Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:29]=1.CN(C)C=O>C(N(CC)CC)C>[C:7]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:29]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A mixture comprising 5 g of triphenylchloromethane and 15 ml of dichloromethane was added dropwise at -30° C. to a mixture comprising 3.1 g of ethyl 2-aminothiazole-4-carboxylate, 25 ml of dimethylformamide and 1.8 g of triethylamine. The reaction mixture was maintained at -30° C. for 10 minutes and was then stirred at room temperature for 2 hours. after which it was poured into ice water and extracted with ethyl acetate. The extract was washed successively with 0.1N hydrochloric acid and aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel chromatography, using as eluent a 10:1 by volume mixture of benzene and ethyl acetate. The crystals obtained thereby were washed with n-hexane, to afford the desired compound as a white powder.
Reaction SMILES: [C:1]([P:3](=[O:10])([O:7]CC)[O:4][CH2:5][CH3:6])#[N:2].Cl.[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13]>CC(N(C)C)=O>[CH2:5]([O:4][P:3]([C:1]#[N:2])(=[O:7])[O-:10])[CH3:6].[CH2:12]([NH+:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13]
Reactant: CCOP(=O)(C#N)OCC
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CCOP(=O)([O-])C#N
Product: CC[NH+](CC)CC
Temperature: 80 °C
Yield: 58.1 %

Procedure:
Diethyl cyanophosphonate (0.50 g, 3.06 mmol) and triethylamine hydrochloride (0.421 g, 3.06 mmol) were added to dimethylacetamide (0.5 mL) which was heated to 80° C. for 3 hours. Then dimethylacetamide was removed under vacuum to give 0.42 g (67% yield) of a viscous residue which was analyzed by NMR and mass spectrometry without additional purification. 31P NMR (D2O) δ (ppm) major peak (94.7%) -19.6 (t, 3JPH =9.3 Hz), minor peak (5.3%) -12.1; 1H NMR (D2O) δ (ppm) 1.25 (tr), 3.20 (q), and 4.05 (qnt); 13C NMR (D2O) δ (ppm) 119.9 (d, 1JCP =174.35 Hz), 63.9 (d, 2JCP =6.6 Hz), 47.0 (t, J=4.0 Hz) 16.0 (d, 3JCP =6.8 Hz), 9.1 (s). Mass spectral analysis (FAB+, thioglycerol) detected a peak at m/z 338.4, corresponding to the complex species [[+HN(C2H5 )3 ]2 --O(OC2H5)POCN]+ !, the presence of a cation at m/z 102 [[HN(C2H5)3 ]+ ] and an anionic species (FAB- thioglycerol) at m/z 133.9 [NCP(O)(OC2H5)O - ], its protonated dimer at m/z 268.9 [(H+) O(OC2H5)POCN- ][O(OC2H5)POCN]-, and to the cluster [[+HN(C2H5)3 ]O(OC2H5)POCN- ][O(OC2H5)POCN]- at m/z 370.1.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].NO.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([C:22]([N:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:34](OC)=[O:35])[CH:30]=3)[CH2:25]2)=[O:23])([CH3:21])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C>CO.CN(C=O)C>[OH:3][NH:2][C:34]([C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:22]([C:18]1([CH3:21])[CH2:19][CH2:20][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:16][CH2:17]1)=[O:23])[CH2:33][CH2:32]2)=[O:35]
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)CCN(C(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)N2CCc3cc(C(=O)NO)ccc3C2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
A mixture of hydroxylamine hydrochloride (2.0 g, 29 mmol) in methanol (10 mL) was heated at 90° C. under a dry nitrogen atmosphere until homogeneous. To this heated solution was added a solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6 mL). A precipitate formed on mixing. After heating at 90° C. for 30 minutes, the mixture was cooled to rt and the solids were allowed to settle. The resulting solution was assumed to contain 1.7 M hydroxylamine.potassium salt and was carefully removed by syringe to exclude solids. An aliquot of the above solution (1.95 mL, 3.31 mmol) was added to a solution of methyl 2-{[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (138 mg, 0.331 mmol) in methanol (0.5 mL) and DMF (0.5 mL). After stirring for 3 h at rt, excess reagent was quenched by the addition of acetic acid (0.188 mL, 3.31 mmol). The mixture was concentrated to dryness and the residue was twice co-evaporated with toluene. The crude product was purified by preparative HPLC to afford tert-butyl 4-{[6-(hydroxycarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-4-methylpiperidine-1-carboxylate (103 mg, 74.5%). LC-MS: (FA) ES+ 418; 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 9.00 (s, 1H), 7.59-7.52 (m, 2H), 7.28 (d, J=8.0 Hz, 1H), 4.71 (s, 2H), 3.79 (t, J=5.8 Hz, 2H), 3.53-3.44 (m, 2H), 3.15-3.03 (m, 2H), 2.83 (t, J=5.4 Hz, 2H), 2.06-1.96 (m, 2H), 1.47-1.39 (m, 2H), 1.37 (s, 9H), 1.24 (s, 3H).
Reaction SMILES: [C:1](#N)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:10]([Mg]Cl)([CH3:12])[CH3:11].CC[O:17]C(C)=O>CCOCC.CCCCCC>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1](=[O:17])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[Mg]Cl
Reactant: CCOC(C)=O
Reactant: N#Cc1ccccc1N
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)C(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
A solution of anthranilonitrile (8.507 gm, 72 mmol) in dry Et2O (20 ml) was added to i-propylmagnesium chloride (2.0M in Et2O, 100 ml, 200 mmol) in dry Et2O (30 ml) at 0° C. over a 15 minute period. After the addition was complete, the mixture was warmed to room temperature and stirred for 4.5 hours. The solution was cooled to 0° C., quenched with 10% HCl (150 ml), then stirred for 25 minutes. The aqueous layer was made basic with solid NaOH (25 gm) and then extracted with Et2O (3×). The combined Et2O extracts were washed with brine, then dried (Na2SO4), filtered and stripped to give a yellow oil. Flash Chromatography of the oil (Merck SiO2, 15% EtOAc in hexane) afforded 1-(2-aminophenyl)-2-methyl-1-propanone (10.916 gm, 93%) as a golden yellow oil.
Reaction SMILES: [Na].C(O)C.[N+]([CH:8]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:20])([O-])=O.Cl>C(Cl)Cl.O.C(O)C.O>[CH2:9]([OH:20])[CH2:8][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: O=C1CCCCCCCCCCC1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCO
Temperature: 15 °C
Reaction time: 0.33 h

