Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([BH2:7])([CH:4]([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:8]1[CH2:12][O:11][CH2:10][CH2:9]1>>[BH3:7].[CH2:8]1[CH2:12][O:11][CH2:10][CH2:9]1.[CH3:2][C:1](=[C:4]([CH3:6])[CH3:5])[CH3:3]
Reactant: BC(C)(C)C(C)C
Solvent: C1CCOC1
Product: B
Product: CC(C)=C(C)C

Procedure:
A 10 mL round-bottomed flask was charged with 5-carbon linked dimer alcohol (57 mg, 0.0885 mmol) in 1 mL of THF. To the reaction mixture was added thexylborane (0.8 mL, 3 eq.) 0.33M in THF solution obtained from BH3THF (1 eq) and 2,3-dimethyl-2-butene (2 eq) at 0° C. for 1 hr. The reaction mixture was stirred for 2 hr and then added 3 N NaOH (0.15 mL, 5 eq) and 30% H2O2 (0.15 mL, 5 eq). The reaction mixture was warmed to room temperature and then stirred for 12 hr. The reaction mixture was quenched with H2O, extracted with EtOAc, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (EtOAc/Hexane=3/1) to give 39.2 mg in 65% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:12][C:13]([CH2:16][OH:17])=[N:14][CH:15]=1.[CH:23]1([CH:26]([C:33]2[CH:38]=[C:37](O)[N:36]=[CH:35][N:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:23]1([CH:26]([C:33]2[CH:38]=[C:37]([O:17][CH2:16][C:13]3[CH:12]=[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[CH:15][N:14]=3)[N:36]=[CH:35][N:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1
Reactant: COc1ccc(F)c(-c2cnc(CO)cc2OCC(C)C)c1
Reactant: CCOC(=O)CC(c1cc(O)ncn1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)CC(c1cc(OCc2cc(OCC(C)C)c(-c3cc(OC)ccc3F)cn2)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of (5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyridin-2-yl)methanol (200 mg) and ethyl 3-cyclopropyl-3-(6-hydroxypyrimidin-4-yl)propanoate (155 mg) in toluene (9.4 mL) were added 1,1′-(azodicarbonyl)dipiperidine (264 mg) and tributylphosphine (261 μL), and the mixture was stirred at room temperature for 24 hr. Hexane/ethyl acetate (1:1) was added to the reaction mixture, the resulting precipitate was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (78 mg) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=1)[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=O)(=[O:5])=[O:4].Cl.[NH2:25][OH:26]>C(O)C>[CH3:1][N:2]([CH3:23])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=1)/[C:10](=[N:25]/[OH:26])/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:5])=[O:4]
Reactant: COc1ccc(C(=O)c2cccc(NS(=O)(=O)N(C)C)c2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1ccc(/C(=N\O)c2cccc(NS(=O)(=O)N(C)C)c2)cc1
Yield: 17.3 %

