Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:46])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:45])[C@H:16]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34]C(OCC1C=CC=CC=1)=O)[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-])=O)(=[O:20])=[O:19])C1C=CC=CC=1.[H][H]>CO.[C].[Pd].O>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:46])=[O:8])=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])(=[O:20])=[O:19]
Reactant: [H][H]
Reactant: O=C(NCCCC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NCCCC[C@H](NS(=O)(=O)c1ccccc1N)C(=O)N1CCC[C@H]1C(=O)O
Yield: 91.1 %

Procedure:
Nα -o-nitrobenzenesulfonyl-Nε -benzyloxycarbonyl-L-lysyl-L-proline benzylester (5.82 g, 8.9 mmole) was dissolved in methanol (40 ml), and hydrogen gas was Passed through the solution in the presence of 5% palladium-carbon as a catalyst for 6 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in water (25 ml). The solution was washed with three 25 ml portions of diethyl ether and the water layer as separated was freeze-dried to obtain Nα -o-aminobenzenesulfonyl-L-lysyl-L-proline (yield: 3.23 g, 90.9%).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:30])[C:4]2[CH:5]=[CH:6][N:7]3[C:20](=[O:21])[N:19](COCC[Si](C)(C)C)[N:18]=[C:8]3[C:9]=2[O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:1][C:2]1[C:3](=[O:30])[C:4]2[CH:5]=[CH:6][N:7]3[C:20](=[O:21])[NH:19][N:18]=[C:8]3[C:9]=2[O:10][C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)CCOCn1nc2c3oc(-c4ccccc4)c(I)c(=O)c3ccn2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c(I)c(-c2ccccc2)oc2c1ccn1c(=O)[nH]nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.1 %

Procedure:
To a stirred ice-cooled solution of 7-iodo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalene-3,6-dione (60 mg, 0.112 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was allowed to warm to RT. After 16 hours, the solvents were removed in vacuo, the residue was dissolved in THF (2 mL) and benzyltrimethylammonium hydroxide (40% in MeOH, 0.05 mL) was added. The reaction mixture was stirred at RT for 1 hour. EtOAc was added and the mixture was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (50.4 mg) as a buff solid. LCMS (Method B): RT=3.84 min, [M+H]+=406.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][CH:6]=1.N1([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)C=CC=C1>>[CH3:1][C:2]1[N:3]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc[nH]1
Reactant: Ic1ccc(Cn2cccc2)cc1
Product: Cc1cccn1Cc1ccc(I)cc1

Procedure:
The titled compound was prepared from 2-methylpyrrole (J. Org. Chem. 1956, 21, 918.) in an analogous manner to that of 4-(pyrrol-1-ylmethyl)phenyl iodide (EP 488 602 A1).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[C:32](Cl)=[O:33]>O1CCCC1>[C:6]1([N:5]([CH2:4][CH2:3][N:2]([CH3:12])[CH3:1])[C:32]([C:22]2[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][O:25][C:21]=2[CH3:20])=[O:33])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: CN(C)CCNc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1C(=O)N(CCN(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of 24.6 grams (0.15 mole) of N,N-dimethyl-N'-phenyl-ethylenediamine and 18.2 grams (0.18 mole) of triethylamine in 500 milliliters of tetrahydrofuran (THF) is cooled to 0° C. and 39.8 grams (0.18 mole) of 5-methyl-3-phenyl-4-isoxazole carbonyl chloride in 100 milliliters of tetrahydrofuran is added dropwise. After the addition is complete, the mixture is warmed to room temperature and stirred for 4 hours. The resulting suspension is filtered and the THF removed in vacuo. The residue is dissolved in methylene chloride and washed with 2N sodium hydroxide and water and then dried over magnesium sulfate. The mixture is filtered and the solvent removed by evaporation. The residue is then treated with hexane to yield crystals of N-phenyl-N-(2-dimethylaminoethyl)-5-methyl-3-phenyl-4-isoxazole carboxamide; M.P. 88°-89° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][NH2:26])[CH3:21]>C1COCC1>[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][NH:26][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[CH3:21]
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCN(CC)CCCN
Solvent: C1CCOC1
Product: CCN(CC)CCCNc1cc(OCCCN(CC)CC)ccc1[N+](=O)[O-]

