Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=O)C1C=CC=CC=1.[CH:20]1[N:24]([CH2:25][O:26][CH:27]([CH2:30]O)[CH2:28][OH:29])[C:23]2[N:32]=[C:33]([NH2:37])[N:34]=[C:35]([OH:36])[C:22]=2[N:21]=1>[Pd].C(O)(C)C>[CH3:16][CH:14]([C@H:13]([NH2:12])[C:17]([O:19][CH2:30][CH:27]([O:26][CH2:25][N:24]1[C:23]2[NH:32][C:33]([NH2:37])=[N:34][C:35](=[O:36])[C:22]=2[N:21]=[CH:20]1)[CH2:28][OH:29])=[O:18])[CH3:15].[ClH:1]
Reactant: Nc1nc(O)c2ncn(COC(CO)CO)c2n1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CC(C)[C@H](N)C(=O)OCC(CO)OCn1cnc2c(=O)nc(N)[nH]c21
Temperature: 0 °C
Yield: 80.4 %

Procedure:
Hydrochloric acid (13 g) and 10% palladium on carbon (5.5 g) was added to a solution of mono-benzyloxycarbonyl-L-valine ganciclovir (50 g) in 23% aqueous iso-propanol (Iso-propanol:water::500 mL:150 mL). The reaction mixture was hydrogenated at about 25° C. to 40° C. under hydrogen pressure of 0.5-1 kg/cm2 for about 1 hour. After completion of the reaction, the reaction mass was filtered and washed with iso-propanol:water mixture (Iso-propanol:water::45 mL:5 mL). Iso-propanol (500 mL) was added over a period of about 1 hour. The reaction mass was cooled to 0° C., maintained at about 0° C. to about −5° C. for about 1 hour, filtered, washed with 10% aqueous iso-propanol solution (50 mL) followed by washing with iso-propanol (50 mL) and dried to obtain valganciclovir hydrochloride (31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[N:18]=[C:17]([C:19](=O)[CH3:20])[CH:16]=[CH:15][CH:14]=1)[CH3:12].[CH2:22]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH3:32])[C:25]=1[NH2:26])[CH3:23]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:19](=[N:26][C:25]2[C:27]([CH2:31][CH3:32])=[CH:28][CH:29]=[CH:30][C:24]=2[CH2:22][CH3:23])[CH3:20])[N:18]=1)[CH3:12]
Reactant: CCc1cccc(CC)c1N
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1N=C(C)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: 25 °C
Yield: 12.1 %