Procedure:
To a solution of 3-[N-(dimethylaminosulfonyl)-amino]-4'-methoxybenzophenone (9 g) in ethanol (180 ml) is added hydroxylamine hydrochloride (11.23 g), and the resultant mixture is refluxed for 7 hours. The reaction mixture is concentrated in vacuum, and the residue is basified with aqueous sodium hydrogencarbonate and shaken with methylene chloride. The methylene chloride layer is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is chromatographed on a column of silica gel, which is eluted with 20% methanolmethylene chloride. The eluate is concentrated in vacuum to give a crystalline product, which is washed with hot isopropyl ether to give a mixture of (Z)- and (E)-isomers (8.5 g). The mixture is crystallized from ethyl acetateisopropyl ether to give (E)-3-[N-(dimethylaminosulfonyl)-amino]-4'-methoxybenzophenone oxime (1.63 g) as crystals melting at 162° to 164° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].C1OCCOCCOCCOCCOCCOC1.C([N-:32]C=O)=O.[Na+].Cl>C(#N)C.O.C(O)C>[ClH:11].[NH2:32][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C[N-]C=O
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: NCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-bromo-4'-chloroacetophenone (10.34 g, 43.40 mmol) and 18-crown-6 (1.16 g, 4.34 mmol) in acetonitrile (150 mL) at room temperature (RT) is added sodium diformylamide (12.51 g, 131.6 mmol). After 3 h at RT and 2 h at 40° C., the suspension is diluted with water (100 mL) and extracted with ethyl acetate (4×150 mL). The combined organics are washed with brine, dried (magnesium sulfate), and concentrated to afford waxy yellow solids. These are taken up in absolute ethanol (150 mL), the stirred solution is treated with concentrated hydrochloric acid (15.00 mL, 174 mmol), and the mixture is heated to reflux for 1.5 h. The suspension is cooled to RT, filtered, and the solids are washed with ethyl acetate. Drying in vacuo at RT afforded the title compound as white solids.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:18]=1[O:25][CH3:26])(=[O:16])=[O:15].[C:27]([N:46]1[C:50]([CH2:51][C:52](O)=[O:53])=[N:49][N:48]=[N:47]1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:23]([C:21]1[CH:20]=[CH:19][C:18]([O:25][CH3:26])=[C:17]([S:14]([NH:13][CH2:12][CH2:11][C:3]2[CH:4]=[CH:5][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]=2[NH:1][C:52](=[O:53])[CH2:51][C:50]2[N:46]([C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:47]=[N:48][N:49]=2)(=[O:16])=[O:15])[CH:22]=1)#[N:24]
Reactant: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1N
Reactant: O=C(O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1NC(=O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.2 %

Procedure:
To a stirred solution of 0.30 g of N-[2-(2-amino-4-isopropylphenyl)ethyl]-5-cyano-2-methoxybezenesulfonamide, 0.298 g of (1-trityl-1H-tetrazol-5-yl)acetic acid and 0.129 g of 1-hydroxybenzotriazole monohydrate in 2.4 mL of N,N-dimethylformamide was added 0.140 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride under ice-cooling, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, water, and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.549 g of N-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]-2-(1-trityl-1H-tetrazol-5-yl)acetamide.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][S:8][CH2:9]Cl.C(N(CC)CC)C>>[C:1]([O:6][CH2:7][S:8][CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: CSCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting butyric acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 71°-73° C./12 mm Hg, nD20 1.4521.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[O:18][CH3:19])=[C:15]([CH2:20][CH3:21])[CH:14]=[C:13]([C:22]([O:24]CC)=[O:23])[C:12]3=[O:27])[CH2:3]1.[OH-].[Li+].C(O)(=O)C>O.C1COCC1>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[O:18][CH3:19])=[C:15]([CH2:20][CH3:21])[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12]3=[O:27])[CH2:3]1
Reactant: CCOC(=O)c1cc(CC)c2c(OC)c(N3CCCC(N)C3)ccn2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)c(=O)n2ccc(N3CCCC(N)C3)c(OC)c12
Temperature: 60 °C
Reaction time: 96 h

Procedure:
8-(3-aminopiperidinyl)-1-ethyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylic acid, ethyl ester (0.028 g) is dissolved in 9 ml of a 2/1 mixture of water and THF and lithium hydroxide (0.035 g) is added. The resulting solution is stirred at 60° C. for 4 days and the solution adjusted to pH 7.2 by addition of acetic acid. The title compound is collected by filtration of the precipitate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:12]([O:14]C)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:12]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:14]
Reactant: COC(=O)c1nnc2ccccc2c1O
Reactant: Nc1ccccn1
Product: O=C(Nc1ccccn1)c1nnc2ccccc2c1O
Temperature: 150 °C
Reaction time: 10 h