Procedure:
A solution of 2-fluoro-4-(3-diethylamino-1-propoxy)nitrobenzene (2 mmol; preparation described in Example 5) in THF (5 mL) is treated with 3-diethylamino-1-propylamine (2.4 mmol at rt. After completion of the reaction, the reaction mixture is concentrated in vacuo. The residue is redissolved in EtOAc (10 mL), washed with saturated sodium bicarbonate solution, water, and brine. The organic phase is then dried over sodium sulfate and the solvent is removed in vacuo to afford the product, 2-(3-diethylamino-1-propylamino)-4-(3-diethylamino-1-propoxy)nitrobenzene (620 mg) which was used for further transformation without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([I:19])=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:27][C:28](Cl)=[O:29]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[I:19][C:7]1[C:6](=[O:20])[C:5]2[C:10](=[C:11]3[C:2](=[CH:3][CH:4]=2)[NH:1][C:28](=[O:29])[CH2:27][O:12]3)[O:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1O
Reactant: O=C(Cl)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=C1COc2c(ccc3c(=O)c(I)c(-c4ccccc4)oc23)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of 7-amino-8-hydroxy-3-iodo-2-phenyl-chromen-4-one (150 mg, 0.40 mmol), benzyltriethylammonium chloride (91 mg, 0.40 mmol) and NaHCO3 (168 mg, 2 mmol) in CHCl3 (5 mL) at 0° C. was added a solution of chloroacetyl chloride (35 μL, 0.44 mmol) in CHCl3 (1 mL) dropwise over 30 mins. The reaction mixture was stirred at 0° C. for 2 hours before heating at 50° C. for 18 hours. The resultant mixture was cooled to RT and was partitioned between DCM and water. The aqueous phase was filtered and the solid collected and azeotroped with methanol to give the title compound as a beige solid (167 mg, 99%). LCMS (Method G): RT=3.18 min, [M+H]+=420.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9].[NH3:11]>CO>[NH2:11][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: N
Reactant: N#Cc1cncc(CCl)c1
Solvent: CO
Product: N#Cc1cncc(CN)c1
Temperature: 80 °C

Procedure:
Dissolve 5-chloromethyl-nicotinonitrile (4.9 mg, 0.032 mmol) in 2.0M NH3 in MeOH (1 mL). Transfer this solution to a pressure tube. Heat the reaction solution at 80° C. for 2 h. Rotary evaporate the reaction solution (40° C.) to yield 5.1 mg of crude 5-aminomethyl-nicotinonitrile as a yellow oil. MS (m/e): 134.00 (M+1).
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][CH:57]=2)[CH:53]([NH:58][C:59](=[O:73])[CH2:60][C:61]2[N:62]=[C:63]([C:66]4[CH:71]=[CH:70][CH:69]=[C:68]([OH:72])[CH:67]=4)[S:64][CH:65]=2)[C:52]3=[O:74])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[OH:72][C:68]1[CH:67]=[C:66]([C:63]2[S:64][CH:65]=[C:61]([CH2:60][C:59]([NH:58][CH:53]3[C:52](=[O:74])[N:51]4[CH:54]3[S:55][CH2:56][CH:57]=[C:50]4[C:48]([OH:49])=[O:47])=[O:73])[N:62]=2)[CH:71]=[CH:70][CH:69]=1
Reactant: O=C(Cc1csc(-c2cccc(O)c2)n1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCSC12
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1csc(-c2cccc(O)c2)n1)NC1C(=O)N2C(C(=O)O)=CCSC12
Yield: 99.1 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8n (152 mg, 0.261 mmol), Et3SiH (0.417 mL, 2.61 mmol), and trifluoroacetic acid (0.804 mL, 10.4 mmol) in dry ClCH2CH2Cl (4 mL) at 0° C. under nitrogen to give 9n (108 mg, 99%) as a white solid after crystallization from THF/Et2O/hexane. mp 195° C. (dec); IR (KBr) 3600-2600 (br), 3343, 1787, 1682, 1532 cm-1 ; 1H NMR (DMSO-d6) δ3.49 (1H, dd, J=19.0 and 6.0 Hz), 3.59 (1H, dd, J=19.0 and 2.6 Hz ), 3.73 (2H, s, CH2), 5.01 (1H, d, J=4.9 Hz), 5.73 (1H, dd, J=8.3 and 4.9 Hz), 6.45 (1H, dd, J=6.0 and 2.6 Hz), 6.88 (1H, d, J=7.8 Hz), 7.22 (1H, t, J=7.8 Hz), 7.28 (1H, d, J=7.8 Hz), 7.29 (1H, s), 7.38 (1H, s), 9.05 (1H, d, J=8.3 Hz, NH), 9.68 (1H, s, OH), 13.15 (1H, br s, CO2H); FDMS m/z 417 (M+), 418 (M+ +1); Anal. Calcd for C18H15N3O5S2 : C, 51.79; H, 3.62; N, 10.07. Found: C, 51.95; H, 3.66; N, 9.80
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=3.[NH:25]1[CH:29]=[CH:28][C:27](B(O)O)=[N:26]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:25]1[NH:26][C:27]([C:2]2[N:6]3[C:7]4[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]3=[N:4][CH:3]=2)=[CH:11][C:10]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=4)=[CH:28][CH:29]=1
Reactant: OCCCNc1nc2cc(OC(F)(F)F)ccc2n2c(Br)cnc12
Reactant: OB(O)c1cc[nH]n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCCNc1nc2cc(OC(F)(F)F)ccc2n2c(-c3ccn[nH]3)cnc12
Temperature: 130 °C
Reaction time: 17 h

