Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([NH:27][NH2:28])(=O)=O)=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:2]1([C:1]2[C:8]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]=3[NH:27][N:28]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2ccccc2)Cc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reaction time: 18 h

Procedure:
A mixture of 2-benzylidene-indan-1-one (3.99 g), p-toluenesulphonyl hydrazine (4.0 g), p-toluenesulphonic acid hydrate (0.7 g) and ethanol (60 ml) was boiled under reflux for 1.5 hours and then left to stand for 18 hours at ambient temperature. The mixture was boiled under reflux for a further 74 hours and then left to stand at ambient temperature for 74 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and 2M sodium hydroxide solution (50 ml). The organic layer was separated, dried over magnesium sulfate and filtered. The magnesium sulfate was washed with ethyl acetate and filtered. The ethyl acetate filtrate was evaporated to dryness to give a solid which was recrystallized from ethanol to give 3-phenyl-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 234-236° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC2N(O)N=[N:32]C=2C=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]([NH2:32])=[O:25])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: NC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12

Procedure:
5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxylic acid (20 mg) was reacted in NMP (0.4 ml) with HOBt.H2O (40 mg), ammonium chloride (40 mg), DIEA (100 ul) and EDCI (50 mg) at 70° C. for 1 hour. Water was added and the precipitate filtered and dried. After trituration in methanol and filtration, 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxamide was isolated as a solid (8 mg). LCMS (ES): >95% pure, m/z 349 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:29][CH:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: NC1CCC(O)CC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3CCC(O)CC3)n(C)c2n1

Procedure:
4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 4-aminocyclohexanol via General Procedure E to give 11.1 mg of 281 following reverse phase purification. MS (Q1) 477.2 (M)+
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[N:6]=1)=O.[BH4-].[Na+]>CO>[CH3:12][O:11][C:7]1[N:6]=[C:5]([CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CO)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Methyl-6-methoxypyridine-2-carboxylate (2 g, 11.96 mmol) in anhydrous methanol (20 mL) was cooled to 0° C. under nitrogen and sodium borohydride (1.36 g, 35.89 mmol) was slowly added to the solution. The reaction was left stirring at 0° C. for 30 minutes, then allowed to warm up to room temperature for 1 hour. The reaction was quenched with water and concentrated on the rotovap. The reaction was diluted with brine (100 mL) and extracted with dichloromethane/2-propanol solution (2:1) (3×, 150 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap to afford (6-methoxypyridin-2-yl)methanol (500 mg, 30%) as an oil. MS M+H calculated 140.1; found 140.1.
Reaction SMILES: P([NH:5][C:6]([O:8][CH2:9][C:10]1[CH2:11][S:12][C@@H:13]2[C@H:20]([NH:21][C:22](=[O:32])/[C:23](/[C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[N:24]\[O:25][CH3:26])[C:19](=[O:33])[N:14]2[C:15]=1[C:16]([OH:18])=[O:17])=[O:7])(O)(O)=O>O.O1CCOCC1>[C:6]([O:8][CH2:9][C:10]1[CH2:11][S:12][C@@H:13]2[C@H:20]([NH:21][C:22](=[O:32])/[C:23](/[C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[N:24]\[O:25][CH3:26])[C:19](=[O:33])[N:14]2[C:15]=1[C:16]([OH:18])=[O:17])(=[O:7])[NH2:5]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)NP(=O)(O)O)CS[C@H]12)c1ccco1
Solvent: O
Solvent: C1COCCO1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1

