:40].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:40]([CH2:39][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)[CH2:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: [BH3-]C#N
Reactant: O=Cc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ccccn3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (52.0 mg) obtained in Example 47-3 was dissolved in methanol (1.6 ml) and then added with pyridine-2-aldehyde (15.9 mg) and sodium cyanoborohydride (15.6 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 14 hours. After completion of the reaction, the reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then separated and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (15.2 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([CH:7]([C:10]#[N:11])[C:8]#[N:9])([CH3:6])[CH3:5]>CCO>[CH:4]([C:7]1[C:10]([NH2:11])=[N:2][NH:3][C:8]=1[NH2:9])([CH3:6])[CH3:5]
Reactant: NN
Reactant: CC(C)C(C#N)C#N
Solvent: CCO
Solvent: O
Product: CC(C)c1c(N)n[nH]c1N
Temperature: 80 °C

Procedure:
Hydrazine monohydrate (2.05 mL, 42 mmol) was added to a solution of the product from Example 112A (1.16 g, 10.7 mmol) in EtOH (15 mL). The reaction flask was evacuated and purged with nitrogen (3 cycles), then heated at 80° C. for 22 hours. The yellow solution was cooled to room temperature and concentrated under vacuum. Toluene (8 mL) was added to the residue, and the mixture was concentrated under vacuum to remove excess hydrazine (repeated twice more) to provide the title compound. MS (ESI) m/z 141 (M+H)+.
Reaction SMILES: C([O:5][N:6]=[C:7]([C:9]1[N:10]=[CH:11][C:12]([NH:15][C:16](=[O:35])[C@@H:17]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[C:26]([Cl:34])[CH:25]=2)[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:13][CH:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:34][C:26]1[CH:25]=[C:24]([C@@H:17]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]([NH:15][C:12]2[CH:11]=[N:10][C:9](/[C:7](=[N:6]\[OH:5])/[CH3:8])=[CH:14][N:13]=2)=[O:35])[CH:29]=[CH:28][C:27]=1[S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC(=NOC(C)(C)C)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C/C(=N/O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
A solution of N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (195.5 mg, 0.38 mmol) in methylene chloride (1.4 mL) was treated with trifluoroacetic acid (2.8 mL). The resulting reaction mixture was stirred at 25° C. for 2 h, at which time, thin layer chromatography still indicated the presence of starting material. The reaction was then heated at 40° C. where it was stirred overnight. At this time, thin layer chromatography again still indicated the presence of starting material. The reaction mixture was then heated at 60° C. where it was stirred for a second night. The reaction mixture was then allowed cool to 25° C. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with a saturated aqueous sodium bicarbonate solution (2×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/2 ethyl acetate/hexanes) afforded the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(1(Z)-hydroxyimino-ethyl)-pyrazin-2-yl]-propionamide (110.0 mg, 63%) as an off-white powdery solid: mp 94.2–102.5° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H25ClN4O4S (M+H)+ 465.1358, found 465.1363.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:5](NN)=[N:6][C:7]([F:10])=[CH:8][CH:9]=1.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:5]1[C:4]([F:3])=[CH:9][CH:8]=[C:7]([F:10])[N:6]=1
Reactant: NNc1nc(F)ccc1F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(F)c(Br)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
Bromine (0.30 mL, 6 mmol) was added dropwise to a stirred solution of (3,6-difluoro-pyridin-2-yl)-hydrazine (435 mg, 3 mmol) in CHCl3 (6 mL) at room temperature. The mixture was stirred at 60° C. for 1 hour. The mixture was cooled at 0° C. and a saturated solution of NaHCO3 was added dropwise. DCM was added, the organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield 2-bromo-3,6-difluoro-pyridine (600 mg, 88% yield) as a dark oil.
Reaction SMILES: [C:1]1([CH:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13][C:12]2=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BrH:20].BrBr>C(O)C>[Br:20][C:11]1([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13][C:12]1=[O:19]
Reactant: O=C1NC(=O)C(c2cccc3ccccc23)C(=O)N1
Reactant: Br
Agent: BrBr
Solvent: CCO
Product: O=C1NC(=O)C(Br)(c2cccc3ccccc23)C(=O)N1
Temperature: 0 °C

Procedure:
A suspension of 5-naphtylbarbituric acid (0.2 g) in 1.5 ml of 95% ethanol, cooled at 0° C. and kept under stirring, is added dropwise with 48% hydrobromic acid (0.5 ml) and successively with 4.4 μl of bromine. After 4 hours under stirring at room temperature the solid is filtered and washed with water, then it is dried under vacuum at 40° C. overnight. 0.25 g of the product are obtained.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17]([N:19]1[CH2:27][CH2:26][CH2:25][C:21]2([NH:24][CH2:23][CH2:22]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[N:24]1([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[C:21]2([CH2:25][CH2:26][CH2:27][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20]2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN2)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC2(CCN2C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of benzyl chloroformate (0.148 mL, 1.039 mmol) in DCM (1 mL) was added to a mixture of tert-butyl-1,6-diazaspiro[3.5]nonane-6-carboxylate (200 mg, 0.866 mmol) and DIPEA (0.378 mL, 2.165 mmol) in DCM (3 mL) and the mixture was stirred at RT for 16 h. The solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (Silica gel column, 4 g, n-hexane/DCM from 20% to 100% DCM) to give the title product as a yellow resin. UPLC-MS (Condition 3) tR=1.21 min, m/z=361.1 [M+H]+.
Reaction SMILES: N1C=CN=C1.C[C@H]1[C@H](O)C(=O)OC[C@]23[C@H](O[C@H]4[C@]5(OC5)[C@]2(C)[C@@H](C4)[O:18][C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][C@H:11]([C@H:41](O)[CH3:42])OCC1)C=C(C)CC3.[Si](Cl)(C(C)(C)C)(C)C>CN(C)C=O>[C:16]([O-:18])(=[O:17])[CH3:15].[CH3:42][CH2:41][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC1=C[C@H]2O[C@@H]3C[C@H]4OC(=O)C=CC=C[C@H]([C@@H](C)O)OCC[C@@H](C)[C@H](O)C(=O)OC[C@@]2(CC1)[C@]4(C)[C@]31CO1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CC1=C[C@H]2O[C@@H]3C[C@H]4OC(=O)/C=C\C=C\[C@H]([C@@H](C)O)OCC[C@@H](C)[C@H](O)C(=O)OC[C@@]2(CC1)[C@]4(C)[C@]31CO1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)[O-]
Product: CCCCCC
Temperature: -5 °C

