Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:6]2[C:5]1=[O:14].[C:15]([O:30]CC(C)C)(=O)[CH:16]1[CH2:28][CH:27]=[CH:26][CH2:25][CH:17]1[C:18]([O:20][CH2:21][CH:22](C)C)=[O:19]>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4].O>[C:18]([O:20][CH2:21][CH2:22][N:4]1[C:5](=[O:14])[CH:6]2[CH2:13][CH:12]=[CH:11][CH2:10][CH:7]2[C:8]1=[O:9])(=[O:19])[CH:17]1[CH2:25][CH:26]=[CH:27][CH2:28][CH:16]1[C:15]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:6]2[C:5]1=[O:14])=[O:30]
Reactant: CC(C)COC(=O)C1CC=CCC1C(=O)OCC(C)C
Reactant: O=C1C2CC=CCC2C(=O)N1CCO
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: O
Product: O=C(OCCN1C(=O)C2CC=CCC2C1=O)C1CC=CCC1C(=O)OCCN1C(=O)C2CC=CCC2C1=O
Temperature: 230 °C
Reaction time: 24 h
Yield: 101 %

Procedure:
N-(2-Hydroxyethyl)-1,2,3,6-tetrahydrophthalimide (195.2 g, 1 mol) was dissolved in diisobutyl 1,2,3,6-tetrahydrophthalate (141.2 g, 0.5 mol). The mixture was kept at 150° C. under vacuum to eliminate any traces of water. Titanium tetrabutoxide (1.7 g) was added under atmospheric pressure and the transesterification reaction was carried out distilling off the isobutyl alcohol formed. As the reaction proceeded the temperature was increased stepwise to 230° C. and the pressure was lowered to 20 Torr (26.7 mbar). After ca. 24 h, 265 g of brown crude bis[2-(1,2,3,6-tetrahydrophthalimido)ethyl] 1,2,3,6-tetrahydrophthalate were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH:20]=[O:21])[CH:7]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH2:20][OH:21])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C)cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)Cc1cccc(Oc2ccc(C)cc2CO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
To [3-(2-formyl-4-methyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.20 g, 0.67 mmol) in MeOH (20 mL) was added sodium borohydride (0.03 g, 0.8 mmol), and the reaction was stirred for 10 minutes at room temperature. Once no starting material was seen by analytical tlc, the mixture was worked-up to give the desired product (0.20 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:8]=3[NH:7][C:6]=2[N:19]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[C:11](=[O:12])[N:10]([CH3:23])[C:9]3[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:8]=3[NH:7][C:6]=2[N:19]=1
Reactant: Cc1cc(C)c2c(n1)Nc1cc(C)c(C)cc1NC2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(n1)Nc1cc(C)c(C)cc1N(C)C2=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 6.7 gm of 6,11-dihydro-2,4,8,9-tetramethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 150 ml of dimethyl formamide and 1.4 gm of 50% sodium hydride in mineral oil was stirred at 50° C. in a nitrogen atmosphere for 30 minutes. Thereafter, a solution of 7.1 gm of methyl iodide in 30 ml of dimethyl formamide was added dropwise at room temperature. The resulting mixture was heated on an oil bath at 120° C. for 1 hour, and was then evaporated in vacuo. The residue was admixed with water, the aqueous mixture was made alkaline with ammonia, and it was then extracted with chloroform. After separation of the 2,4,6,8,9,11-hexamethyl compound which had simultaneously formed in a silica gel column, the product was recrystallized from petroleum ether (b.p. 100°-140° C.), yielding 63% of theory of the compound named in the heading, which had a melting point of 225°-227° C.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:13][N:14]([CH:16]=[O:17])C>N1C=CC=CC=1>[CH3:13][NH:14][C:16]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:17]
Reactant: CN(C)C=O
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Solvent: c1ccncc1
Product: CNC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 60 °C
Yield: 85 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3-adamantanediol and one drop of pyridine were dissolved in 10 mL of DMF. To the mixture, 10 mmole of methylisocyanato was added dropwise with stirring. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3-adamantanediol was 99% and 1-(N-methylcarbamoyloxy)-3-adamantanol (yield 85%) was formed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH2:5]I.[CH2:12]([O:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18])[CH3:13]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH2:5][P:15](=[O:19])([O:16][CH2:17][CH3:18])[O:14][CH2:12][CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: Fc1cc(CI)cc(F)c1F
Product: CCOP(=O)(Cc1cc(F)c(F)c(F)c1)OCC
Temperature: 135 °C
Reaction time: 8 h

