Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:17]2[CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:24]#[N:25])[CH:10]=2.[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1.CN(C=O)C>ClCCl>[C:24]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:4][C:3]1[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=1[NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[C:17]1[CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:13][C:12]2=1)#[N:25]
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2ccccc2N)C1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2ccccc2NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 53.1 %

Procedure:
Suspend N-[9-(2-amino-benzyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 109) (116 mg, 0.3 mmol) in anhydrous dichloromethane (3 mL) under nitrogen. Add methanesulfonyl chloride (0.028 mL, 0.36 mmol) and pyridine (0.032 mL, 0.39 mmol), followed by anhydrous DMF (2 mL) to effect solution. Stir 5.5 h at room temperature. Add additional methanesulfonyl chloride (0.010 mL, 0.13 mmol) and pyridine (0.010 mL, 0.12 mmol) and stir 18 h at room temperature. Dilute with dichloromethane and wash with 1N hydrochloric acid. Backwash the aqueous portion with dichloromethane. Combine the organic portions and wash with brine, dry (MgSO4), filter, and concentrate in vacuo to provide 74 mg of a yellow oil. Absorb the oil on silica with THF and a small amount of methanol and purify by flash chromatography. Elute with a step gradient of 10% ethyl acetate/dichloromethane, 25% ethyl acetate/dichloromethane, and 50% ethyl acetate/dichloromethane to obtain 19 mg (14%) of a light yellow solid. MS (ES): m/z 465 (M+1), 463 (M−1); 1H NMR(DMSO-d6): δ 9.43 (s, 1H), 8.02 (s, 1H), 7.88 (d, 1H, J=7.5 Hz), 7.43-7.36 (m, 3H), 7.31 (dt, 1H, J=7.6, 1.0 Hz), 7.12 (dt, 1H, J=7.5, 0.9 Hz), 6.21 (d, 1H, J=7.5 Hz), 5.54 (s, 2H), 4.06 (m, 1H), 3.12 (s, 3H), 3.04 (dd, 1H, J=15.4, 5.3 Hz), 2.70 (m, 2H), 2.59 (dd, 1H, J=15.4, 8.4 Hz), 2.41 (m, 1H), 1.97 (m, 1H), 1.85 (m, 1H), 1.02 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[CH:10]OCC)=[CH:5][CH:4]=1.[Cl:14][C:15]1[C:16]2[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:17]=2[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:14][C:15]1[C:16]2[C:28]([CH:10]=[N:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:27]([OH:29])[CH:26]=[CH:25][C:17]=2[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC=Nc1ccc(OC)cc1
Reactant: CCOC(=O)c1sc2ccc(O)cc2c1Cl
Product: CCOC(=O)c1sc2ccc(O)c(C=Nc3ccc(OC)cc3)c2c1Cl
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A round bottomed flask containing a mixture of the product from the previous reaction (6.04 g) and ethyl N-(4-methoxyphenyl)formimidate (4.50 g) was submerged rapidly in an oil bath pre-heated to 160° C., and the mixture stirred at 160-80° C. for 4 hours, the ethanol produced in the reaction being removed by distillation. More of the formimidate (0.80 g) was then added and the mixture heated at 180-90° C. for a further 1 hour. The cooled mixture was then treated with boiling methanol (100 ml) and the resulting light brown solid collected by filtration, washed with methanol (100 ml) and dried to give ethyl 3-chloro-5-hydroxy-4-[N-(4-methoxyphenyl)iminomethyl]benzo[b]thiophene-2-carboxylate (4.03 g); m.p. 162-163° C.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[F:19])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:10]=2[CH3:27])=[CH:6][C:5]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][N:3]=1.[F:34][CH:35]([F:52])[O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:34][CH:35]([F:52])[O:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[C:7]([NH:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=4[F:19])[N:12]=[C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:10]=3[CH3:27])=[CH:6][C:5]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:4][N:3]=2)=[CH:39][CH:38]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1Cl
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1-c1ccc(OC(F)F)cc1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine (49.7 mg, 0.11 mmol), 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (58.6 mg, 0.22 mmol), tricyclohexylphosphine (5.1 mg, 0.018 mmol), and tris(dibenzylideneacetone)dipalladium (0) (8.6 mg, 9.4 μmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (2.0 mL) and aq. 1.3M potassium phosphate tribasic (0.21 mL, 0.27 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-40% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford a film that was triturated with MeOH to afford a light yellow solid as N-(2-(4-(difluoromethoxy)phenyl)-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.69 (1H, d, J=4.6 Hz), 8.05 (2H, m), 7.86 (2H, m), 7.63 (2H, m, J=8.6 Hz), 7.59 (2H, m), 7.43 (1H, m), 7.09 (3H, m), 6.48 (1H, d, J=2.0 Hz), 3.78 (4H, m), 3.14 (4H, m), 2.16 (3H, s). Mass Spectrum (pos.) m/e: 576.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.[NH2:31][C@H:32]([C:34]([OH:36])=[O:35])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH:31][C@@H:32]([CH3:33])[C:34]([OH:36])=[O:35])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C[C@H](N)C(=O)O
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O

