Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]([NH:27][NH:28]C(OC(C)(C)C)=O)=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]([NH:27][NH2:28])=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
TFA (15 mL) was added dropwise to a solution of tert-butyl 2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinecarboxylate (3 g, 7.7 mmol) in DCM (30 mL) at 0° C. The resulting mixture was stirred at rt for 1 h, and then concentrated. The residue was further dried under high vacuum and washed with Et2O (3×) to afford (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide TFA salt (3 g, 93%) as a white solid. ESI-MS (EI+, m/z): 291 [M+H]+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl-].[Cl-].[O:7]=[C:8]1[NH:16][C:11]2=[NH+:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]1[CH:17]1[CH2:22][CH2:21][NH2+:20][CH2:19][CH2:18]1.N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>ClCCl>[O:7]=[C:8]1[NH:16][C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]1[CH:17]1[CH2:22][CH2:21][N:20]([C:1]([Cl:4])=[O:2])[CH2:19][CH2:18]1
Reactant: O=C(Cl)Cl
Reactant: O=c1[nH]c2[nH+]cccc2n1C1CC[NH2+]CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(Cl)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 2 h
Yield: 49.9 %

Procedure:
Phosgene (20% wt. in toluene; 1.8 mL, 3.43 mmol) was added to a suspension of 2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-ium dichloride (100 mg, 0.343 mmol) and 2,6-lutidine (0.50 mL, 4.293 mmol) in dichloromethane (5 mL) at 0° C. After 2 h, the solution was added to saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Dichloromethane (10 mL) was added, and the mixture was filtered to give the title compound as a solid (48 mg). MS: m/z=281 (M+1). 1H NMR (500 MHz, (CD3)2SO) δ 11.58 (s, 1H), 7.90 (d, J=5.1 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.01-6.99 (m, 1H), 4.52-4.46 (m, 1H), 4.31-4.23 (m, 2H), 3.38-3.33 (m, 1H), 3.19-3.14 (m, 1H), 2.32-2.24 (m, 2H), 1.84-1.81 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10]>O1CCCC1>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:1][C:9]1=[O:10]
Reactant: Nc1ncccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ncccc2o1

Procedure:
5.5 g (0.05 mol) of 2-amino-3-hydroxypyridine are introduced into a three-necked flask and the system is placed under argon. 100 ml of anhydrous tetrahydrofuran (THF) are added. 12.15 g (0.075 mol) of 1,1'-carbonyl-diimidazole are then introduced. The mixture is heated to reflux for 5 hours (under argon). The THF is then evaporated off. The residue is taken up with dichloromethane. Washings of the organic phase are performed with NaOH (5%) solution (6×150 ml); the cyclized product passes into the aqueous phase and precipitates at a pH in the region of 5 (by adding 2 N hydrochloric acid solution). The product is filtered off and stored in a desiccator.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)[O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc(COC(=O)Cl)cc1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: COc1ccc(COC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)cc1