Procedure:
3,4,5-trifluorobenzyl iodide (5.075 g, 22.55 mmol) was combined with triethylphosphite (11.6 mL, 67.7 mmol) and the mixture heated and stirred at 135° C. overnight. The mixture was put under hi-vacuum and heated to 70° C. for 12 hours. The final product was a clear oil (6.10 g, 96% yield). 1H NMR (400.14 MHz, CDCl3) δ 6.93 (m, 2H), 4.07 (quint, J=7.10 Hz, 4H), 3.06 (d, J=21.7 Hz, 2H), 1.28 (t, J=7.05 Hz, 6H). 13C {1H} NMR (100.62 MHz, CDCl3) δ 150.8 (dddd, J=249.7, 9.8, 3.8, 3.8 Hz, 2C), 138.74 (dtd, J=250.6, 15.2, 3.9 Hz), 128.2-127.9 (m), 113.9-113.6 (m, 2C), 62.30 (d, J=6.74 Hz, 2C), 32.93 (d, J=139.8 Hz), 16.20 (d, J=6.01 Hz, 2C). 31P{1H} NMR (202.45 MHz, CDCl3): δ 24.96. Analysis calculated (found) %: C, 46.82 (46.72), H, 5.00 (4.96). MS (FAB, m/z): 269 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 269.05544 (269.05616).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[C:42]1(=O)[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[O:43]1>O1CCOCC1>[O:43]=[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[N:1]1[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:3]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N1C(=O)c3ccccc3C1=O)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 110 °C

Procedure:
(R)-1-(3-Amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 47, Step 1; 503 mg, 0.934 mmol) and isobenzofuran-1,3-dione (159 mg, 1.074 mmol) were added to a 1.5 mL microwave vial, charged with dioxane (4 mL), and heated to 110° C. for 4.5 h. The solvents were concentrated in vacuo and the residue was purified by flash chromatography (2-10% EtOAc/DCM) to give (R)-1-(3-(1,3-dioxoisoindolin-2-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C42H32N6O3 [M+1]+ 669. found 669.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([C:26]2[C:27](=O)[NH:28][C:29]3[C:34]([N:35]=2)=[CH:33][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>ClCCl>[N:16]1([C:26]2[C:27]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[N:28][C:29]3[C:34]([N:35]=2)=[CH:33][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccccc43)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCc4ccccc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic anhydride (315.6 mg, 1.12 mmol) was added to a solution of methyl 3-(3, 4-dihydroquinolin-1(2H)-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200.0 mg, crude) and pyridine (176.8 mg, 2.24 mmol) in dichloromethane (50 ml). After stirring overnight at room temperature, the reaction was quenched with water (50 ml) and extracted with dichloromethane (3×80 ml). Then the organic layers were combined dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 3-(3,4-dihydroquinolin-1(2H)-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (300 mg, crude), which was used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][N:4]3[C:3]1=[O:18].C1C(=O)N([Cl:26])C(=O)C1>CN(C)C=O>[Cl:26][C:10]1[CH:9]=[C:8]2[C:13]3=[C:12]([C:2](=[O:1])[C:3](=[O:18])[N:4]3[CH2:5][CH2:6][CH:7]2[C:14]([O:16][CH3:17])=[O:15])[CH:11]=1
Reactant: COC(=O)C1CCN2C(=O)C(=O)c3cccc1c32
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)C1CCN2C(=O)C(=O)c3cc(Cl)cc1c32
Temperature: 80 °C
Yield: 96.2 %