Procedure:
4-Hydroxy-cinnoline-3-carboxylic acid, methyl ester (6 g), prepared accoring to J. Chem. Soc. 687 (1968), is reacted with 2-aminopyridine (16.6 g, stepwise added) in polyphosphoric acid (300 g:160 g of H3PO4 and 140 g of P2O5) under stirring at 150° C. for 10 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate is filtered and washed with water. Crystallization from dimethylformamide gives 4.9 g of 4-hydroxy-N-(2-pyridyl)-cinnoline-3-carboxamide, m.p. 341°-343° C.
Reaction SMILES: Br.Br[CH2:3][CH2:4][CH2:5][NH2:6].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][N:33]=[C:34]=[S:35])[CH2:27][CH2:26]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-:37].[Na+].[Na+]>O1CCCC1>[OH2:37].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][NH:33][C:34]3[S:35][CH2:3][CH2:4][CH2:5][N:6]=3)[CH2:29][CH2:30]2)=[CH:10][CH:9]=1
Reactant: NCCCBr
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Agent: Br
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCNC4=NCCCS4)CC3)nc3ccccc32)cc1
Product: O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.2 parts of 3-bromo-1-propanamine hydrobromide, 4.1 parts of 1-[(4-fluorophenyl)methyl]-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine, 2.2 parts of sodium carbonate and 135 parts of tetrahydrofuran was stirred overnight at room temperature. The reaction mixture was further stirred and refluxed for 3 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.5 parts of 1-[(4-fluoro-phenyl)methyl]-N-[1-[2-[(5,6-dihydro-4H-1,3-thiazin-2-yl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine monohydrate; mp. 121.4° C. (compound 117).
Reaction SMILES: C(Cl)(Cl)Cl.[CH:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][C:18](=[O:20])[C:17]([C:21](=O)[CH2:22][CH3:23])=[C:16]([OH:25])[CH2:15]2)=[CH:10][CH:9]=1)=[O:6].[CH2:26]([O:28][NH2:29])[CH3:27]>C(O)C>[CH2:26]([O:28][N:29]=[C:21]([C:17]1[C:18](=[O:20])[CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][CH:5]=[O:6])=[CH:9][CH:10]=2)[CH2:15][C:16]=1[OH:25])[CH2:22][CH3:23])[CH3:27]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NC=O)cc2)CC1=O
Reactant: CCON
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc(NC=O)cc2)CC1=O
Reaction time: 3 h
Yield: 66.9 %

Procedure:
Into 25 ml of chloroform was dissolved 1.3 g of 5-(4-formamidophenyl)-3-hydroxy-2-propionyl-2-cyclohexen-1-one and to the solution was added 1.0 g of ethoxyamine and 5 ml og ethanol. The mixture was kept for 3 hours in a water bath having 40° C. and the reacting solution was washed with a dilute hydrochoric acid solution and water. The solution was extracted with 15 ml of aqueous solution containing 5% of sodium hydroxide and to the alkaline solution was added a dilute hydrochloric acid solution and the crystal sedimented was extracted with chloroform. The solution was washed with water and to the solution was added anhydrous magnesium sulfate and a small amount of active carbon. And then, the mixture was agitated and filtered and the filtrate solution was concentrated. Ethyl ether was added in the residue and the crystal sedimented was collected with a filtering step and 1.0 g of desired compound was obtained. It was in the form of colorless crystals having a melting point of 111°-113.5° C.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[C:13]([CH:15]=[C:16]([O-])[CH3:17])#[N:14].[Na+].[NH2:20][C:21]1[C:26]([CH3:27])=[CH:25][NH:24][C:23](=[O:28])[CH:22]=1.C(O)(=O)C>CC(O)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:22]3[C:23](=[O:28])[NH:24][CH:25]=[C:26]([CH3:27])[C:21]=3[NH:20][C:16]([CH3:17])=[C:15]2[C:13]#[N:14])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: Cc1c[nH]c(=O)cc1N
Reactant: COc1cc(C#N)ccc1C=O
Reactant: CC([O-])=CC#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1cc(C#N)ccc1C1C(C#N)=C(C)Nc2c(C)c[nH]c(=O)c21