Procedure:
Preparation of 13'-O-tert-butyldimethylsilyl-Roridin A. 100 mg (1.47 mmol) of imidazole was added to a solution of 232 mg (0.436 mmol) of Roridin A in 3 ml of dry dimethylformamide. The mixture was cooled to -5° C. and then 72 mg (0.478 mmol) of tert-butyldimethylsilyl chloride (Aldrich Chemical Co.) was added. The resultant mixture was stirred at -5° C. to 5° C. for 4 hours and then concentrated. The residue was chromatographed on silica gel, eluting first with 30% ethyl acetate/hexane, next with 50% ethyl acetate/hexane and finally with 70% ethyl. acetate/hexane, to afford 137 mg of the product as a foamy white solid (49%): TLC-Rf 0.32 (30% ethyl acetate/hexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:33]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH:30][S:39]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)(=[O:41])=[O:40])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)N1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(NS(=O)(=O)N1CCOCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 65 %

Procedure:
A solution of the product from Example AI ([S-(R*,R*)]-2-(2-amino-4-methyl-pentanoylamino)-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (397 mg, 0.90 mmol), morpholine-4-sulphonyl chloride (334 mg, 1.8 mmol, prepared by the method of von Geldem, et al., J. Med. Chem., 1996;39:968-981), N,N-diisopropylethyl-amine (246 mg, 1.9 mmol), and DMAP (25 mg) in benzene (5 mL) was heated under reflux for 3 hours, then concentrated in vacuo and the residue dissolved in ethyl acetate, and washed with saturated NaHCO3 solution, water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The amber oil thus obtained was purified via flash chromatography (silica gel, 35% EtOAc/Hexane) to give 346 mg (65%) of the title compound as a yellow foam, mp=54-57° C.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[N:11][CH:12]=1)=[O:5].Cl[C:34]([C:36]1[CH:37]=[C:38]([CH:47]=[CH:48][CH:49]=1)[CH2:39][S:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[O:35].N1C=CC=CC=1>O1CCCC1.O>[N:27]1([C:24]2[CH:25]=[CH:26][C:2]([NH:1][C:34]([C:36]3[CH:37]=[C:38]([CH:47]=[CH:48][CH:49]=3)[CH2:39][S:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[O:35])=[C:3]([C:4](=[O:5])[NH:6][C:7]3[CH:8]=[N:9][C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=4)=[N:11][CH:12]=3)[CH:23]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed 2-amino-5-(piperidin-1-yl)-N-(2-(3-(trifluoromethyl)phenyl)pyrimidin-5-yl)benzamide (234 mg, 0.53 mmol, 1.00 equiv), tetrahydrofuran (5 mL), a solution of methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (145 mg, 0.53 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and pyridine (80 mg, 1.01 mmol, 2.00 equiv). The resulting solution was stirred for 4 h at room temperature. The reaction was diluted with 10 mL of water and then extracted with 2×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford 0.28 g (78%) of product as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:10]=1.[CH3:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH2:33].CC=CC1C=CC=CC=1>C(OCC)(=O)C.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:32]([CH3:33])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:14]=1
Reactant: C=C(C)c1ccccc1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Agent: CC(C)[O-]
Agent: CC=Cc1ccccc1
Agent: [Al+3]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3cc(C(C)(C)c4ccccc4)c(O)cc3O)n2)c(C)c1
Temperature: 175 °C
Yield: 67.7 %

Procedure:
To a 1 L three-necked, round-bottomed flask equipped with a magnetic stirrer, condenser, dropping funnel, thermometer, and a nitrogen atmosphere are charged 15.0 g (37.8 mmol) of 2-(2,4-dihydroxyphenyl)-4,6-bis-(2,4-dimethylphenyl)-s-triazine and 390 mg of aluminum isopropoxide. The mixture is heated to 175° C. and 4.47 g (37.9 mmol) of α-methylstyrene are added dropwise at a rate of one drop every two seconds. A total of six equivalents of or-methyl styrene are added in this fashion over a 4.5 hour period. After cooling to room temperature, the mixture is diluted with ethyl acetate, washed twice with water and once with brine, and is dried over anhydrous magnesium sulfate. Following filtration, the solvent is removed under reduced pressure to yield a yellow solid. The crude product is purified with medium pressure chromatography with 12% ethyl acetate/heptane to afford 13.2 g of the title compound as a yellow solid; mp 168°-170° C.