Procedure:
A mixture of methyl 5,6-dihydro-1,2-dioxo-4H-pyrrolo[3,2,1-ij]quinoline-6-carboxylate (Example 1; 3 g)and N-cholorsuccinimide (NCS, 1.96 g) in dimethylformamide (DMF, 30 ml) was heated at 80° C. with stirring for an hour. After cooling, the mixture was concentrated. The residue was extracted with chloroform (200 ml). Chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated to give the title compound (3.28 g, 96.2%) which was recrystallized form acetonitrile to dark red needles, mp 132° C.-133° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].CCN(C(C)C)C(C)C.Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S([O-])([O-])(=O)=O.[Mg+2]>CN(C=O)C>[C:20]1([CH2:19][CH2:18][CH2:17][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CN
Reactant: BrCCCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.4 %

Procedure:
Under argon condition, glycine methyl ester (330 mg, 2.63 mmol) was dissolved in 3 mL of dry DMF and then DIPEA (573 μL, 3.29 mmol) and 1-bromo-3-phenylpropane (100 μL, 0.658 mmol) were added. The reaction mixture was then stirred for one day at room temperature. Upon completion of the reaction, the reaction was terminated by adding 5 mL of water, and the reaction mixture was extracted with diethyl ether (4 mL×4). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 19.6 mg (0.0946 mmol, 14%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:23](=[O:24])[N:22]([CH:25]([F:27])[F:26])[C:21]([CH3:28])=[N:20]2)=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1.[S:29]([CH:33]([CH3:35])[CH3:34])(=[O:32])(=[O:31])[NH2:30]>C(Cl)Cl>[CH3:34][CH:33]([S:29]([NH:30][C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:14]=[C:15]([N:19]3[C:23](=[O:24])[N:22]([CH:25]([F:26])[F:27])[C:21]([CH3:28])=[N:20]3)[C:16]([F:18])=[CH:17][C:2]=2[Cl:1])=[CH:6][CH:7]=1)=[O:12])(=[O:32])=[O:31])[CH3:35]
Reactant: CC(C)S(N)(=O)=O
Reactant: Cc1nn(-c2cc(Oc3ccc(C(=O)Cl)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Solvent: ClCCl
Product: Cc1nn(-c2cc(Oc3ccc(C(=O)NS(=O)(=O)C(C)C)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 195 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
A stirred mixture of 0.59 g (0.0014 mole) of 4-[2-chloro-4-fluoro-5-(4-difluoromethyl -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4 triazol-1-yl)phenoxy]phenyl-carboxylic acid chloride and 0.17 g (0.0014 mole) of 2-sulfamylpropane was heated at 195° C. for approximately 15 minutes. The mixture was cooled and 2 mL of methylene chloride was added. The mixture was allowed to stand at room temperature for approximately 18 hours. A brown solid formed, was collected and triturated with petroleum ether. Recovery of the solid by filtration gave 0.58 g of N-(1-methylethyl)sulfonyl-4-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]phenylcarboxamide as a solid, m.p. 185°-187° C., Compound 130 of Table 1.
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH:12]([CH2:19][C:20]1([CH3:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:13]2=[O:18]>C1COCC1.C(O)C>[C:3]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH:12]([CH2:19][C:20]1([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH:13]2[OH:18]
Reactant: CC1(CC2Cc3c(cccc3-c3ccccc3-c3ccccc3)C2=O)CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(CC2Cc3c(-c4ccccc4-c4ccccc4)cccc3C2O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
Sodium borohydride (0.56 g, 14.83 mmol, 1.5 equiv) was added in portions at 0° C. to a solution of compound 21 (3.9 g, 9.88 mmol, 1.0 equiv) in THF (50 mL) and ethanol (50 mL). The reaction mixture was stirred at room temperature overnight, when L/CMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (300 mL) and water (50 mL). 1 M aqueous HCl was added dropwise to quench the reaction. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated brine (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound 22 (4.0 g, >99% yield) as a pale-yellow oil. This material was used subsequently.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:33](Cl)([Cl:35])=[O:34]>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:33]([Cl:35])=[O:34]
Reactant: O=C(Cl)Cl
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)Cl)CCC5(C)C4CCC32CN1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
Compound 7B (125 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0° C. Triethylamine (150 μL, 1.1 mmol) and phosgene (20% in toluene, 0.23 mL, 0.44 mmol) were added to it. The mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with water, extracted with dichloromethane. The combined extracts were dried over Na2SO4, filtered and concentrated to give crude desired product (144.6 mg, 97.8%), which was used in next step without further purification.
Reaction SMILES: [O-2].[Ca+2].[O-2].[Mg+2].[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[CH2:15]=[CH:16][CH3:17]>[O-2].[Fe+2]>[CH:16]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8]2)([CH3:17])[CH3:15]
Reactant: c1ccc2c(c1)CCCC2
Reactant: C=CC
Agent: [Fe+2]
Agent: [Ca+2]
Agent: [Mg+2]
Product: CC(C)c1ccc2c(c1)CCCC2
Yield: 92 %