Procedure:
As shown in scheme H, 2,4-dinitrobenzoyl chloride prepared from 2,4-dinitrobenzoic acid is treated with L-alanine in presence of sodium carbonate to yield (S)-2-(2,4-dinitrobenzamido)propanoic acid (intermediate 11). Treatment of intermediate 11 either with K18F or K19F gave (S)-2-(2-fluoro-4-nitrobenzamido)propanoic acid, which on reduction with iron powder in presence of acetic acid gave (S)-2-(4-amino-2-fluorobenzamido)propanoic acid (compound 10). In an analogous manner, treatment of 2,4-dinitrobenzoyl chloride with D-alanine gave (R)-2-(2,4-dinitrobenzamido)propanoic acid (intermediate 12), which on treatment either with K18F or K19F and further reduction with iron powder gave (R)-2-(4-amino-2-fluorobenzamido)propanoic acid (compound 11).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[N:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]2=[O:11].[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:18][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[N:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]2=[O:11]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CN1C(=O)c2cccc(O)c2C1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)c2cccc(OC)c2C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of methyl 2-(4-hydroxy-1,3-dioxoisoindolin-2-yl)acetate (160 mg, 0.680 mmol) in DMF (5 ml), K2CO3 (94 mg, 0.680 mmol) and iodomethane (88 μl, 1.361 mmol) were added, and the mixture was stirred under microwave irradiation at 100° C. for 1 hour. The insoluble inorganic salts were filtered off, the solvent was removed and the resulting crude product (130 mg, 0.522 mmol, 77% yield) was used in the following step without further purification. MS/ESI+ 250.1 [MH]+.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[C:9](=[O:31])[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:11]([C:19]([O:21][CH3:22])=[O:20])[N:12]([CH2:14][CH:15]([OH:18])CO)[CH:13]=1>O>[Br:7][C:8]1[C:9](=[O:31])[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:11]([C:19]([O:21][CH3:22])=[O:20])[N:12]([CH2:14][CH:15]([OH:2])[OH:18])[CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(O)CO
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
A reactor was charged with sodium periodate (1.67 kg, 7.8 mol) and 44 L of deionized water. To the agitated mixture was added 8.5 kg of ice. This was stirred until all the ice melted and the mixture temperature was 1.4° C. To this was added methyl 5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 19 (2.73 kg, 6.62 mol) via a powder addition funnel. The mixture was allowed to warm to rt and the slurry was stirred for 16 h. A sample was monitored by 1H NMR and showed the disappearance of starting material. The mixture was filtered and the cake washed with 20 kg of deionized water. This was repeated until a negative starch/iodide paper result was obtained (4×20 L washes). The solids were dried in a vacuum oven at 45-55° C. to provide methyl 5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 20 (2.176 kg, 88%) as a mixture with the corresponding aldehyde form 21. Purity was determined to be 99.5% by HPLC. 1H NMR (300 MHz, acetone-d6) δ 8.12 (s, 1H), 7.49-7.30 (m, 5H), 5.56 (dd, J=6.0, 2.4 Hz, 1H), 5.23 (m, 1H), 5.20 (s, 2 H), 3.97 (d, J=5.1 Hz, 2H), 3.87 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Br.Br[CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2[O:8][CH2:16][CH2:17][N:18]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCCBr
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(C2=NCCO2)cc1
Reaction time: 18 h
Yield: 72.9 %