Procedure:
A solution of (6R,7R)-3-phosphonocarbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (0.35 g) in water (4 ml) and dioxan (1 ml) was kept successively at 40° for 5 hours, room temperature for 16 hours, 40° for 6 hours and 20° for 16 hours. The conversion to the title compound was monitored by t.l.c. A precipitate was formed and this was filtered off. The pH was altered from 4 to 7 by addition of saturated aqueous sodium bicarbonate solution.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[CH2:4][CH:5](C(O)=O)[C:6]([OH:8])=[O:7]>CCOCC>[Br:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C(Cc1ccc(C(F)(F)F)cc1Br)C(=O)O
Solvent: CCOCC
Product: O=C(O)CCc1ccc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
[2-Bromo-4-(trifluoromethyl)benzyl]malonic acid (9.80 g, 28.7 mmol) in a round-bottom flask was heated to 180° C. and heating was continued at 180° C. for 1.5 hrs. After cooling to room temperature, the solid was dissolved in ether. The resulting solution was dried over MgSO4 and concentrated. The solid was washed with hexane to give the title compound (7.20 g, 85%). MS calculated for C10H8BrF3O2: (M+H)+ 297; found 297.0, 299.0.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][CH:8]=1.[C-:13]#[N:14].[K+]>C(O)C.O>[F:10][C:9]([F:12])([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][C:13]#[N:14])=[CH:4][CH:5]=1
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(C(F)(F)F)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
5-Chloromethyl-2-trifluoromethylpyridine (19.5 g, 99.7 mmol) in ethanol (160 mL) was added to a solution of potassium cyanide (9.74 g, 150 mmol) in water (80 mL) at 90° C. over 30 minutes. The mixture was stirred at 90° C. for 3 hours. Most of the ethanol was removed under reduced pressure and the aqueous layer was extracted with AcOEt (3×100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% AcOEt in hexanes) to afford (6-trifluoromethylpyridin-3-yl)-acetonitrile as a brown oil (9.79 g, 75%). 1H NMR (400 MHz, CDCl3) δ ppm 8.63 (s, 1 H), 7.90 (d, J=8.0 Hz, 1 H), 7.70 (d, J=8.0 Hz 1 H), 3.88 (s, 2 H). 19F NMR (400 MHz, CDCl3):168 cm−1. MS m/z 187.14
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O1CCOCC1>CCOC(C)=O>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16]
Reactant: Cc1ccc2c(c1)N(CCCCl)C(=O)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc2ccc(=O)n(CCCCl)c2c1
Yield: 62.7 %

Procedure:
A microwave vial was charged with 1-(3-chloropropyl)-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.21 g, 0.88 mmol), DDQ (0.30 g, 1.3 mmol), dioxane (4 mL) and sealed. After microwave irradiation, 175° C., 10 min, the reaction was diluted with EtOAc (50 mL), washed with sat aqueous NaHCO3 (2×15 mL) and the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified with prep RP-HPLC to yield the crude title compound (0.130 g), which was used without further purification. HPLC-MS (ammonium acetate) [M+H]+=236.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11](=O)[NH:10]1.O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([Cl:24])=[N:10]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C1=C(C)NC(=O)NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(C)NC(Cl)=NC1c1ccc(F)cc1Br
Temperature: 110 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3.56 g, 10 mmol) and POCl3 (15 mL) was stirred at 110° C. for 4 hours under N2, then cooled to 25° C. POCl3 was removed in vacuo and the residue was dissolved in chloroform (100 mL). Then the mixture was adjusted to pH 6-8 with strong ammonia. The organic phase was washed with brine (80 mL×3), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=5/1) to give the title compound as a white solid (1.73 g, 46%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH:3]=[CH:2]1.Cl.O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O.Cl>CO>[N:12]1([C:3]2[C:4]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[NH:1][CH:2]=2)[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1
Reactant: c1cnc2cc[nH]c2c1
Reactant: O=C1CCCCN1
Agent: Cl
Solvent: CO
Solvent: O
Product: C1=CCN(c2c[nH]c3cccnc23)CC1