Procedure:
4-Methoxybenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (41 mg, 0.14 mmol) and 4-methoxybenzyl carbonochloridate (45.8 mg, 0.15 mmol) according to General Procedure H to give 28 mg (44%) of light brown solid. Anal. Calcd. for C27H34N4O3 m/z 462.3, found: 463.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.04 (d, J=8.77 Hz, 1H), 6.96 (d, J=8.9 Hz, 2H), 6.87 (d, J=8.2 Hz, 2H), 4.94 (m, 2H), 3.86 (m, 1H), 3.73 (s, 4H), 3.08 (m, 1H), 2.76 (m, 1H), 2.36 (m, 2H), 1.90 (m, 1H), 1.80 (m, 2H), 1.65 (m, 1H), 1.45 (m, 1H), 1.18 (m, 5H), 1.02 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].C([Li])CCC.CCCCCC.[CH2:30]1[O:33][CH:31]1[CH3:32].[NH4+].[Cl-]>C1COCC1.C(OCC)C>[CH3:1][N:2]([CH3:18])[S:3]([N:6]1[C:10]([CH2:30][CH:31]([OH:33])[CH3:32])=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Reactant: CC1CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)Cc1cnc([Si](C)(C)C(C)(C)C)n1S(=O)(=O)N(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5.426 g (18.7 mmol) of 1-(N,N-dimethylsulphamoyl)-2-tert-butyldimethylsilylimidazole are dissolved in 100 ml of freshly distilled THF under nitrogen and cooled to −78° C., and a solution of n-butyl-lithium in hexane (2.5M; 15 ml; 37.5 mmol) is added dropwise over a period of 10 min. The mixture is stirred for 30 min at −78° C. The solution is warmed to 0° C. with rapid stirring, and a solution of 3.0 ml (2.49 g; 42.9 mmol) of propylene oxide in 20 ml of freshly distilled THF is added dropwise over a period of 15 min. The mixture is stirred for 18 hours with heating at 20° C., and the mixture is then hydrolysed by adding 100 ml of saturated NH4Cl solution. The THF is removed under reduced pressure and the mixture obtained is extracted three times with 100 ml of dichloromethane. The organic layers are combined, dried (MgSO4) and evaporated under reduced pressure to yield an oil, which is subjected to column chromatography with diethyl ether as eluent to yield 1-(N,N-dimethylsulphamoyl)-2-tert-butyldimethylsilyl-5-(2-hydroxypropyl)imidazole in the form of a viscous yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:27](OCC)(=[O:29])[CH3:28]>>[C:27]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[C:19](=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:29])[CH3:28]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc([N+](=O)[O-])cc21
Reactant: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc([N+](=O)[O-])cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-1-(ethoxycarbonyl)-6-nitroindole (step 2). tlc: Rf=0.2 (50% ethyl acetate in hexanes)
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH2:6]O)=[C:4]([F:14])[CH:3]=1.P(Br)(Br)[Br:16]>C(OCC)C>[Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH2:6][Br:16])=[C:4]([F:14])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: CC(C)Oc1cc(CO)c(F)cc1Cl
Solvent: CCOCC
Product: CC(C)Oc1cc(CBr)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 254 %

Procedure:
124 g (0.56 mol) of 4-chloro-2-fluoro-5-isopropoxybenzyl alcohol was dissolved in 900 ml of diethyl ether, and 55 g (0.20 mol) of phosphorus tribromide was dropwise added thereto under cooling with ice. After stirring at room temperature for 3 hours, the reaction solution was poured into ice water and extracted with diethyl ether. The extract was washed with water and an aqueous sodium hydrogencarbonate solution, and then, the organic layer was dried over anhydrous magnesium sulfate. Diethyl ether was distilled off under reduced pressure to obtain 143 g (yield: 89%) of the desired product.
Reaction SMILES: [N+:1]([O-])([O-])=O.[Na+].[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:14])=[C:11]([CH:13]=1)[NH2:12].O.O.[Sn](Cl)Cl.[OH-].[Na+]>O.Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:14])=[C:11]([NH:12][NH2:1])[CH:13]=1
Reactant: Nc1cc(Br)ccc1F
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A solution of sodium nitrate (0.49 g, 0.007 mM) in water (1.5 ml) was added drop wise to a vigorously stirred heterogeneous solution of 5-bromo-2-fluoroaniline (1.4 g) in concentrated HCl(aq) (3.5 ml) over a 30 minutes period at 0° C. Tin (II) chloride dihydrate (4.5 g, 0.02 mM) in concentrated HCl(aq) (3.5 ml) was added drop wise to the above solution over a period of 30 minutes. After the addition, the solution was allowed to stir at 0° C. for one hour. The reaction solution was basified (pH>7) by slowly adding a solution of 50% aqueous NaOH to the reaction mixture. The water layer was washed with diethyl ether (3×). The organic layers were combined, dried (MgSO4), and concentrated. The resultant solid was thoroughly washed with hexanes. The undissolved solid was captured on filter and further washed with hexanes to afford 0.81 g (54% yield) of the desired product as an off-white solid. NMR (CHCl3) δ 5.45 (bs, 1H); 6.80–6.86(m, 2H); 7.25–7.28 (m, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])([C:9]#[N:10])[CH:6]([CH3:8])[CH3:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]>>[C:9]([C:5]([C:11]1[CH:20]=[CH:19][CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=1)([CH:6]([CH3:8])[CH3:7])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29])#[N:10]
Reactant: CNCCc1cccc(C(=O)OC)c1
Reactant: COC(=O)c1cccc(C(C#N)(CCCBr)C(C)C)c1
Product: COC(=O)c1cccc(CCN(C)CCCC(C#N)(c2cccc(C(=O)OC)c2)C(C)C)c1

