Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:7]([O:6][CH:5]([O:9][CH2:10][CH3:11])/[C:4](/[CH3:12])=[CH:3]/[CH2:2][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1)[CH3:8]
Reactant: CCOC(OCC)/C(C)=C/CBr
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(OCC)/C(C)=C/COc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
A mixture of 12.65 g of crude (E)-4-bromo-1,1-diethoxy-2-methyl-2-butene, 6.4 ml of m-methoxyphenol, and 8.1 anhydrous potassium carbonate in 100 ml sieve dried dimethylformamide is stirred at room temperature under nitrogen for about 43 hours and the reaction mixture diluted to 500 ml with water and extracted with a 300 ml and two 100 ml portions of hexane. The combined hexane extracts are washed with two portions of brine and dried with sodium sulfate. Concentration of the hexane extracts yields 6.45 g (E)-1,1-diethoxy-(4-m-methoxyphenoxy)-2-methyl-2-butene.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([NH:27][CH2:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:36])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].Cl>O1CCCC1.[OH-].[Li+]>[Cl:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:36])[C:29]=1[CH2:28][NH:27][CH:4]([CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8])[C:3]([OH:37])=[O:2]
Reactant: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NCc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CN(c2ccccc2)C2(CCN(C(=O)NCC(NCc3c(Cl)cccc3Cl)C(=O)O)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
To a solution of 132 mg (0.24 mmol) of 2-(2,6-dichlorobenzylamino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 3 ml of tetrahydrofuran, 2.6 ml of 0.1M aqueous lithium hydroxide solution was added, and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, 0.1M hydrochloric acid was added, and the resulting mixture was extracted with chloroform. Organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was reprecipitated from ether/chloroform to obtain 103 mg of 2-(2,6-dichlorobenzylamino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid (yield: 81%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[N:16][N:17]=2)=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[N:16][N:17]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2nnc(-c3ccc(OC)cc3)s2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(-c2nnc(-c3ccc(O)cc3)s2)cc1
Reaction time: 8 h

Procedure:
A 1M solution of boron tribromide in dichloromethane (100 cm3) is added dropwise to a solution of 2,5-bis(4-methoxyphenyl)-1,3,4-thiadiazole [J. prakt. Chem., (1 980) Vol. 322, pp. 933] (2.0 g) and dichloromethane (50 cm3) at 0° C. under an atmosphere of nitrogen. The reaction solution is stirred overnight and water (100 cm3) added. The organic layer is separated off and the aqueous layer extracted with dichloromethane (2×100 cm3). The combined organic layers are washed with brine (2×100 cm3) and then dried (MgSO4), filtered and evaporated down. The residue is purified by column chromatography on silica gel using a 9:1 hexanelethyl acetate mixture as eluent and recrystallisation from ethanol to yield 1.0 g of g 2,5-bis(4-hydroxyphenyl)-1,3,4-thiadiazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:29][C:28](=O)[CH:27]=[C:26]([O:31]C)[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:25][C:26](=[O:31])[CH:27]=[CH:28][CH2:29]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)C=C(OC)C2)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc(C2CC=CC(=O)C2)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a 0° C. solution of the title compound of Example 31, 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-methoxy-2-cyclohexen-1-one (500 mg, 1.15 mmole), in ether (20 ml) was added lithium aluminum hydride (20 mg, 0.53 mmole). The reaction mixture was stirred for 30 minutes at 0° C., acidified with 1 N hydrochloric acid and stirred for 2 hours at room temperature. The ether phase was removed, washed successively with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and evaporated. The crude oil was purified via column chromatography on 100 g of silica gel eluted with 50% ether-pentane to yield 353 mg (76%) of the title compound as an oil.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:14](I)[CH3:15]>C1COCC1>[CH2:14]([O:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[CH3:15]
Reactant: CCI
Reactant: OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
Sodium hydride (506 mg, 12.65 mmol) was added to a solution of 1,4-Dioxa-spiro[4.5]decan-8-ol (2 gm, 12.65 mmol) in dry THF (20 mL) at 0° C. After 15 minutes, ethyl iodide (2 gm, 12.65 mmol) was added and the mixture was allowed to stir at RT overnight. After removing the THF under reduced pressure, the mixture was poured into ice cold water and extracted into ethyl acetate. The crude product was purified by flash column chromatography (EtOAc:Hexane 5:95) to isolate the title compound (1.3 gm, 55%). 1H NMR (CDCl3, 500 MHz): δ 1.2 (t, 3H, J=7), 1.45-1.92 (m, 8H), 3.4 (m, 1H), 3.45 (m, 2H), 3.98 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[O:6][CH2:7][CH:8]([OH:11])[CH2:9][CH3:10].[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C.C(N(CC)CC)C.CCCCCC>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[O:6][CH2:7][CH:8]([O:11][C:25](=[O:26])[NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH3:10]
Reactant: CCC(O)COc1cccc(C(F)(F)F)c1
Reactant: O=C=NCc1ccccc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(COc1cccc(C(F)(F)F)c1)OC(=O)NCc1ccccc1
Reaction time: 20 h