Procedure:
Bouncer, EP 160145A, has taught that tetralin can be selectively monoalkylated with olefins using as catalysts a wide pore amorphous silica-alumina. Muganlinsk et al., SU1076424-A have obtained [presumably] monoalkyltetralins in 95-98% yield by alkylating tetralins with aliphatic alcohols containing 4 to 10 carbon atoms using a sulfated silica-alumina (approximately 7:1) containing iron oxide, calcium oxide, and magnesium oxide. However, it seems likely that alkylation occurs via olefin arising from the alcohol, since olefinic oligomers are the principal side products of the reaction. The patentee in J81009958-B used a 7:1 silica-alumina in the alkylation of tetralin with propylene to give 6-isopropyltetralin in 92% yield. More recently Innes et al., U.S. Pat. No. 4,891,458, have used zeolite β to alkylate aromatic hydrocarbons with olefins of 2-4 carbon atoms in the liquid phase, claiming that zeolite β has a higher selectivity to the monoalkyl products and a longer catalyst lifetime than other zeolites.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(Cl)[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:4]([C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:2][CH3:1])[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: C=CCOC(=O)C(Cl)(Cc1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)C(Cc1ccccc1)(OC)c1ccccc1
Reaction time: 2 h
Yield: 94.7 %

Procedure:
Into a solution of 1.1 g of sodium methylate in 20 cc of methanol was added a solution of 6.0 g of allyl α-benzyl-α-chlorophenylacetate in 10 cc of methanol under cooling, and the mixture was stirred for 2 hours, whereby white precipitates were deposited. The reaction mixture was poured in water and the resultant was subjected to extraction with ether. The ether extract was washed with an aqueous solution saturated with sodium chloride and dried over sodium sulfate, and thereafter evaporation of ether gave 5.6 g of oily allyl α-benzyl-α-methoxyphenylacetate, nD25 1.5486.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=O)[C:5]([OH:7])=[O:6].[NH2:10][C@H:11]([C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>>[C:5]([CH:4]([NH:10][C@H:11]([C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:28])[NH2:29])=[O:20])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][CH:2]([CH3:9])[CH3:1])([OH:7])=[O:6]
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Reactant: CC(C)CC(=O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CC(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O)C(=O)O