Procedure:
Reaction of 1r with 2d produced 3ap. MS found M+H=451. The oxalate salt of 3ap was recrystallized from methanol/ether; mp 129-136° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH2:17]([NH2:19])[CH3:18]>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:19][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Reactant: CCN
Agent: Cl
Product: CCNC1CCc2c(cccc2NC(C)=O)C1

Procedure:
Starting from 2.03 g (0.01 mol) of 5-acetylamino-2-tetralone and 2.45 g (0.03 mol) of ethylaminehydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 1.2 g (44.6% of theory) and with a melting point of 351° C. which does not change after recrystallisation from methanol/ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(C=CC(=O)OCC)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cccc(CCC(=O)OCC)c1
Reaction time: 16 h
Yield: 94 %

Procedure:
A stirred solution of the intermediate from Step A (6.5 g, 23.7 mmol) in MeOH (300 mL) was flushed with nitrogen gas and palladium (650 mg; 10 wt. % (dry basis) on activated carbon) was added. The reaction flask was then placed under vacuum and flushed with hydrogen gas (3 cycles). The reaction mixture was stirred overnight (16 hours) and then flushed with nitrogen gas. The mixture was filtered and the solvent removed under reduced pressure to provide 6.2 g of the title intermediate (94% yield), which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]3)[CH:17]=1)[C:10]([CH3:31])([CH3:30])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:28][CH:26]1[O:25][CH:24]([CH3:29])[CH2:23][N:22]([C:18]2[CH:17]=[C:16]([CH:11]3[C:10]([CH3:30])([CH3:31])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:21]=[CH:20][CH:19]=2)[CH2:27]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CC(C)OC(C)C3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1CN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC(C)O1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
To a stirred mixture solution of 2-[3-(2,6-dimethyl-morpholin-4-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.9 g, 2.1 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(2,6-dimethyl-morpholin-4-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (745 mg, 90%) as a white solid: LC/MS m/e calcd for C24H30N2O3 (M+H)+: 395.52, observed: 395.0.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:12]=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: Fc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cc(F)ccc1-c1ccccc1
Reaction time: 0.5 h

Procedure:
Chlorosulfonic acid (8.7 mL, 0.13 mole) was added dropwise to 4-fluorobiphenyl (10.2 grams, 59 mmol) while stirring in an ice bath. Stirring was continued with ice cooling for 0.5 hours and then the reaction mixture was poured onto ice. The resulting white precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water and brine, dried over magnesium sulfate and concentrated to afford a white solid. The desired product, 4-fluorobiphenylsulfonyl chloride (4.3 grams, 27%), was separated from 4-fluorobiphenylsulfonic acid (an unwanted side product) by crystallization of the latter from ethyl acetate and crystallization of the remaining material from hexane.
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20].[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][N:40]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3C(F)(F)F)C2=O)sc1C(=O)NCc1ccccc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 1-(bromomethyl)-2-(trifluoromethyl)benzene to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 34% yield: mp 138-140° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.67-7.65 (m, 1H), 7.59-7.46 (m, 2H), 7.42-7.27 (m, 6H), 5.89 (t, J=5.5 Hz, 1H), 4.68 (s, 2H), 4.56 (d, J=5.5 Hz, 2H), 4.11-4.05 (m, 2H), 3.49-3.43 (m, 2H), 2.61 (s, 3H); 13C NMR (75 MHz, CDCl3); 162.3, 157.2, 155.7, 153.2, 137.9, 134.7, 132.5, 130.0, 128.8, 127.8, 126.1, 125.9, 122.3, 117.4, 44.0, 43.9, 42.0, 41.9, 17.2; MS (ES+) m/z 475.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:10][C:11](OC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:23][CH:22]([F:24])[O:21][C:18]1[CH:17]=[CH:16][C:15]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][OH:12])=[CH:20][CH:19]=1
Reactant: COC(=O)C[C@@H](NC(=O)OC(C)(C)C)c1ccc(OC(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCO)c1ccc(OC(F)F)cc1
Reaction time: 3.5 h
Yield: 54.8 %