Procedure:
1.00 g of 1-{6-[1-(2-chloro-4,6-dimethylphenylimino)-ethyl]pyridin-2-yl}ethanone (3.3 mol), 0.99 g of 2,6-diethylaniline (6.6 mmol) and 1.0 g of Sicapent were heated under reflux under argon in 50 ml of tetrahydrofuran for 2 h. A further portion of Sicapent (0.5 g) was added and the mixture was heated under reflux under argon for a further 1.5 h. A further portion of Sicapent (0.5 g) and 0.50 g of 2,6-diethylaniline (3.3 mmol) were added and the mixture was heated under reflux under argon for a further 15 h and then cooled to room temperature. The reaction mixture was filtered and the residue on the filter was washed with 10 ml of tetrahydrofuran. The filtrate was topped up to 125 ml with tetrahydrofuran, 4 g of Sicapent were added and the mixture was heated again under reflux under argon for 2.5 h and then cooled to room temperature. It was filtered and the residue on the filter was washed with 10 ml of tetrahydrofuran. The solvent was then distilled off completely and the residue was stirred with 10 ml of methanol. The precipitate formed was filtered off and washed twice with methanol. After drying in vacuo, 0.36 g (0.8 mmol) of 2-[1-(2-chloro-4,6-dimethylphenylimino)ethyl]-6-[1-(2,6-diethylphenylimino)ethyl]pyridine was obtained in a yield of 25%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.C([N-]C(C)C)(C)C.[Li+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH:8]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]2
Reactant: CCOC(=O)CBr
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCc2cc(OC)c(OC)cc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
3,4-Dihydro-6,7-dimethoxy-1(2H)-naphthalenone (10.0 g) was dissolved in tetrahydrofuran (200 ml), and thereto was added dropwise a 2M solution of lithium diisopropylamide in tetrahydrofuran (37 ml) at -70° C. The mixture was stirred for 30 minutes, and thereto was added dropwise ethyl bromoacetate (10.5 g) at -70° C. The mixture was stirred at the same temperature for two hours, and then stirred at 20° C. overnight. The reaction mixture was poured into ice-water, and extracted with diethyl ether. The ether layer was washed successively with water, 10% hydrochloric acid and 10% aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The resultant was concentrated under reduced pressure to remove the solvent to give ethyl 1,2,3,4-tetrahydro-6,7-dimethoxy-1-oxo-2-naphthaleneacetate (12.0 g) as an oily product.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:26]1([CH:30]=O)[CH2:29][CH2:28][CH2:27]1.O>O1CCCC1>[CH:26]1([CH:30]=[C:11]2[CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]=3[C:2]2=[O:1])[CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: O=CC1CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCC(=CC1CCC1)C2=O
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (600 mg, 2.9 mmol) in tetrahydrofuran (10 mL) was cooled to ice bath temperature and treated with 1.0 M lithium hexamethyldisilazide in tetrahydrofuran (5 mL). After stirring for twenty minutes, cyclobutanecarboxaldehyde (J. Med. Chem. 1989, 32, 1001-6) (24 mL of 0.5 M solution in tetrahydrofuran) was slowly added and the mixture allowed to warm to room temperature and stir for 3 days. The mixture was poured into water, extracted three times with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by normal phase flash column chromatography on a 50 g silica gel column (5-50% ethyl acetate/hexanes gradient). Pure fractions were pooled and concentrated in vacuo to yield methyl 6-(cyclobutylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (300 mg, 1.1 mmol, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-2.03 (m, 4H), 2.14-2.27 (m, 2H), 2.71 (t, J=6.58 Hz, 2H), 2.93-3.00 (m, 2H), 3.34-3.44 (m, 1H), 3.88 (s, 3H), 6.91 (d, J=9.13 Hz, 1H), 7.84-7.95 (m, 2H), 8.01 (d, J=8.06 Hz, 1H). ES-MS m/z 271 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[C:4]2[C:10]3[CH2:11][CH2:12][CH2:13][C:9]=3[S:8][C:5]2=[N:6][CH:7]=1.CN(C)C1C=CC=CC=1.[F:30][C:31]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>ClCCl>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:3]1[C:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:31]=2[F:30])=[CH:7][N:6]=[C:5]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:4]=12
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Nc1cnc2sc3c(c2c1-c1ccccc1Cl)CCC3
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: O=C(Nc1cnc2sc3c(c2c1-c1ccccc1Cl)CCC3)c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of 3-amino-4-(2-chlorophenyl)-6,7-dihydro-5H-cyclopenta[1',2':5,4]thieno[2,3-b]pyridine (150 mg) and N,N-dimethylaniline (0.065 ml) in dichloromethane (3 ml) was added dropwise 2,4-difluorobenzoyl chloride (0.07 ml) with ice-cooling. The mixture was stirred for 10 minutes with ice-cooling and then stirred at room temperature for 2 hours. Then, the mixture was washed in turn with water, aqueous saturated NaHCO3 solution and water, and dried over MgSO4The solvent was distilled off to obtain 4-(2-chlorophenyl)-3-(2,4-difluorobenzoylamino)-6,7 -dihydro-5H-cyclopenta[1',2':5,4]thieno[2,3-b]pyridine (206 mg, 93.6%) as crystals. The crystals were recrystallized from acetone to obtain colorless prisms, mp: 219°-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[C:10]([CH3:16])[CH:9]=1.C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.O>[CH3:26][S:27]([O:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][C:10]=1[CH3:16])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2ccccc2Cl)ccc1CO
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccccc2Cl)ccc1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2′-chloro-3-methylbiphenyl-4-yl)methanol from step 1 in CH2Cl2 (0.13M) at 0° C. was added diisopropyl ethylamine (1.5 eq.) then methanesulfonyl chloride (1.1 eq.). The reaction mixture was stirred at room temperature for 2 h, poured in water and extracted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated to afford the title compound which was used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>[Cu](I)I.C(NCC)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:16]1[CH:17]=[C:18]([C:19](=[O:20])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[CH:32]=[CH:33][C:15]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCNC(=O)OC(C)(C)C
Reactant: COc1ccc(NC(=O)c2ccc(N)c(I)c2)cc1OC
Agent: I[Cu]I
Solvent: CCNCC
Product: COc1ccc(NC(=O)c2ccc(N)c(C#CCCCNC(=O)OC(C)(C)C)c2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 500 mL round bottom flask was charged with pent-4-ynyl-carbamic acid tert-butyl ester (1.35 g, 7.37 mmol), 4-amino-N-(3,4-dimethoxyphenyl)-3-iodobenzamide (1.35 g, 6.98 mmol), copper iodide (0.16 g, 0.814 mmol), palladium tetrakistriphenylphosphine (0.81 g, 0.701 mmol), and diethylamine (230 mL) and the resulting mixture stirred at room temperature for 24 h. The resulting mixture was then concentrated in vacuo and the residue purified via flash silica gel chromatography (Analogix IF-280, SF40-400 g column, gradient 90:10-10:90 Heptane:EtOAc) to yield {5-[2-amino-5-(3,4-dimethoxy-phenylcarbamoyl)-phenyl]-pent-4-ynyl}-carbamic acid tert-butyl ester. MS (ES+) 454 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>O1CCCC1>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:30][CH:31]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NC(C)=O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
(±)-Cis-N-[1-(4-acetylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide was prepared from (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. To a solution of (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. (100 mg, 0.24 mmol) in 2.5 ml tetrahydrofuran was added acetyl chloride (44 mL, 0.63 mmol) followed by triethylamine (88 μL, 0.63 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (3:1) to give the title compound (51 mg, 46%).
Reaction SMILES: [Li]CCCC.[C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]([O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[C:28](N(C)C)=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[CH2:18]([O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[C:28]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:13]=1)=[O:29])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)C(=O)c1ccccc1OCc1ccccc1
Reactant: c1ccc(-c2ccccn2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Temperature: -10 °C