Procedure:
4-(trifluoromethyl)benzoyl chloride (4.6 mL, 31 mmol) was slowly added to a solution of 2-bromoethanamine hydrobromide (6.27 g, 30.6 mmol) and triethylamine (23 mL, 165 mmol) in dry DCM (150 mL) at 0° C. The reaction was stirred for 18 h, allowing the cooling bath to expire. The resulting mixture was filtered through a Buechner funnel and the filter cake was washed thoroughly with DCM. The collected filtrate was washed with water (100 mL), brine (75 mL), and dried (Na2SO4). The volume was reduced in vacuo to 5 mL and the resulting crystals were harvested. The remaining filtrate was again reduced in volume to provide a second crop of crystals to give a total of 4.8 g of 2-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole. The combined crop of crystals were dissolved in CCl4 (200 mL) and the resulting solution was decanted away from a dark oily residue and was carried forward without further purification: LC/MS (m/z): 216.1 (MH+), tR=0.60 min.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:13][C:11]([F:12])([F:14])[C:8]1[N:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NCc1ccc(C(F)(F)F)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
5-(azidomethyl)-2-(trifluoromethyl)pyridine (2.6 g, 12.86 mmol) in THF at −78° C. was added LAH (0.54 g, 14.2 mmol). The resulting mixture was stirred for 15 min. and warmed to room temperature for one hour. Then the reaction was quenched with saturated aqueous NH4Cl and stirred for a couple of hours. Anhydrous Na2SO4 was added to make the mixture clear two phases, filtered and washed with EtOAc. The combined organic solution was concentrated to provide (6-(trifluoromethyl)pyridin-3-yl)methanamine as a red syrup (2.1 g). 1H NMR (300 MHz, CDCl3+CD3OD), d: 8.729 (s, 1H), 7.928 (d, J=9.1 Hz, 1H), 7.706 (d, J=9.1 Hz, 1H), 4.054 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH4+].[Cl-]>CCOCC.CCCCC>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCC
Product: CCOC(=O)C(=O)c1ccccc1OC
Reaction time: 0.75 h