Procedure:
1773 mg (11.0 mmol) of 4-formyl-3-methoxybenzonitrile are dissolved with 1156 mg (11.0 mmol) of sodium 1-cyanoprop-1-en-2-olate, 1366 mg (11.0 mmol) of 4-amino-5-methylpyridin-2(1H)-one [Bisagni, E., Hung, N. C., Synthesis, 765-766 (1984)] and 945 μl (16.5 mmol) of acetic acid in 50 ml of 2-propanol and heated at the reflux temperature under argon for 20 h. After cooling, the reaction mixture is filtered and the precipitate is washed with 2-propanol and diethyl ether. The crude product is dissolved in 800 ml of dichloromethane/methanol by heating and, after addition of 500 ml of ethyl acetate, again concentrated to a volume of 50 ml. The precipitated product is filtered off and washed with ethyl acetate and diethyl ether. Drying under high vacuum results in 3.63 g (99% of theory) of the title compound in the form of yellowish crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.Cl[C:11]1C(F)=CC=C(F)[C:12]=1CN.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:30]([F:33])([F:32])[F:31])=[C:26]([CH:29]=1)[CH2:27][NH2:28]>>[Br:9][C:5]1[N:6]=[C:7]2[N:28]([CH2:27][C:26]3[CH:29]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=3[C:30]([F:31])([F:32])[F:33])[CH2:11][CH2:12][NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NCc1cc(Cl)ccc1C(F)(F)F
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1c(F)ccc(F)c1Cl
Product: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(Br)nc21

Procedure:
7-bromo-1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine was prepared as described in Example 1 from 2-amino-3,5-dibromopyrazine as described in Example 1 by replacing 2-chloro-3,6-difluorobenzylamine in step 1 with 5-chloro-2-trifluoromethyl-benzylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C:11]2([O:15][C:14](=[O:16])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[N:25][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C:11]2([O:15][C:14](=[O:16])[N:13]([C:21]3[CH:26]=[N:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC1)CNC(=O)O2
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CC(C)(C)OC(=O)N1CCCC2(CC1)CN(c1ccc([N+](=O)[O-])nc1)C(=O)O2
Yield: 92.4 %

Procedure:
Following general N—C coupling procedure 1, 2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester (0.510 g, 1.887 mmol) (Reference: German Patent DE10 2005 030051A1 (Dec. 28, 2006)) was combined with 5-bromo-2-nitropyridine (0.400 g, 1.971 mmol, 1.05 eq) which gave 3-(6-Nitro-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester as a brown solid (0.684 g, 1.743 mmol) in 92% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (br. s., 9H) 1.54-1.72 (m, 1H) 1.86-2.16 (m, 3H) 3.30 (d, J=8.03 Hz, 1H) 3.66 (br. s., 2H) 3.81 (d, J=9.03 Hz, 1H) 3.94 (d, J=7.53 Hz, 1H) 8.33 (d, J=9.03 Hz, 1H) 8.52 (br. s., 1H) 8.60 (dd, J=9.03, 3.01 Hz, 1H). MS m/z 337.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:23][CH2:22][C:21]([NH2:26])([C:24]#[N:25])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:9]([CH3:27])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](O)=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)C>[C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:23][CH2:22][C:21]([NH:26][C:40](=[O:41])[C:39]3[CH:43]=[C:44]([C:46]([F:48])([F:49])[F:47])[CH:45]=[C:37]([O:36][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:38]=3)([C:24]#[N:25])[CH2:20][CH2:19]2)(=[O:16])=[O:17])=[C:9]([CH3:27])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC(N)(C#N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC(C#N)(NC(=O)c2cc(OCc3ccccc3)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[2-(4-Amino-4-cyano-piperidine-1-sulfonyl)-ethyl]-3-methyl-benzoic acid tert-butyl ester (500.0 mg, 1.23 mmol), 3-benzyloxy-5-trifluoromethyl-benzoic acid (436.1 mg, 1.47 mmol) and DIPEA (0.321 ml, 1.85 mmol) were dissolved in DMF (5.50 ml). HATU (561.2 mg, 1.47 mmol) was added and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with diethyl ether, and the organic layer was washed with a 1 M aqueous hydrochloric acid solution, an aqueous sodium bicarbonate solution and saline. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane-ethyl acetate) to give 4-{2-[4-(3-benzyloxy-5-trifluoromethyl-benzoylamino)-4-cyano-piperidine-1-sulfonyl]-ethyl}-3-methyl-benzoic acid tert-butyl ester as a yellow amorphous (796.2 mg, 94.4% in two steps).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.ClC(Cl)(Cl)C(=N)O[C:13]([CH3:16])([CH3:15])[CH3:14].C([O-])(O)=O.[Na+]>CCCCCC.C1COCC1>[CH:1]1([CH2:4][CH2:5][C:6]([O:8][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C(O)CCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cool (0° C., precooled for at least 15 min), stirred solution of 3-cyclopropylpropanoic acid (5 g, 43.8 mmol) in hexane (30.0 mL) and THF (30 mL) under N2 was added tert-butyl 2,2,2-trichloroacetimidate (15.7 mL, 88 mmol) portion wise over 5 min. The reaction mixture was stirred for 15 min. Boron trifluoride ether complex (0.555 mL, 4.38 mmol) was added and the reaction mixture was allowed to warm to room temperature as the bath warmed overnight. To the clear reaction mixture was added NaHCO3 (5 g) and stirred for 60 min. The suspension was filtered through MgSO4 and washed with 300 mL hexane. The filtrate was allowed to sit, then the resulting solid was filtered through the same MgSO4 filter, washed with hexane (100 mL). The filtrate was concentrated under vacuo with the water bath not turned on. The residue was purified by silica gel chromatography (hexanes/EtOAc) to provide Intermediate S1B (6.05 g, 81%) as clear oil: 1H NMR (400 MHz, CDCl3) δ 2.29 (2H, t, J=7.48 Hz), 1.35-1.54 (11H, m), 0.60-0.75 (1H, m), 0.29-0.46 (2H, m), −0.06-0.10 (2H, m).
Reaction SMILES: [N:1]1[C:2](=[O:13])[CH2:3][C:4](=[O:12])[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:21]([CH3:23])[CH3:22].O>CS(C)=O.C(OCC)(=O)C>[CH3:22][CH:21]([N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:12])[CH2:3][C:2]1=[O:13])[CH3:23]
Reactant: O=C1CC(=O)N=c2ccccc2=N1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)N1C(=O)CC(=O)Nc2ccccc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 8.3 %