Procedure:
To a solution of 12.9 g (145 mmol) of 2-N,N-dimethylaminoethanol in 100 mL of hexanes, 116 mL (290 mmol) of 2.5 M nBuLi in hexanes was added dropwise with vigorous stirring at −10° C. This mixture was slowly warmed to 0° C., stirred for 30 min, and then 7.54 g (48.6 mmol) of 2-phenylpyridine was added at −10° C. The resulting mixture was stirred for 2 hr at 0° C. and then added dropwise to a solution of 43.2 g (179 mmol) of 16 in 725 mL of THF at −10° C. This mixture was slowly warmed to room temperature, stirred for 12 hr, and then 20 mL of water was added. The organic solvent was evaporated using a rotary evaporator. 17 was isolated from the residue by flash chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-ethyl acetate=5:1, vol.). The obtained product was additionally washed with 30 mL of diethyl ether and then dried in vacuum. Yield 11.0 g (62%) of white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:14][O-:15].[Na+].CN([CH:20]=[O:21])C>>[CH3:14][O:15][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:20]=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(N2CCNCC2)n1
Reactant: C[O-]
Reactant: CN(C)C=O
Agent: [Na+]
Product: COc1cccc(N2CCN(C=O)CC2)n1
Temperature: 100 °C
Yield: 81 %