Procedure:
To a solution of 3-(1-bromo-7-trifluoromethoxy-imidazo[1,2-a]quinoxalin-4-ylamino)-propan-1-ol (300 mg; 0.74 mmol; 1 eq) in N,N-dimethylformamide (8 mL), pyrazoleboronic acid (166 mg, 1.48 mmol; 2 eq) is added under argon followed by sodium carbonate (314 mg; 2.96 mmol; 4 eq) and tetrakis(triphenylphosphine)palladium (257 mg; 0.22 mmol; 0.3 eq). The solution is allowed to stir for 17 hours at 130° C. until the reaction is complete on TLC. The crude mixture is cooled to room temperature, diluted with ethyl acetate (50 mL), washed once with a saturated solution of sodium hydrogenocarbonate (90 mL) and three times with brine (3×25 mL). The resulting organic phase is dried over sodium sulfate, filtered and concentrated under vacuum to afford a crude brown powder. This solid is purified by chromatography on silica gel (gradient dichloromethane/methanol 98:2→95:5) to afford the title compound as an orange powder. Recristallization of this solid from ethyl acetate at 0-5° C. afforded the pure title compound (88 mg; 0.22 mmol; 30%) after filtration, washing with diethyl ether and drying of the resulting beige powder.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[NH:29][C:28](=[O:30])[NH:27][N:26]=2)[N:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[NH:29][C:28](=[O:30])[NH:27][N:26]=2)[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]nc(-c2cc3ccccc3c(NC[C@@H]3CCCN3)n2)[nH]1
Reaction time: 2 h

Procedure:
To crude (S)-tert-butyl-2-(((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)methyl)pyrrolidine-1-carboxylate (653 mg) suspended in DCM (3 mL) was added TFA (2 mL). The mixture was stirred for 2 hours and then concentrated. The product was purified by preparative HPLC eluting with a gradient of 5-30% ACN in water (acid mode) to give the title compound.
Reaction SMILES: [C:1]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[Cl:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1.Cl.CN(C)CCCCl>>[ClH:18].[C:1]1([CH:11]2[CH2:16][CH2:15][N:14]([CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:30]3)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(C3CCNCC3)cccc2c1
Reactant: ClCCCN1Cc2ccccc2C1
Agent: CN(C)CCCCl
Agent: Cl
Product: c1ccc2c(c1)CN(CCCN1CCC(c3cccc4ccccc34)CC1)C2
Yield: 77.6 %