Procedure:
A solution of 1,5-benzodiazepine-2,4-dione (5.5 g, 0.031 mole) in DMSO (70 mL) was treated with cesium carbonate (10.17 g, 0.031 mole) and 2-iodopropane (5.27 g, 0.03 1 mole). The reaction was heated to 80° C. for two hours and then stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate (400 mL) and poured into water (500 mL). The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (400 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 3:1 ethyl acetate:hexane to give 560 mg of product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl-].[CH3:14][O:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:36]([N:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N1CCCCC1>O1CCCC1>[CH2:36]([N:43]1[CH2:48][CH2:47][C:46](=[CH:14][O:15][CH3:16])[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: C1CCNCC1
Product: COC=C1CCN(Cc2ccccc2)CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of di-isopropylamine (11.1 g, 15.4 mL, 110 mmol) in anhydrous tetrahydrofuran (100 mL) was cooled to 0° C. under a nitrogen atmosphere. A solution of n-butyl lithium in hexanes (2.5 M, 44 mL, 110 mmol) was added dropwise with stirring. The pale yellow solution was stirred for 15 minutes at 0° C., then transferred via cannula to a suspension of methoxymethyl-triphenylphosphonium chloride (37.7 g, 110 mmol) in dry tetrahydrofuran (300 mL) stirred at -20° C. After 30 minutes, the reaction mixture was cooled to -40° C. and a solution of 1-benzylpiperid-4-one (18.9 g, 18.5 mL, 100 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise over 15 minutes. The reaction mixture was warmed gradually to ambient temperature over 23 h. The reaction mixture was then poured onto water, mixed and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and filtered; solvent was removed in vacuo. Column chromatography (ethyl acetate) gave starting piperidine (Rf =0.7, 0.5 g) and the product (Rf =0.51, 11.6 g), an orange-yellow liquid:1HNMR:7.4-7.25(m,5H), 5.8(s,1H), 3.5(s,2H), 3.45(s,3H), 2.5-2.3(m,5H), 2.05(t,2H,J=7); MS:217.