Procedure:
To a stirred solution of Na (2.53 g, 110 mmol, 11 eq) in absolute methanol (50 ml) at room temperature was added the appropriate pyrrolopyridine (10.00 mmol) and piperidone monohydrate hydrochloride (4.60 g, 30.0 mmol, 3.0 eq). The resultant mixture was then heated at reflux under nitrogen for 2-24 hours depending on the substrate. The resultant reaction mixture was cooled, and concentrated hydrochloric acid (37%, 9.0 ml, 110 mmol) wasadded dropwise with vigorous stirring. The resultant mixture was then evaporated under reduced pressure, and the residual slurry placed in water(50 ml). This aqueous mixture was extracted with ethyl acetate (5×50 ml), and these extracts were combined, dried (Na2SO4), and evaporated under reduced pressure. The residue was either triturated directly or column chromatographed using silica gel (approximately 100 g) and elution with the appropriate solvent system yielding the desired 3-(1,2,5,6-tetrahydropyridyl)pyrrolopyridine, one of Compounds 1a-1m or compound 2, 3a, 3b, 3c or 4.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[NH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39]>C1COCC1>[F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:21])[NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(/N=c1\[nH]c2ccc(CN3CCOCC3)cc2n1[C@H]1CC[C@@H](C(=O)Cl)CC1)c1ccc(F)cc1
Reactant: CC(C)(N)CO
Solvent: C1CCOC1
Product: CC(C)(CO)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCOCC4)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To a 0° C. suspension of cis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonyl chloride (50 mg, 0.100 mmol) in THF (1 mL) was added 2-amino-2-methylpropan-1-ol (17.8 mg, 0.401 mmol). The mixture was stirred for 1 hour at RT. The solvent was removed, and the residue was purified by reverse-phase preparative HPLC, using 0.1% NH4OH in ACN/water. The product fractions were combined and concentrated to provide (E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a white powder (8.5 mg, 15.4% yield). MS, m/z (C30H38FN5O4): calcd, 551.3. found, 552.4 [M+H].
Reaction SMILES: C[O:2][C:3]1[C:8]2[NH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:7]=2[C:6]([C:19]#[N:20])=[CH:5][N:4]=1.Br[C:22]1[CH:23]=[C:24]([C:27]([NH2:29])=[O:28])[S:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>[Cu]I.O>[C:19]([C:6]1[C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:10][N:9]([C:22]3[CH:23]=[C:24]([C:27]([NH2:29])=[O:28])[S:25][CH:26]=3)[C:8]=2[C:3](=[O:2])[NH:4][CH:5]=1)#[N:20]
Reactant: COc1ncc(C#N)c2c(-c3ccccc3C)c[nH]c12
Reactant: NC(=O)c1cc(Br)cs1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccccc1-c1cn(-c2csc(C(N)=O)c2)c2c(=O)[nH]cc(C#N)c12
Temperature: 200 °C
Reaction time: 1 h
Yield: 3.5 %

Procedure:
A mixture of 7-methoxy-3-(2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-4-carbonitrile (50 mg), 4-bromothiophene-2-carboxamide (47 mg), copper(I) iodide (3.6 mg), potassium carbonate (31.5 mg) and N-methylpyrrolidone (2 mL) was stirred under microwave irradiation at 200° C. for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, methanol/ethyl acetate). The obtained fraction was purified by HPLC (C18, mobile phase: water/acetonitrile (containing 5 mM ammonium carbonate)), to the obtained fraction was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.5 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][C@:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:3]1[CH2:4][CH2:5][C@H:6]2[O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1.[N-]=[N+]=[N-].[Na+].[C:43](O)(=[O:45])[CH3:44]>C(OC(OCC)OCC)C>[C:43]([NH:1][C@@H:2]1[CH2:8][C@:7]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:3]1[CH2:4][CH2:5][C@H:6]2[O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)O
Reactant: N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Product: CC(=O)N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 90 °C
Yield: 24 %

Procedure:
To (1R*,2R*,5S*,6R*)-6-amino-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 108; 256 mg, 0.48 mmol) and sodium azide (75 mg, 1.15 mmol) in triethylorthoformate (0.25 ml) was added glacial acetic acid (2.5 ml) and the reaction mixture heated at 90° C. for 3 hours. The reaction mixture was cooled then concentrated in vacuo and partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organics were dried (MgSO4) and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [5% methanol in dichloromethane] to give the title compound (66 mg, 24%).
Reaction SMILES: COC(=O)CC.C[O:8][C:9](=[O:40])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:20][CH:21]=[CH:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)[CH:13]=1>O=[Pt]=O.CO>[C:34]1([S:31]([N:19]([CH2:18][C:14]2[CH:13]=[C:12]([CH2:11][CH2:10][C:9]([OH:40])=[O:8])[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)(=[O:33])=[O:32])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)CCc1cccc(CN(CC=Cc2cc(Cl)cc(Cl)c2)S(=O)(=O)c2ccccc2)c1
Agent: O=[Pt]=O
Solvent: CCC(=O)OC
Solvent: CO
Product: O=C(O)CCc1cccc(CN(CCCc2cc(Cl)cc(Cl)c2)S(=O)(=O)c2ccccc2)c1
Yield: 103.7 %