Procedure:
To a stirred mixture of 384 (7.1 g, 20.6 mmol) in THF (150 mL) at −78° C. was added dropwise 1M LiAlH4 (30.8 mL, 30.8 mmol) and stirring was continued for 3 to 4 h. The mixture was diluted with THF, quenched by portion-wise addition of Na2SO4 decahydrate and filtered. Solids were rinsed with additional THF, and the filtrate concentrated. The crude product was purified by SiO2 chromatography eluting with 50% EtOAc/hexanes to afford 3.58 g (55%) of (R)-tert-butyl 1-(4-(difluoromethoxy)phenyl)-3-hydroxypropylcarbamate (386) as a clear viscous liquid which was ca. 95% ee by chiral HPLC.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH2:19][C:20]1[C:24]([C:25]#[N:26])=[CH:23][NH:22][N:21]=1>O1CCCC1>[O:18]=[C:10]1[C:9](=[CH:8][NH:19][C:20]2[C:24]([C:25]#[N:26])=[CH:23][NH:22][N:21]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11]1
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: N#Cc1c[nH]nc1NC=C1C(=O)Nc2ccccc21

Procedure:
The named compound is prepared by substituting 3-amino-1H-pyrazole-4-carbonitrile for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1511 gms. of 3-amino-1H-pyrazole-4-carbonitrile by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:3]=1[NH2:4].Br[CH2:12][CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:3]=1[NH:4][CH2:12][CH:13]=[O:14]
Reactant: O=CCBr
Reactant: COc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(C)c1NCC=O
Temperature: 150 °C

Procedure:
2-Methyl-6-methoxyaniline (100 grams), the dipropyl acetal of 2-bromoacetaldehyde (59.1 grams) and sodium carbonate (31.8 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture is heated at a temperature of about 150°C for a period of about 30 hours. After this time the reaction mixture is cooled to room temperature and is filtered. The filtrate is then distilled under vacuum to yield the desired product the dipropyl acetal of 2-(2-methyl-6-methoxyanilino)acetaldehyde as the residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7].CO>C(O)C.[Pd]>[NH2:25][C:24]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])c(OC)c1)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)c(OC)c1)C(=O)OCC
Reaction time: 1 h

Procedure:
A solution of diethyl N-(3-methoxy-4-nitrobenzoyl)-(L)-glutamate (11.0 g, 28.8 mmoles) in 95% ethanol (200 mL) was mixed with 10% palladium on carbon (0.8 g) and placed on a Parr apparatus. The mixture was shaken under hydrogen atmosphere for 1 hour. The reaction mixture was filtered, spin evaporated, and dried to give a clear viscous oil which on long-standing hardened to a white wax; yield, 9.95 g (99%); 1H-NMR (DMSO-d6) δ 1.15 and 1.17 (2t overlapped, 6H), 1.8-2.2 (m, 2H), 2.40 (t, 2H), 3.79 (s, 3H), 4.0-4.2 (2 q overlapped, 4H), 4.36 (m, 1H), 5.29 (br s, 2H), 6.60 (d, Jo =8 Hz, 1H), 7.3-7.4 (m, 2H), 8.25 (d, 1H); uv (MeOH) 301 nm max (17800), 280 sh (15700), 266 min (12600), 263 max (13200), 256 sh (12500), 245 min (8630), 204 max (40900); mass spec (CI) m/e 353 (56%), 150 (100).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][CH2:15][C:16](=[O:18])[CH3:17].[BH4-].[Na+]>CO>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][CH2:15][CH:16]([OH:18])[CH3:17]
Reactant: CC(=O)CCc1ccc2c(c1)Cc1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CCc1ccc2c(c1)Cc1ccccc1-2
Yield: 86.5 %

Procedure:
To 200 ml of methanol was added 11 grams of 4-(2-fluorenyl)-butan-2-one, the mixture was cooled with ice, and 1.32 grams of sodium borohydride was slowly added thereto with stirring. After being stirred for one hour, methanol was removed therefrom by evaporation in vacuo, to the residue was added water, and the mixture was extracted with chloroform. The extract was washed with water, dried with magnesium sulfate, and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give 9.6 grams of 4-(2-flourenyl)-butan-2-ol, white crystals, m.p. 120°-121° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CCCCCc1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4-pentylphenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (4%, light brown oil). HPLC-MS: m/z=298.2 (M+1); Rt: 5.61 min.