Procedure:
For purposes of analytical determinations, the process of Example 2 was carried out with sodium boroduteride (NaBD4) To 40 milliliters of absolute ethanol was added about 2.5 grams of NaBD4 (0.05972 mole). The suspension was stirred and about 6.78 grams (0.02986 mole) solid 2-nitro cyclododecan-1-one were added in portions maintaining the temperature at about 15° C. The addition took about 20 minutes and some foaming was evidenced (gas evolution). After the addition was complete, a white, fairly thick precipitate was evident. An additional 10 milliliters of ethanol was added to facilitate stirring. The reaction mass was allowed to warm to room temperature and stirred overnight. The acidification process of the previous examples was followed and the precipitate again disappeared at a pH of 2 after addition of about 100 milliliters of 2% HCl. The solution had a fine white appearance. The ethanol/water was stripped to about 1/2 the starting volume and the water-oil emulsion left was taken up in methylene chloride. After two washings with methylene chloride, the combined organic layers were dried over magnesium sulfate and the solvent stripped off and vacuumed. A yellow oil was recovered which solidified fairly rapidly. The material melts at 40° C. and approximately 6.95 grams of product were recovered. Using the deuterium ions supplied in place of hydride ions from the NaBD4, the nuclear magnetic resonance spectroscopy confirmed the ring opening of the cyclic compound to form a dodecanol having a nitro substituent at the opposite end of the hydroxy function. Furthermore, the analysis confirmed that the carbonyl function had been converted to the hydroxy function.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH2:43][CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])=[O:41])=[CH:38][CH:37]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH2:43][CH2:44][CH2:45][N:46]([CH3:47])[CH3:48])=[O:41])=[CH:38][CH:37]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: CN(C)CCCNC(=O)c1ccc(N)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CN(C)CCCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(F)(F)C(=O)N3C)cc1
Yield: 69.5 %