Procedure:
A mixture of 1-(6-chloro-2-pyridinyl)piperazine (6.0 g) and NaOMe (16.42 g) in DMF (25 mL,) was heated at 100° C. under nitrogen atmosphere for 20 h. The excess DMF was then removed under reduced pressure. Water (5 mL) was added to the residue and the mixture extracted with CH2Cl2. The combined organic layers were washed with sat. NaCl solution, dried with anhydrous MgSO4, filtered and concentrated under reduced pressure. Silica gel chromatography (CH2Cl2 /MeOH; 98:2) of the concentrate yielded the 4-(6-methoxy-2-pyridinyl)1-piperazinecarboxaldehyde (5.13 g; 81%).
Reaction SMILES: O[C@@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[O:26][CH2:25]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C@H:5]1[CH2:20]O.S(Cl)(Cl)=O.[CH2:37]([NH2:40])[CH:38]=[CH2:39].[I-].[Na+]>C(OCC)(=O)C>[CH2:37]([N:40]1[CH:2]([C:22]2[C:23]([CH3:32])=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[O:26][CH2:25]3)[CH2:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:6][C@H:5]2[CH2:20]1)[CH:38]=[CH2:39]
Reactant: C=CCN
Reactant: Cc1c([C@H](O)CN2CCN(C(=O)OCc3ccccc3)C[C@H]2CO)ccc2c1COC2=O
Agent: [I-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: C=CCN1C[C@@H]2CN(C(=O)OCc3ccccc3)CCN2CC1c1ccc2c(c1C)COC2=O
Temperature: 90 °C

Procedure:
A solution of (S)-benzyl 4-((S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (1.4 g, 3.2 mmol) in thionyl chloride (20 mL, 274 mmol) was heated at reflux for 1 h. After removing the volatiles, the residue was dissolved in N,N-dimethylformamide (20 mL) and treated with allylamine (1.31 mL, 17.48 mmol) at 0° C. The resulting solution was treated with sodium iodide (0.088 g, 0.318 mmol) and heated at 90° C. for 1 h. The solution was diluted in ethyl acetate (300 mL) and was washed with saturated sodium bicarbonate three times, dried over sodium sulfate, concentrated and the residue was purified by MPLC on a Biotage system using 40-100% ethyl acetate/hexane to give the title compound. LC/MS: (M+1)+: 462.12.
Reaction SMILES: [ClH:1].[CH2:2]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][C@H:5]2[OH:10])[CH2:3]1.C(N(CC)CC)C.C(O)(=O)C.C(OC([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH:37]=O)[C:31](=[O:39])[CH:30]1[CH3:40])=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:1].[ClH:1].[OH:10][C@@H:5]1[CH2:6][N:7]([CH2:37][CH2:36][CH2:35][N:32]2[CH2:33][CH2:34][NH:29][CH:30]([CH3:40])[C:31]2=[O:39])[CH2:8][CH2:9][C:4]21[CH2:3][CH2:2]2
Reactant: CC1C(=O)N(CCC=O)CCN1C(=O)OC(C)(C)C
Reactant: O[C@@H]1CNCCC12CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1NCCN(CCCN2CCC3(CC3)[C@H](O)C2)C1=O
Reaction time: 2 h
Yield: 282.2 %