Procedure:
Using 4-(1-naphthyl)piperidine (124 mg, 0.50 mmol) and 2-(3-chloropropyl)isoindoline hydrochloride (139 mg, 0.72 mmol) instead of 4-(3-indolyl)piperidine and 3-dimethylaminopropyl chloride hydrochloride respectively, reaction, extraction, and concentration were carried out in the same procedure as Example 4. The resulting crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=20:1) to afford a free form (158 mg) of the title compound as a yellow viscous oil. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then recrystallized from methanol/ether to afford the title compound (91 mg, yield: 44%) as white crystals.
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH:13]=[CH:12][C:11]=1[O:24][CH3:25])(C)[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+]>O.C(O)C>[CH3:25][O:24][C:11]1[CH:12]=[CH:13][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:15][C:10]=1[CH:3]([CH3:1])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)(C#N)c1cc(Oc2ccccc2Cl)ccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Oc2ccccc2Cl)cc1C(C)C(=O)O
Yield: 68.2 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-5-(2-chlorophenoxy)phenyl]propionate (5.5 g) and potassium hydroxide (4.3 g) in water 40 ml and ethanol (80 ml) was treated in a similar manner to that of Example 14-(7) to give oily 2-[2-methoxy-5-(2-chlorophenoxy)phenyl]propionic acid (3.2 g).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[CH:22]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:29][C:20]2[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NC1CCCCCC1
Product: O=[N+]([O-])c1ccc2c(c1)COC(NC1CCCCCC1)=N2
Yield: 99.1 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (5.0 g, 15 mmol) and cycloheptylamine (1.8 g, 16 mmol) according to the procedure described for Example 1. Obtained the title compound as a yellow foam (4.3 g, 100%), MS (ISP) m/e=288.3 [(M−H)+].
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[Cl:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[CH2:27][CH2:26][C@H:25](C(O)=O)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(#N)C.[N+]([O-])([O-])=O.[Ag+]>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][CH:25]([C:2]3[C:3](=[O:14])[C:4]4[C:9]([C:10](=[O:13])[C:11]=3[Cl:12])=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1
Reactant: O=C(O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: O=C1C(Cl)=C(C2CCC(c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21

Procedure:
condensing 2,3-dichloro-1,4-naphthoquinone of formula (3) with trans 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid of formula (4) in acetonitrile in presence of silver nitrate and ammonium persulfate in a suitable solvent to provide 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-1,4-naphthoquinone of formula (5);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18](OCC)=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:18][OH:19])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cc2cc(OCc3ccccc3)ccc2[nH]1

Procedure:
The title compound was prepared from ethyl 5-(benzyloxy)-1H-indole-2-carboxylate and lithium aluminum hydride according to the procedure described in step 3 of Example 1. The product was obtained as a white solid, mp: 106-107° C. Mass spectrum (ESI, [M+H]+) m/z 254. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.45 (d, 2H, J=7.33 Hz), 7.37 (t, 2H, J=7.49 Hz), 7.30 (d, 1H, J=7.18 Hz), 7.20 (d, 1H, J=8.71 Hz), 7.04 (s, 1H), 6.74 (dd, 1H, J=8.70 and 1.46 Hz), 6.16 (s, 1H), 5.16 (t, 1H, J=5.49 Hz), 5.01 (s, 2H), 4.55 ppm (d, 2H, J=5.50 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[C:17]([CH2:19][C:20](O)=[O:21])#[N:18].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:20](=[O:21])[CH2:19][C:17]#[N:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCC(=O)O
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC#N)CC1
Yield: 57.9 %