Procedure:
4.7 g of 1-(3-trifluoromethylphenoxy)-butan-2-ol and 2.7 g of benzyl isocyanate are dissolved in 60 ml of ethyl acetate. After addition of one drop of triethylamine, the reaction mixture is allowed to stand for 20 hours at 22° C. The solvent is stripped off and the residue is stirred in n-hexane. The desired crystalline product, O--[1-(3-trifluoromethylphenoxy)-2-butyl]-N-benzylcarbamate, is obtained in a yield of 5.2 g; m.p. 73°-74° C.
Reaction SMILES: [Na].C([O:4][C:5]([C:7]1[C:8]([S:22][CH2:23][CH2:24]C(OCC)=O)=[N:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)=[O:6])C.ICC>CO>[CH2:23]([S:22][C:8]1[C:7]([C:5]([OH:6])=[O:4])=[C:16]([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:19])[F:20])=[CH:13][CH:14]=2)[N:9]=1)[CH3:24]
Reactant: CCOC(=O)CCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)OCC
Agent: [Na]
Solvent: CCI
Solvent: CO
Product: CCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
400 mg (17.4 mmol) sodium were added slowly to MeOH (50 ml) and the solution was stirred for 5 min at RT. Then a solution of 800 mg (2.0 mmol) 2-(3-ethoxy-3-oxopropylthio)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (precursor VVV07) in MeOH (10 ml) was added at RT. The reaction solution was then heated for 30 min at 70° C. After cooling to RT 488 μl (6.0 mmol) 1-iodethane were added and the mixture was stirred for 2 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with EE. It was washed with water and the aqueous phase was extracted with EE. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated to small volume under vacuum. 391 mg (1.2 mmol, 62%) 2-(ethylthio)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]1.C(O[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:34]([N:28]1[CH2:29][CH:10]2[CH:9]([C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12][C:11]2=[O:14])[CH2:27]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(c2ccccc2F)(c2ccccc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2ccccc2F)(c2ccccc2F)C2CN(Cc3ccccc3)CC12
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (3 drops) is added to a solution of 4,4-bis-(2-fluorophenyl)-cyclohexenone (4.3 g) and N-butoxymethyl-N-trimethylsilylmethylbenzylamine (5.8 cc) in dry dichloromethane (30 cc). The reaction mixture is brought to reflux and then stirred for 16 hours after having allowed the temperature to return to 25° C. N-Butoxymethyl-N-trimethylsilymethylbenzylamine (2.5 cc) and trifluoroacetic acid (3 drops) are added and the mixture is stirred for 3 hours under reflux. The reaction mixture is treated with potassium carbonate (3 g) and stirred for 15 minutes. After filtering and concentrating the filtrate to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 4 cm, height 32 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (85/15) and collecting 20 cc fractions. Fractions 13 to 22 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-bis-(2-fluorophenyl)-4-perhydroisoindolone (2.28 g). m.p.=138° C.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([CH3:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19][CH3:20])=[O:18])[CH2:8][NH:9]C(OC(C)(C)C)=O)=[O:5]>FC(F)(F)C(O)=O.ClCCl>[NH2:9][CH2:8][C@@H:7]([C:17]([O:19][CH3:20])=[O:18])[NH:6][C:4](=[O:5])[C:3]1[C:2]([CH3:1])=[CH:24][C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])=[CH:22][C:21]=1[CH3:36]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1C