Procedure:
To a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 25; 0.03 g, 0.2 mmol) in dichloromethane (1 ml) was added triethylamine (0.03 ml, 0.2 mmol) and acetic acid (0.02 ml, 0.4 mmol) followed by a solution of crude 2-methyl-3-oxo-4-(3-oxo-propyl)-piperazine-1-carboxylic acid tert-butyl ester (intermediate 14c; 0.06 g, 0.24 mmol) in dichloromethane (1 ml). Sodium triacetoxyborohydride (0.06 g, 0.26 mmol) was then added and the mixture stirred for 2 h, after which time the mixture was washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. The crude residue was then treated with HCl in dioxane (2 ml, 4 N) and stirred for 30 minutes after which time the reaction was concentrated to afford crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride as a white powder (0.1 g). To a solution of crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3,4-dichlorocinnamic acid (0.2 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (4 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=480.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24]C2C=NC(C(F)(F)F)=CC=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35](OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.Br[C:60]1[CH:61]=N[CH:63]=[C:64]([CH:66]([F:68])[F:67])[CH:65]=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:60]2[CH:61]=[CH:35][CH:63]=[C:64]([CH:66]([F:68])[F:67])[CH:65]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cn1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: FC(F)c1cncc(Br)c1
Product: FC(F)c1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[6-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine (Intermediate 9) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 3-bromo-5-difluoromethylpyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:1]=[C:17]([CH3:24])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CC(C)(C)COc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(neopentyloxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a white solid (64%). 1H NMR (400 MHz, DMSO-d6) δ 1.06 (s, 9H), 1.32 (t, J=6.8 Hz, 3H), 2.54 (s, 3H), 3.86 (s, 2H), 4.31 (q, J=6.8 Hz, 2H). 6.88-6.91 (m, 1H), 7.22-7.25 (m, 1H), 7.50 (t, J=8.0 Hz, 1H), 8.06 (s, 2H). MS 317 (MH+).
Reaction SMILES: CC(C)=[O:3].[Cl:5][C:6]1[C:7]2[O:25][CH:24]([CH2:26][OH:27])[CH2:23][C:8]=2[C:9]2[O:13][N:12]=[C:11]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[C:10]=2[CH:22]=1.S(=O)(=O)(O)O>[O-2].[Cr+6].[O-2].[O-2].O>[Cl:5][C:6]1[C:7]2[O:25][CH:24]([C:26]([OH:3])=[O:27])[CH2:23][C:8]=2[C:9]2[O:13][N:12]=[C:11]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[C:10]=2[CH:22]=1
Reactant: OCC1Cc2c(c(Cl)cc3c(-c4c(F)cccc4F)noc23)O1
Reactant: CC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)C1Cc2c(c(Cl)cc3c(-c4c(F)cccc4F)noc23)O1
Reaction time: 9 h

Procedure:
To the stirred acetone (50 ml) solution of 2.8 g of the 5-chloro-3-(2,6-difluorophenyl)-7,8-dihydrofuro[2,3-g]1,2-benzisoxazole-7-methanol prepared in Example 20, a mixture of chromium (VI) oxide (3.0 g), water (7 ml) and concentrated sulfuric acid (4.2 g) was added dropwise over time, and the agitation was continued for 9 hours at room temperature. The insolubles were filtered off by suction and the acetone was distilled off. Water was added to the residue, and the solution was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 1.0 g of 5-chloro-3-(2,6-difluorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 239.5°-241° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 351.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14](Br)[CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[Cl:24]>>[CH2:1]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[C:23]([Cl:24])[CH:22]=3)[CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1cc(Br)c2ncccc2c1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CCCCCc1cc(-c2ccc(Cl)c(Cl)c2)c2ncccc2c1

Procedure:
6-pentyl-8-bromoquinoline and 3,4-dichlorobenzene boronic acid can be combined to form 6-pentyl-8-(3,4-dichlorophenyl)quinoline,
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:11][C:12]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1.CO>C(Cl)Cl.N1C=CC=CC=1>[CH:1]1([CH2:6][CH2:7][C:8]([NH:11][C:12]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(N)nn2cccnc12
Reactant: O=C(Cl)CCC1CCCC1
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)CCC2CCCC2)nn2cccnc12
Reaction time: 4 h

Procedure:
A solution of 3-cyclopentylpropionyl chloride (0.58 mL, 3.8 mmol) in CH2Cl2 (0.5 mL) was added to a suspension of the product from Example 125A (300 mg, 1.56 mmol) in pyridine (5 mL) at room temperature. After 4 hours, methanol (10 mL) was added to quench the excess acyl chloride, and the mixture was stirred for 15 minutes, and then concentrated under vacuum. The residue was crystallized from 86% methanol-water (24 mL) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.22 (m, 2H) 1.39-1.69 (m, 6H) 1.68-1.88 (m, 3H) 2.46-2.54 (m, 2H) 3.81 (s, 3H) 7.25 (dd, J=6.9, 4.2 Hz, 1H) 8.75 (dd, J=4.4, 1.6 Hz, 1H) 9.18 (dd, J=6.9, 1.8 Hz, 1H) 10.04 (s, 1H); MS (ESI) m/z 317 (M+H)+; Anal. Calculated for C16H20N4O3: C, 60.75; H, 6.37; N, 17.71. Found: C, 60.71; H, 5.85; N, 17.48.