Procedure:
A solution of 27 g of 1-bromo-2-methoxybenzene in 270 ml of ether is cooled to −70° C. under an argon atmosphere, 90 ml of a 1.6 M solution of n-butyl-lithium in pentane are added dropwise and the mixture is then left stirring for 45 minutes. 78 ml of diethyl oxalate are added rapidly and the mixture is left stirring, while allowing the temperature to return to RT. After stirring for 1 hour at RT, saturated NH4Cl solution is added to the mixture, the phases are separated after settling has taken place, the aqueous phase is extracted with ether, the combined organic phases are washed with water and then with saturated NaCl solution and dried over Na2SO4, and the solvents are evaporated off under vacuum. The excess diethyl oxalate is removed by distillation under vacuum (b.p.=87° C. at 2 000 Pa). The resulting product is chromatographed on silica gel, eluting with a DCM/hexane mixture (50/50; v/v) and then with DCM. The product obtained is purified by distillation under vacuum. 13 g of the expected product are obtained; b.p.=110° C. at 3 Pa.
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][N:5]2[CH2:6][C@@H:7]([C:14]3[CH:19]=[CH:18][C:17](N)=[CH:16][CH:15]=3)[C:8]3[C:13]([C@@H:4]2[CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[N+]([O-])([O-])=O.[Na+].[ClH:28]>O>[ClH:28].[ClH:28].[CH3:1][N:2]1[CH2:22][CH2:21][N:5]2[CH2:6][C@@H:7]([C:14]3[CH:19]=[CH:18][C:17]([Cl:28])=[CH:16][CH:15]=3)[C:8]3[C:13]([C@@H:4]2[CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CN1CCN2C[C@@H](c3ccc(N)cc3)c3ccccc3[C@@H]2C1
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN1CCN2C[C@@H](c3ccc(Cl)cc3)c3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of cis-1,3,4,6,7,11b-hexahydro-2-methyl-7-(4-aminophenyl)-2H-pyrazino[2,1-a]isoquinoline (6.0 g, 0.0205 m) in conc HCl (40 ml) maintained under nitrogen at 0° was added dropwise a solution of sodium nitrate (1.55 g, 0.0225 m) in water (10 ml) over a period of 30 minutes. The mixture was stirred an additional 15 minutes, then added dropwise to a solution of cuprous chloride (4.0 g, 0.04 m) in conc HCl (20 ml) maintained at 0°. After the addition was complete, the ice bath was removed and the mixture allowed to warm to ambient temperature and stirred for 3 hours, during which time nitrogen evolution was observed. The mixture was heated briefly to 60° for 3 minutes, then cooled and poured onto 1000 cc of ice/water, and treated with chloroform (300 ml), then basified to pH 11 with 50% NaOH. The mixture was stirred for 15 minutes, then a jelly-like precipitate removed by filtration through glass wool. The filtrate was transferred to a separatory funnel and the layers separated, the aqueous phase extracted with chloroform (2×100 ml), and the combined chloroform extracts dried and evaporated to a yellow oil, 5.84 g. This material was purified by chromatography on a Prep 500 HPLC on silica gel, eluting with 1.5% ammoniated methanol/chloroform. The pure fractions were combined and evaporated to an oil, 2.82 g. This was dissolved in methanol (30 ml) and acidified with HCl gas. Upon standing, a solid crystallized and was collected by filtration and vacuum dried at 90° for 24 hours to give 2.31 g of cis-1,3,4,6,7,11b-hexahydro-2-methyl-7-(4-chlorophenyl)-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, m.p. 274°-276°.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[H-].[Na+].[CH3:11]I>C1COCC1.O>[CH3:11][O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OCC1CC=CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1CC=CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Cyclohexene-1-methanol (8.92 mmol, 1.00 g) and NaH (17.8 mmol, 428 mg) were mixed in THF (30 mL) at rt, and the THF solution was stirred for 1 h at rt. MeI (17.8 mmol, 1.10 mL) was added slowly into the above THF solution. After stirring for 16 h at rt, the solution was diluted with water (30 ml), and then was extracted with diethyl ether (2×30 mL). The organic layer was dried over Na2SO4, was concentrated by rotory evaporation, and then was distilled to generate the final product 17 as a colorless liquid (460 mg, 41%). 1H-NMR (500 MHz) δ 5.68 (m, 2H), 3.36 (s, 3H), 3.28 (dd, J=6.5 Hz, J=4 Hz), 2.06-2.14 (m, 3H), 1.92 (m, 1H), 1.83 (m, 1H), 1.75 (m, 1H), 1.29 (m, 1H). 13C-NMR (100 MHz) δ 127.2, 126.1, 78.0, 58.9, 34.0, 28.6, 25.8, 24.7. LC-MS (APCI): Peak time=1.59 min, m/z calcd for C8H15O [M+H]+ 127.11, found 127.10.
Reaction SMILES: [C:1]([CH:3]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]>CCO.[Co]>[NH2:2][CH2:1][CH:3]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5]
Reactant: COc1ccc(CC(C#N)C(=O)OC(C)(C)C)cc1
Agent: [Co]
Solvent: CCO
Product: COc1ccc(CC(CN)C(=O)OC(C)(C)C)cc1
Yield: 98.9 %

Procedure:
A solution of tert-butyl 2-cyano-3-(4-methoxyphenyl)propanoate (50 mg, 0.191 mmol) in EtOH (4 ml) was hydrogenated with Raney-Cobalt at 50° C. (30 atm) for 2 hours. The reaction mixture was concentrated under reduced pressure to give tert-butyl 3-amino-2-(4-methoxybenzyl)propanoate (50.1 mg); Retention time=1.24 minutes (condition A); MS (m+1)=266.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[CH:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C(N(C(C)C)CC)(C)C.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl.O>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:6]([CH:5]=[CH:4][C:3]=1[O:10][CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[CH:7]=[O:8]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCOc1ccc(C=O)cc1Cl
Reaction time: 8 h