Procedure:
A solution of crude N-[2,6-dimethyl-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester (144 mg, 0.235 mmol) in trifluoroacetic acid (2 mL) and dichloromethane (2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated and ethyl acetate was added. The solution was washed with saturated aqueous sodium hydrogen carbonate, and the aqueous layer was back-extracted seven times with ethyl acetate. The combined organic layers were dried (MgSO4), filtered, and evaporated to give crude 3-amino-N-[2,6-dimethyl-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester (104 mg, 110% of the theoretical amount).
Reaction SMILES: C([N:4]1[CH2:8][CH:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:6]([CH2:14][OH:15])[CH2:5]1)C=C.CC#N>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].O>[OH:15][CH2:14][CH:6]1[CH:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:8][NH:4][CH2:5]1
Reactant: C=CCN1CC(CO)C(c2ccsc2)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: OCC1CNCC1c1ccsc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 3.5 g (15.7 mmol) of 1-allyl-3-(SR)-hydroxymethyl-4-(RS)-(3-thienyl)pyrrolidine and 400 mg (0.43 mmol) of Wilkinson's catalyst [Rh(PPh3)3Cl] in 200 mL of an 85% solution of CH3CN and water was heated to 90° C. and stirred for 3 h. The reaction mixture was cooled to rt and concentrated to give the title compound which was used without further purification.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[CH2:44][O:45][CH3:46]>C1COCC1>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:44][O:45][CH3:46])[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COCCl
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCn1cc2cc(C)c(NC(=O)c3cc(OC)nn3-c3ncccc3Cl)c(C(=O)NC(C)C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (500 mg, 1.07 mmol) and diisopropylethylamine (225 μL, 1.2 mmol) in THF (10 mL) was treated dropwise with chloro-methoxy-methane (90 μL, 1.2 mmol). The resulting reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated in vacuo. Purification of the residue by flash-chromatography (SiO2, CH2Cl2/acetone 7:3) afforded the title compound as a colorless crystalline solid. M.p. 148° C., LC/MS:512/514 (M+H)+.
Reaction SMILES: NC1C=C(C=CC=1)O[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=O)[CH:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[C:26]([F:29])([F:28])[F:27].ClC1C=CN=C(C#N)C=1>>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:14])[CH:7]=2)=[CH:21][C:20]=1[C:26]([F:27])([F:28])[F:29]
Reactant: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Reactant: Nc1ccc(O)cc1C(F)(F)F
Agent: N#Cc1cc(Cl)ccn1
Product: N#Cc1cc(Oc2ccc(N)c(C(F)(F)F)c2)ccn1

Procedure:
This material is prepared by a method analogous to that described for preparation of 2C, starting from 4-amino-3-(trifluoromethyl) phenol and 4-chloro-2-cyanopyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([F:16])[C@@H:13]([OH:17])[C@H:12]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([Si:32]([CH3:35])([CH3:34])Cl)([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([F:16])[C@@H:13]([O:17][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:35])[CH3:34])[C@H:12]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1[C@H](O)[C@@H](F)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C[C@@H]1F
Temperature: 25 °C

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester (1.90 g, 5.09 mmol) in DMF (40 mL) were added tert-butyldimethylchlorosilane (0.844 g, 5.60 mmol), triethylamine (0.709 ml, 5.09 mmol) and DMAP (0.062 g, 0.509 mmol). The reaction mixture was stirred 25° C. for 1 week. Then quenched by addition of a saturated aqueous solution of NaHCO3. The layers were separated and the organic extract was dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 9:1). MS (UPLC): 588.4 [M+H]+, 505.5 [M+NH4]+, 510.4 [M+Na]+; tR (HPLC conditions f): 2.90 min.
Reaction SMILES: [NH2:1]/[C:2](=[N:33]\[OH:34])/[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.[C:35](OCC)(=[O:37])C.C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCCC1>[CH2:13]([C:8]1[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[C:6]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]3[NH:1][C:35](=[O:37])[O:34][N:33]=3)[CH:4]=2)[N:9]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(/C(N)=N/O)cc23)cc1
Reactant: CCOC(C)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4noc(=O)[nH]4)cc23)cc1
Yield: 90 %

Procedure:
To a solution of tert-butyl [6-[(Z)-amino(hydroxyimino)methyl]-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (0.25 g, 0.54 mmol) in tetrahydrofuran (10 ml)-ethyl acetate (10 ml) was added N,N-carbonyldiimidazole (0.26 g, 1.6 mmol), and the mixture was heated under reflux for 3 hrs. The reaction mixture was partitioned between ethyl acetate and 0.1M aqueous citric acid solution. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from n-hexane-ethyl acetate to give tert-butyl [2-isobutyl-4-(4-methylphenyl)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)quinolin-3-yl]methylcarbamate (0.24 g, yield 90%) as a white powder.
Reaction SMILES: [C:1]([NH:5][C@@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:26])[CH2:14][NH:15]C(=O)OCC2C=CC=CC=2)[C@H:8]([CH2:27][OH:28])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:15][CH2:14][C:13]([NH:12][C@H:9]1[CH2:10][CH2:11][C@@H:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:7][C@H:8]1[CH2:27][OH:28])=[O:26]
Reactant: CC(C)(C)N[C@@H]1CC[C@H](NC(=O)CNC(=O)OCc2ccccc2)[C@H](CO)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)N[C@@H]1CC[C@H](NC(=O)CN)[C@H](CO)C1