Procedure:
In the manner described in Example 54, 4-methyl-2-oxopentanoic acid and L-phenylalanyl-L-arginine are condensed in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-methylbutyl)-L-phenylalanyl-L-arginine. The product is eluted from the ion exchange resin with 10% ammonia. The nmr spectrum in D2O gave a singlet at 7.2 (5H), a broad triplet centered at 3.0 (6H), a broad multiplet at 1.3 (6H), and a broad doublet at 0.9 (6H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:24])=[CH:4][CH2:5][CH2:6][C:7]([CH3:23])=[CH:8][CH2:9][CH2:10][C:11]([CH3:22])=[CH:12][CH:13]=[C:14]([CH:19]([CH3:21])[CH3:20])[CH:15]([OH:18])[C:16]#[N:17].[CH:25]([O:27][CH2:28][CH3:29])=[CH2:26].C(=O)([O-])O.[Na+].CCCCCC.CCOCC>ClCCl>[Cl:1][CH2:2][C:3]([CH3:24])=[CH:4][CH2:5][CH2:6][C:7]([CH3:23])=[CH:8][CH2:9][CH2:10][C:11]([CH3:22])=[CH:12][CH:13]=[C:14]([CH:19]([CH3:20])[CH3:21])[CH:15]([O:18][CH:25]([O:27][CH2:28][CH3:29])[CH3:26])[C:16]#[N:17]
Reactant: CC(=CCCC(C)=CCCC(C)=CC=C(C(C)C)C(O)C#N)CCl
Reactant: C=COCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(C)OC(C#N)C(=CC=C(C)CCC=C(C)CCC=C(C)CCl)C(C)C
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
To a solution of 15-chloro-2-hydroxy-3-(1-methylethyl)-6,10,14-trimethyl-3,5,9,13-pentadecatetraenenitrile (204 mg, 0.56 mmol) prepared in Reference Example 6 and ethyl vinyl ether (100 μl, 0.96 mmol) in dichloromethane (5 ml) is added a very small amount of paratoluenesulfonic acid while stirring under nitrogen atmosphere on an ice-water bath. After 10 minutes, to the mixture are added a saturated aqueous sodium hydrogencarbonate solution (15 ml) and n-hexane/ether (1:1) solution (20 ml) and the organic layer is separated. The aqueous layer is then extracted with n-hexane/ether (1:1) solution (20 ml) for several times. The organic layers are combined and dried over anhydrous sodium sulfate and the solvent is removed by distillation under reduced pressure. The resulting residue is purified by silca gel column chromatography (n-hexane/ ethyl acetate=20:1) to give 15-chloro-2-(1-ethoxyethoxy)-3-(1-methylethyl)-6,10,14-trimethyl -3,5,9,13-pentadecatetraenenitrile (207 mg, 85%).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:20])[C@@H:18]([NH2:19])[C@H:15]3[S:14][C@:13]2([CH2:22][O:23][C:24](=[O:29])[NH:25][C:26](=[O:28])[CH3:27])[CH3:21])=[O:11])=CC=1)([O-])=O.[H][H]>[Pd].O>[C:26]([NH:25][C:24]([O:23][CH2:22][C@@:13]1([CH3:21])[C@H:12]([C:10]([OH:11])=[O:9])[N:16]2[C:17](=[O:20])[C@@H:18]([NH2:19])[C@H:15]2[S:14]1)=[O:29])(=[O:28])[CH3:27]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Yield: 65.1 %

Procedure:
To a prehydrogenated suspension of 10% palladium on carbon (0.83 gm), water-washed ethyl acetate (8.3 ml) and water (4.1 ml) was added (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-6-amino-2-methylpenam-3-carboxylic acid p-nitrobenzyl ester (0.83 gm, 1.84 mmol). The mixture was shaken at 50 psi hydrogen pressure for 80 minutes and filtered through Dicalite-coated paper. The aqueous phase was separated, concentrated at reduced pressure to remove volatile solvent and gases, frozen and lyophilized. There was obtained 0.38 gm of the title compound as a white amorphous solid. Its nmr spectrum was consistent with the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.C([NH:35][C:36](NC(OC(C)(C)C)=O)=[N:37]S(C(F)(F)F)(=O)=O)(OC(C)(C)C)=O.C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)[C:36]([NH2:37])=[NH:35]
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=N)N)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.43 %

Procedure:
A mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (30 mg, 81.87 μmol), 1,3-di-boc-2-(trifluoromethylsulfonyl)guanidine (38.45 mg, 98.25 μmol) and triethylamine (22.82 μL, 163.7 μmol) in DCM was stirred at room temperature for 5 hours. Then to the mixture was added TFA (6.308 μL, 81.87 μmol) and the mixture was stirred overnight. The crude product was purified by column chromatography to afford the title compound as brown oil in 49.43% yield. LCMS m/z (%)=409 (M+H, 100). 1H NMR (400 MHz, MeOH-d4) δ 3.5 (t, J=5.1 Hz, 2H) 3.7 (s, 3H) 3.9 (s, 3H) 4.1 (t, J=5.1 Hz, 2H) 6.3 (d, J=2.0 Hz, 1H) 7.1 (d, J=5.6 Hz, 1H) 7.2 (d, J=9.1 Hz, 1H) 7.4 (t, J=7.8 Hz, 1H) 7.5 (m, 2H) 7.5 (d, J=2.0 Hz, 1H) 7.6 (d, J=3.0 Hz, 1H) 7.8 (dd, J=8.8, 2.8 Hz, 1H).