Procedure:
3-[3-Benzenesulfonyl-[3-(3,5-dichloro-phenyl)-propyl]-amino}-methyl)-phenyl]-propionic acid methyl ester. A mixture 3-[3-({benzenesulfonyl-[3-(3,5-dichloro-phenyl)-allyl]-amino}-methyl)-phenyl]-propionic acid methyl ester of Step A (237 mg), PtO2 (30 mg), and MeOH was hydrogenated on a Parr shaker at 50 psi for 2 h. The catalyst was removed by filtration through Celite and the volatiles were removed in vacuo to provide the title compound (240 mg). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, 2H), 7.76-7.50 (m, 3H), 7.23 (m, 1H), 7.07 (m, 4H), 6.74 (s, 2H), 4.26 (s, 2H), 3.64 (s, 3H), 3.09 (t, 2H), 2.90 (t, 2H), 2.56 (t, 2H), 2.37 (t, 2H), 1.56 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][C@H:9]1[C:31](O)=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C@H:67]1([NH2:77])[C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH2:70][CH2:69][CH2:68]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][C@H:9]1[C:31](=[O:32])[NH:77][C@H:67]1[C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH2:70][CH2:69][CH2:68]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O
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: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21

Procedure:
To a solution of (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (Aldrich) (7.5 g, 16.593 mmol) in DMF (100 mL) were added HATU (6.93 g, 18.252 mmol) and DIPEA (14.36 mL, 82.965 mmol) and the mixture was cooled to 0° C. (R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (2.44 g, 16.593 mmol) was added dropwise and the cooling bath removed. After 4 h the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated to afford the title compound as an off white solid (9.6 g) which was used without purification. LC-MS: 582 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17]>>[OH:10][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=[C:5]([CH3:9])[C:4]=1[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17]
Reactant: CCOC(=O)CCCCCC(=O)Cl
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)CCCCCC(=O)c1c(C)cc(C)c(C)c1O

Procedure:
2,3,5-Trimethylphenol (formula VII wherein R=H3C, X=H, Y=OH)(0.9 part), aluminum chloride (2.1 parts) and ethyl 6-chloroformylhexanoate (1.3 part) were treated as in Example 1 (1). The procedure provided colorless needles of ethyl 6-(2'-hydroxy-3',4',6'-trimethylbenzoyl)hexanoate (formula II-1 wherein R=H3C, X=H, Y=OH, n=5, in the form of ethyl ester) (1.5 part) melting at 47°-48° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([NH:17][CH3:18])[C:9]2=O.Cl>[Pd].C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([NH:17][CH3:18])[CH2:9]2
Reactant: CNC1CCc2c(ccc(OC)c2OC)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNC1CCc2c(ccc(OC)c2OC)C1
Reaction time: 24 h

Procedure:
14.0 g of 5,6-dimethoxy-2-methylamino-1-tetralone hydrochloride (0.051 mole), 400 ml of absolute ethanol, 10 ml of 1M methanolic HCl and 4.0 g of 5% Pd/C are placed into an autoclave (50% humidity), then the mixture is hydrogenated (P about 7 atm., T=80° C.) with stirring for 24 hours. The mixture is filtered, washing thoroughly the filtration cake with hot methanol, then the alcoholic solution is evaporated to dryness. The resulting solid is taken up into 150 ml of acetone, then the precipitate is filtered and dried under vacuum at 60° C. Yield: 10.8 g, 82% (moles), 77% (weight); M.p.=219°-220° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1CC[CH2:22][CH2:21][N:20]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCC1CCN(C(OCC2C=CC=CC=2)=O)CC1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:19][CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 4-(bromomethyl)-1-piperidinecarboxylate. LCMS (System B): tRET=2.70 min; MH+ 469
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[CH:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].[CH3:29][N:30]([CH3:37])[C:31](=[O:36])[CH2:32]C(C)=O>C1C=CC=CC=1.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[C:28][CH2:32][C:31]([N:30]([CH3:37])[CH3:29])=[O:36])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: CC(=O)CC(=O)N(C)C
Reactant: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccccc1
Product: COC(=O)C12CC3CC(CC(C(=O)NC(CC#CCC(=O)N(C)C)C(=O)OC(C)(C)C)(C3)C1)C2
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-(3-methoxycarbonyladamant-1-ylcarbonylamino)pent-4-ynoate (0.44 g) was dissolved in 0.8 mL of dry benzene under nitrogen. To this solution was added a catalytic amount of CuSO4 and the reaction mixture was brought to reflux. N,N-Dimethyl acetoacetamide was added dropwise in excess. Evolution of nitrogen was observed. The addition was complete after 30 min. The reaction was then heated for another 30 min. After cooling the reaction mixture, the solvent was evaporated under reduced pressure and the crude product was purified on a prep plate (silica gel; EtOAc/hexanes, 2:3) to afford the title compound as an oil.