Procedure:
A mixture of 0.0562 g (0.18 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0514 g (0.27 mmole) of toluenesulfonic acid monohydrate, 0.0398 g (0.18 mmole) of 4-amino-N-(3-dimethylamino-propyl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 16 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (80:20:2) to give 0.0645 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-benzamide (I-265).
Reaction SMILES: C([O:8][CH:9]1[CH2:24][CH2:23][C:12]2([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:8][CH:9]1[CH2:10][CH2:11][C:12]2([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:13]2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCC(OCc3ccccc3)CC2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(CCC(O)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of tert-butyl 7-(benzyloxy)-2-azaspiro[3.5]nonane-2-carboxylate (290 mg, 0.96 mmol, 1.0 equiv) in MeOH (8 mL) was added Pd(OH)2 (43.5 mg, 15 wt %). The mixture was carefully vacuumed and refilled with Hydrogen. The mixture was then stirred at room temperature under hydrogen balloon for 2 hrs. The mixture was passed through a pad of celite and eluted with MeOH (50 mL). The combined methanol solution was concentrated to afford 218 mg (yield 94%) of tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:27]3[CH:28]=[CH:29][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(C(C)=O)cc3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-acetyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.[BH4-].[Na+].CCN(C(C)C)C(C)C.O=S(Cl)[Cl:32]>CO.C1COCC1>[Cl:32][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:18])([F:17])[F:1])=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccccc1-c1ccc(CCl)cc1
Reaction time: 1 h
Yield: 147.8 %

Procedure:
To a solution of the product of Example 36, Step A (0.15 g, 0.6 mmol) in MeOH (3 m) NaBH4 (0.028 g; 0.74 mmol) was added in portion wise at room temperature. After 1 h of stirring the solvent was evaporated and the residue was diluted to 20 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue (0.25 g, 0.99 mmol) was dissolved in anhydrous THF (5 ml). To this DIPEA (0.19 ml, 1.1 mmol) was added at 0° C. under N2, with stirring, followed by SOCl2 (0.08 ml, 1.1 mmol). This was stirred overnight at room temperature. The solvent was distilled off and the crude product was diluted to 20 ml with EtOAc and washed with NaHCO3 solution. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was passed through silica gel bead and washed with fresh EtOAc (20 ml). The combined filtrates were evaporated to dryness to give the title compound (0.24 g, 89%) as colourless oil. 1H-NMR (CDCl3) 4.64 (s, 2H); 7.30 (d, 3H, J=8.12 Hz); 7.4-7.58 (m, 4H); 7.73 (d, 2H, J=7.84 Hz).
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].O[C:17]1[CH:18]=[C:19]([C:27]([O:29][CH3:30])=[O:28])[CH:20]=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:26]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[CH:20]=[C:19]([CH:18]=1)[C:27]([O:29][CH3:30])=[O:28])(=[O:5])=[O:4]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Reaction time: 1 h