Procedure:
A solution of benzyl 2-((1S,2R,4R)-4-(tert-butylamino)-2-(hydroxymethyl)cyclohexylamino)-2-oxoethylcarbamate (4.0 g, 0.01 mol), in 30 mL of MeOH was treated with 0.5 g of 10% Pd/C and hydrogenated overnight at 55 psi. The mixture was filtered through Celite and concentrated on a rotary evaporator to give 2-amino-N-((1S,2R,4R)-4-(tert-butylamino)-2-(hydroxymethyl)cyclohexyl)acetamide as a white solid. This was used without further purification.
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:14]Br>C(Cl)Cl>[CH2:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([Br:14])[C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: BrBr
Reactant: O=C1CCCCCCCCCCC1
Solvent: ClCCl
Product: O=C1CCCCCCCCCCC1Br

Procedure:
reacting cyclododecanone with elemental bromine in boiling methylene chloride to form α-bromocyclododecanone;
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4]2([CH2:10][C@@H:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7]2)[O:3]1.[Cl:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:31]=[C:30]([N:6]2[CH2:5][C@:4]3([CH2:10][C@@H:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7]3)[O:3][C:2]2=[O:1])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC2(CNC(=O)O2)CN1C(=O)OC(C)(C)C
Reactant: Clc1cccc(Br)c1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)OC(C)(C)C
Yield: 21.7 %

Procedure:
Following the procedure from Example 1 step C using (8S)-di-tert-butyl 2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-7,8-dicarboxylate (2) (189 mg, 0.55 mmol, 1 eq.) and 3-chloro bromobenzene (60 μl, 0.55 mmol, 1 eq.) gave 54 mg (119) of (5R,8S)-di-tert-butyl 3-(3-chlorophenyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-7,8-dicarboxylate (A4). 1H NMR (300 MHz, DMSO) 7.68 (m, 1H), 7.55-7.38 (m, 2H), 7.2 (m, 1H), 4.38-4.28 (m, 1H), 4.2-4.05 (m, 2H), 3.75-3.6 (m, 2H), 2.7-2.4 (m, 2H), 1.4 (m, 18H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][C:12]2[N:16]([CH2:17][CH2:18][CH3:19])[CH:15]=[N:14][N:13]=2)=[N:8][CH:9]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][C:12]2[N:16]([CH2:17][CH2:18][CH3:19])[CH:15]=[N:14][N:13]=2)=[N:8][CH:9]=1
Reactant: CCCn1cnnc1CSc1ccc([N+](=O)[O-])cn1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCCn1cnnc1CSc1ccc(N)cn1
Yield: 92.4 %

Procedure:
5-nitro-2-(4-propyl-4H-1,2,4-triazol-3-yl)methylthiopyridine (4.0 g), reduced iron (4.0 g), and calcium chloride (0.79 g) was added to 85% aqueous solution of ethanol (100 ml), and the mixture was refluxed for 3 hours. The reaction solution was filtered with Celite, and the solvent of the filtrate was distilled off. The residue was purified by basic silica gel column chromatography (elution solvent: methanol/ethyl acetate), to give 5-amino-2-(4-propyl-4H-1,2,4-triazol-3-yl)methylthiopyridine (3.3 g) as red oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:14]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([CH2:25]Br)=[CH2:24]>CN(C)C=O>[Cl:12][C:13]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:14]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([CH2:25][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[CH2:24]
Reactant: C=C(CBr)c1ccccc1OCc1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(Cn1cncn1)c1ccccc1OCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
1,2,4-Triazole (59 mg, 0.854 mmole) and potassium carbonate (129 mg, 0.933 mmole) were suspended in dimethylformamide (1 ml) and a solution of 2-[2-(2,4-dichlorobenzyloxy)phenyl]-3-bromo-1-propene (290 mg, 0.779 mmole) in dimethylformamide (2 ml) was added dropwise to the suspension. Then, after stirring overnight at room temperature, the reaction mixture was worked up according to the same manner as in Example 25 to obtain the title compound (0.20 g, 71.2%). By comparing 1H-NMR and Rf value of TLC of the resulting compound with those of the product of the alternative process described in Example 34, it was confirmed that both chemical structures were identical with each other.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)[CH:6]=[CH:7][CH:8]=1)[CH3:2]>S1(CCCC1)(=O)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]2[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:11]=3[CH2:10][CH2:9][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cccc(CCc2cc(C)ccc2C(=O)O)c1
Solvent: O=S1(=O)CCCC1
Product: CCc1ccc2c(c1)CCc1cc(C)ccc1C2=O
Temperature: 130 °C

Procedure:
A mixture of the product from step (v) in polyphosphoric acid (40 g) and sulpholane (20 ml) was heated at 130° C. for 5 hours and partitioned between ethyl acetate and water. The organic phase was washed with aqueous sodium bicarbonate and water, dried (MgSO4) and evaporated. Purified by chromatography eluting with 5% ethyl acetate in isohexane.