Procedure:
5 g (31.93 mmol) of 5-chloro-4-hydroxybenzaldehyde are dissolved in 300 ml of methylene chloride and 6.7 ml (38.3 mmol) of N,N-diisopropyl-N-ethylamine and 5.9 ml (33.52 mmol) of 2-trimethylsilylethoxymethyl chloride (SEMCl) are added to this at 0° C. The mixture is allowed to return to room temperature and stirred overnight. Water is then added and the mixture is extracted with methylene chloride. The organic phase is dried and the solvent is evaporated off. The product of the title is obtained, which is purified by chromatography on a silica gel column, eluting with a 95/5 and then 9/1 heptane/ethyl acetate mixture.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:20]1([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:26]2[CH:27]=[CH:28][C:29]([NH:30][C:2]3[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:31][CH:32]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: COCCN1C(=O)C(Nc2ccc(C3CCCCC3)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-cyclohexylaniline in a similar manner as described for e.g. Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 1.19-1.44 (m, 5H), 1.64-1.84 (m, 5H), 2.31-2.40 (m, 1H), 3.38 (s, 3H), 3.72 (t, 2H), 3.90 (t, 2H), 6.67-6.72 (m, 2H), 6.80-6.85 (m, 2H), 7.05-7.14 (m, 4H), 7.19-7.24 (m, 1H), 7.75 (bs, 1H); Mass Spectrum: M+H+ 441.
Reaction SMILES: [F:1][C:2]([S:5]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])([F:4])[F:3].[C:15]1([CH2:25][C:26]([OH:28])=O)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([OH:24])=O)[CH:16]=1>>[F:1][C:2]([F:4])([F:3])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:22](=[O:24])[CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:25][C:26](=[O:28])[NH:14][C:11]3[CH:12]=[CH:13][C:8]([S:5]([C:2]([F:4])([F:1])[F:3])(=[O:7])=[O:6])=[CH:9][CH:10]=3)[CH:16]=2)=[CH:10][CH:9]=1)(=[O:6])=[O:7]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Product: O=C(Cc1cccc(CC(=O)Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)c1)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1

Procedure:
Same procedure as example 20 except 4-aminophenyl trifluoromethyl sulfone and 1,3-phenylenediacetic acid were used. 1H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 2H, 2×NH), 8.05 (d, J=9.1 Hz, 4H), 7.99 (d, J=9.1 Hz, 4H), 7.21-7.29 (m, 4H), 3.73 (s, 4H, 2×CH2). MS 609 [M++1].
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([C:8]2[CH:31]=[CH:30][C:11]([CH2:12][N:13]3[C:17]([CH:18](OCC)[O:19]CC)=[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:31]=[CH:30][C:11]([CH2:12][N:13]3[C:17]([CH:18]=[O:19])=[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ncn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1C(OCC)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ncn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1C=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 95.6 %

Procedure:
In 20% aqueous acetic acid (15 ml) was dissolved ethyl 1-[4-(4-chlorobenzoyl)benzyl]-5-(diethoxymethyl)-imidazole-4-carboxylate (1.70 g) and the solution was stirred at room temperature for 23 hours. This solution was diluted with water and extracted with ethyl acetate. The extract was washed serially with water, saturated aqueous NaHCO3 solution, and water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide the title compound as white powder (1.37g; yield 95%). 1H-NMR (CDCl3) δ: 1.45(3H,t,J=7.2Hz), 4.47(2H,q,J=7.2Hz), 5.65(2H,s), 7.28(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.69-7.77(5H,m), 10.51(1H,s).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH:10]1[CH:22]=[C:23]([CH3:25])[CH3:24])C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)C>[ClH:1].[CH3:24][CH:23]([CH3:25])[CH2:22][CH:10]1[CH2:11][NH:12][CH2:13][CH2:14][NH:9]1
Reactant: CC(C)=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC1CNCCN1
Reaction time: 2 h

Procedure:
Concentrated hydrochloric acid (3 ml) and palladium hydroxide (683 mg) were added to an ethanol solution (300 ml) of 1,4-dibenzyl-2-(2-methyl-1-propenyl)piperazine (5.2 g), followed by stirring for 2 hours under a hydrogen gas stream of 1 atmospheric pressure. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure. The residue was recrystallized from methylene chloride—hexane, followed by washing with diethyl ether and drying under reduced pressure, whereby the title compound (2.95 g) was obtained as a brown solid.