Procedure:
With cooling with ice, trifluoromethanesulfonic acid anhydride (4.04 mL, 24.0 mmol) was added to a mixture of dimethyl 5-hydroxyisophthalate (4.20 g, 20.0 mmol), triethylamine (6.69 mL, 48.0 mmol) and chloroform (40 mL), and stirred for 1 hour with cooling with ice. The reaction mixture was diluted with chloroform, shaken with aqueous saturated sodium hydrogencarbonate solution, then the organic layer was dried with sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a colorless solid.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].[P:9](Cl)([Cl:12])([Cl:11])=[O:10].NC1C=CC(S(C=CC#N)(=O)=O)=CC=1.CCCCCCCC>CC(C)=O.N1C=CC=CC=1>[Cl:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Cl:8])[P:9]([Cl:12])([Cl:11])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCNCCCl
Agent: Cl
Agent: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: CCCCCCCC
Product: O=P(Cl)(Cl)N(CCCl)CCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Di-(2-chloroethyl)amidophosphorodichloridate is prepared according to H. Brintzinger et al in Chemische Berichte 82, 389-99 (1949) from bis-(2-chloroethyl)amine hydrochloride and phosphoryl chloride in the presence of pyridine. 0.03 mol (7.8 g) of this material is dissolved in 100 ml of acetone and added to an acetone solution of 0.03 mole (6.3 g) of 2-cyanovinyl 4-aminophenyl sulfone. To the stirred mixture is added in 2-3 portions a 10% solution of 1,4-diazabicyclo[2.2.2.]octane in acetone. After a few minutes a yellow slurry forms which is stirred at room temperature for 30 minutes. After filtration to remove the amine hydrochlorides the filtrate is reduced to about half its volume by evaporation and then mixed with chloroform, washed with water and worked up. The light yellow solid is di-(2-chloroethyl)amido-di-4-(2-cyanoethenesulfonylanilido)phosphine oxide: ##SPC57##
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[CH:24]([O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([CH2:26][CH3:27])[CH3:25]>>[CH:24]([O:28][C:29]1[CH:30]=[CH:31][C:32]([N:33]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:19]([CH2:18][CH:17]([CH3:23])[CH3:16])(=[O:21])=[O:20])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:34][CH:35]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: CCC(C)Oc1ccc(N)cc1
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCC(C)Oc1ccc(N2CCC3(CCN(S(=O)(=O)CC(C)C)CC3)C2=O)cc1

Procedure:
Light brown solid. MS (ESI): 423.23 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methyl-propane-1-sulfonyl chloride and 4-sec-butoxy-aniline.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: Clc1cnccn1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(C)c21
Temperature: 90 °C
Yield: 38.1 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)acetic acid ethyl ester (0.5 g, 2.0 mmol) in anhydrous DMF (5 mL) were added Cs2CO3 (1.629 g, 5.0 mmol) and 2-chloro-pyrazine (0.275 g, 2.4 mmol) at room temperature. The reaction mixture was heated to 90° C. for 3 hours then poured into ice-water (10 mL). The mixture was acidified to pH 2 using dilute hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexane/AcOH=3:2:trace) to give the product as an oil (0.250 g, 38.1%). 1HNMR (400 MHz, DMSO-d6) δ9.22 (s, 1H), 8.53 (d, J=1.17 Hz, 1H), 8.35 (d, J=2.64 Hz, 1H), 8.18 (dd, J=2.78, 1.32 Hz, 1H), 7.25 (d, J=2.05 Hz, 1H), 7.10 (d, J=1.46 Hz, 1H), 5.53 (dd, J=9.08, 2.34 Hz, 1H), 3.94-4.11 (m, 2H), 3.13 (dd, J=15.52, 2.63 Hz, 1H), 2.20-2.40 (m, 4H), 1.06-1.26 (m, 3H). MS (ESI) m/z=329 [M+H]+.
Reaction SMILES: C1(N2C(C(F)(F)F)=C(C3[O:20]N=C4C5C(CCC=34)=CC(C=O)=CC=5)C=N2)C=CC=CC=1.[CH:31]1([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[O:47][N:46]=[C:45]4[C:48]5[C:53]([CH2:54][CH2:55][C:44]=34)=[CH:52][C:51]([CH:56]=C)=[CH:50][CH:49]=5)=[CH:39][C:38]=2[C:58]([F:61])([F:60])[F:59])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[O:47][N:46]=[C:45]4[C:48]5[C:53]([CH2:54][CH2:55][C:44]=34)=[CH:52][C:51]([CH:56]=[O:20])=[CH:50][CH:49]=5)=[CH:39][C:38]=2[C:58]([F:59])([F:60])[F:61])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(C2CCCCC2)c(C(F)(F)F)c1