Procedure:
To a stirred solution of provide 1-(2-tert-butylphenyl)piperazine (0.203 g, 0.69 mmol), 2-cyanoacetic acid (0.065 g, 0.77 mmol) and triethylamine (0.279 g, 2.76 mmol) in methylene chloride (5.0 mL) was added bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.202 g, 0.77 mmol) at room temperature. After 2.5 h the reaction mixture was diluted with methylene chloride (10.0 mL), washed with water (20.0 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50% ethyl acetate/heptanes) to provide 3-(4-(2-tert-butylphenyl)piperazin-1-yl)-3-oxopropanenitrile (0.114 g, 58%) as an off-white solid, mp 163-164° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][C:46]([CH3:51])([CH3:50])[CH2:47][CH2:48][NH2:49]>CN(C=O)C>[CH3:45][C:46]([CH3:51])([CH3:50])[CH2:47][CH2:48][NH:49][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CC(C)(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCCC(C)(C)C)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 3,3-dimethylbutylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(3,3-dimethylbutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C@H:3]1[C:12]([O:14]C(C)(C)C)=[O:13]>C1(C)C=CC=CC=1>[CH3:19][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Yield: 82.5 %

Procedure:
A mixture of 2.3 g of the product of Step C, 20 mg of hydrated p-toluene sulfonic acid and 20 ml of toluene was refluxed for 40 minutes and the mixture was then evaporated to dryness under reduced pressure. The 2.1 g of residue were chromatographed over silica gel and were eluted with a 60-39-1 cyclohexane-ethyl acetate-acetic acid mixture to obtain 1.5 g of (1R,cis) 2,2-dimethyl-3-[Z-2-(ethoxycarbonyl)-ethenyl]-cyclopropane-carboxylic acid melting at 96° C.
Reaction SMILES: [CH2:1]([C@@:3]1([CH2:13][CH2:14][C:15]([O:17]CCO)=O)[CH2:12][CH2:11][CH2:10][CH2:9][C:4]21[O:8][CH2:7][CH2:6][O:5]2)[CH3:2].[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOCC>[CH2:1]([C@@:3]1([CH2:13][CH2:14][C:15]([C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:4]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:17])[CH2:12][CH2:11][CH2:10][CH2:9][C:4]21[O:5][CH2:6][CH2:7][O:8]2)[CH3:2]
Reactant: CC[C@@]1(CCC(=O)OCCO)CCCCC12OCCO2
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: CC[C@@]1(CCC(O)(c2ccccc2)c2ccccc2)CCCCC12OCCO2

Procedure:
(S)-6-Ethyl-1,4-dioxaspiro[4.5]decane-6-propanoic acid, 2-hydroxyethyl ester (one half of the material produced in step (d), 460 g) was diluted to 1 L with anhydrous ether and added dropwise (quickly, almost as a slow stream) to a solution of phenylmagnesium bromide (5.05 mol, 1.68 L of a 3M solution) in ether at 0° C. After 5 minutes the reaction was quenched with 1M hydrochloric acid until all of the salts dissolved. The mixture was extracted with ether (3×500 mL), dried over magnesium sulfate, and concentrated to a yellow oil (175 g, some material was lost in workup).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].CC1(C)O[C:11](=[O:13])[CH:10]=[C:9]([CH3:14])[O:8]1>C1(C)C(C)=CC=CC=1.C(OCCCC)(=O)C.C1(=O)C=CC(=O)C=C1>[C:11]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])(=[O:13])[CH2:10][C:9]([CH3:14])=[O:8]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: C=CC(N)=O
Agent: O=C1C=CC(=O)C=C1
Solvent: CCCCOC(C)=O
Solvent: Cc1ccccc1C
Product: C=CC(=O)NC(=O)CC(C)=O
Temperature: 80 °C
Yield: 63.2 %

Procedure:
A solution of acrylamide (21.3 g, 0.3 mol), butylated hydroxytoluene (BHT, 0.66 g, 1%) and benzoquinone (BQ, 0.22 g, 0.7%) in a mixture of 75 mL of xylene and 150 mL of n-butyl acetate was heated to about 80° C. When the reaction mixture reached 80° C., 42.6 g (0.3 mol) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one was added as a small stream over a period of about 10 minutes; the reaction mixture was then heated rapidly up to about 120° C., and maintained at that temperature for about 10 minutes. Once heating of the reaction mixture was complete, the reaction mixture was allowed to cool and 29.4 g (63% yield; mp 128° to 130° C.) of N-acetoacetyl acrylamide was collected as a white precipitate and air dryed.