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 89B employing 3-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (118D) as a starting material. The compound had an HPLC retention time=4.43 min. (condition C); LC/MS M+1=426.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:11])[C:7]([CH3:10])=[CH:8][CH:9]=1)([O-])=O.[CH2:12]([C:14]([CH2:16][CH3:17])=O)[CH3:13].[H][H]>[Pt].O.C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>[CH2:12]([CH:14]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH3:11])[CH:5]=1)[CH2:16][CH3:17])[CH3:13]
Reactant: [H][H]
Reactant: CCC(=O)CC
Reactant: Cc1ccc([N+](=O)[O-])cc1C
Agent: [Pt]
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: O
Product: CCC(CC)Nc1ccc(C)c(C)c1
Yield: 99.8 %

Procedure:
A mixture of 151 grams (1.0 mole) 4-nitro-o-xylene, 138 grams (1.6 moles) diethyl ketone, 5.8 grams of 5% platinum on carbon and 3.7 grams of 2-naphthalenesulfonic acid monohydrate were added to a pressure vessel. Hydrogen was fed into the reactor at a pressure of 30-40 psi and a temperature of 80°-100° C. When hydrogen uptake ceased, the vessel was cooled and vented. After filtering the catalyst, the aqueous phase was separated and the upper layer concentrated in vacuo to give 191 grams of 96% pure N-(1-ethylpropyl)-3,4-xylidine (96% yield).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2([C:11]#[N:12])[CH2:10][CH2:9]C2)=[C:4]([I:15])[CH:3]=1.C1(C#N)CC1.BrC1C=CC(CBr)=C(I)C=1>>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[C:4]([I:15])[CH:3]=1
Reactant: N#CC1(Cc2ccc(Br)cc2I)CCC1
Agent: BrCc1ccc(Br)cc1I
Agent: N#CC1CC1
Product: N#CC1(Cc2ccc(Br)cc2I)CC1
Yield: 55 %

Procedure:
The title compound (2.1 g, 55% yield) was prepared as described for 1-(4-Bromo-2-iodobenzyl)cyclobutanecarbonitrile (Intermediate 37) starting from cyclopropanecarbonitrile (1.96 mL, 26.6 mmol) and 4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239) (4.0 g, 10.6 mmol): 1H NMR (400 MHz, CDCl3) δ ppm 1.02-1.07 (m, 2 H), 1.33-1.37 (m, 2 H), 2.98 (s, 2 H), 7.35 (d, 1 H), 7.51 (dd, 1 H), 8.02 (d, 1H); MS (CI) m/z 362 [M+H]|.
Reaction SMILES: C[N:2]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C@H:3]([C:8](Cl)=[O:9])[CH2:4][C:5](=[O:7])[OH:6].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1[C:37]([C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)=[O:38].[CH:46](Cl)(Cl)Cl>>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([C:37]([C:30]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=2[NH:28][C:8](=[O:9])[C@H:3]([CH2:4][C:5]([O:6][CH3:46])=[O:7])[NH:2][C:11]([O:13][CH2:14][CH:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:12])=[O:38])=[CH:40][CH:41]=1
Reactant: COc1ccc(N)c(C(=O)c2ccc(Cl)cc2)c1
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](CC(=O)O)C(=O)Cl
Reactant: ClC(Cl)Cl
Product: COC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(OC)cc1C(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methyl N-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-α-aspartyl chloride (Int. J. Peptide Protein Res. 1992, 40, 13-18) (93 g, 0.24 mol) was dissolved in CHCl3 (270 mL) and [2-amino-5-(methyloxy)phenyl](4-chlorophenyl)methanone (for a preparation see Reference compound B) (53 g, 0.2 mol) was added. The resulting mixture was stirred at 60° C. for 1 h before being cooled and concentrated to 60% in volume. Ether was added at 0° C. and the resulting precipitate was filtered and discarded. The filtrate was concentrated under reduced pressure and used without further purification.