Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[S:11][N:10]=[C:9]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].CCN(C(C)C)C(C)C>CN1CCCC1=O>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[S:11][N:10]=[C:9]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5]1
Reactant: C1CN(c2nc(C3CCOCC3)ns2)CCN1
Reactant: Cc1ccccc1CCl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1CN1CCN(c2nc(C3CCOCC3)ns2)CC1
Temperature: 180 °C

Procedure:
A mixture of 5-(piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)-1,2,4-thiadiazole (19.1 mg, 75.0 μmol), 1-(chloromethyl)-2-methylbenzene (31.6 mg, 225 μmol) and DIPEA (96.9 mg, 131 μL, 750 μmol) in N-methyl-2-pyrrolidinone (1 mL) was heated under microwave irradiation for 10 min at 180° C. The resulting reaction solution was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield, after evaporation of the product containing fractions 13 mg (48%) of the title compound. MS (m/e): 359.2 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1)=[O:4].[OH-].[Na+]>C(O)C>[C:3]([C:5]1[CH:6]=[C:7]([Br:14])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(Br)c2occc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Br)c2occc2c1
Yield: 81.7 %

Procedure:
A solution of 0.52 gm (2.03 mMol) 5-methoxycarbonyl-7-bromobenzofuran and 0.41 gm (10.13 mMol) sodium hydroxide in 4 mL ethanol was stirred at room temperature until all of the starting material had been consumed. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water. This solution was then made basic by the addition of 1N sodium hydroxide and was extracted well with ethyl acetate. The remaining aqueous phase was made acidic (pH about 2) by treatment with potassium hydrogen sulfate and the resulting solid removed by filtration. The aqueous phase was extracted well with ethyl acetate and the organics were combined and concentrated under reduced pressure to provide 0.40 gm (82%) of 5-carboxy-7-bromobenzofuran as an off-white solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])([CH3:5])[CH3:4].I[CH3:25]>O>[C:3]([C:7]1[CH:8]=[C:9]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[CH:10]=[C:11]([C:14]([CH3:16])([CH3:17])[CH3:15])[C:12]=1[O:13][CH3:25])([CH3:4])([CH3:5])[CH3:6]
Reactant: CI
Reactant: CC(C)(C)c1cc(N2CCCC2=O)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1c(C(C)(C)C)cc(N2CCCC2=O)cc1C(C)(C)C
Yield: 81.2 %

Procedure:
To a stirred mixture of 0.3 g (7.5 mmol) of 60% sodium hydride in a mineral dispersion previously washed with hexane, in 20 ml of dimethylsulfoxide, there was added 2 g (6.9 mmol) of 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-pyrrolidin-2-one. Gas evolution was observed. Twenty minutes later, 1 g (7 mmol) of iodomethane was added. The reaction mixture was stirred for thirty minutes and then diluted with 70 ml of water. The precipitated solid was collected by filtration and recrystallized from acetone-hexane to yield 1.7 g (5.6 mmol) of 1-(3,5-di-tert-butyl-4-methoxyphenyl)pyrrolidin-2-one, melting point 90°-91° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N+:9]([O-])=[CH:10]2)=[O:4].FC(F)(F)C1C=CC=CC=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C(OCC)(=O)C>[C:26]([NH:30][C:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=2[CH:7]=[CH:8][N:9]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N
Reactant: COC(=O)c1cccc2c[n+]([O-])ccc12
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: FC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c(NC(C)(C)C)nccc12
Yield: 62.9 %

Procedure:
5-(Methoxycarbonyl)isoquinoline 2-oxide (2.0 g, 9.84 mmol) obtained in Step (4) above and trifluorotoluene (20 mL) were mixed and stirred. The reaction solution was slowly added with t-butylamine (3.6 g, 49.25 mmol) and p-toluenesulfonic acid anhydride (6.42 g, 19.68 mmol) at about 5° C., and stirred for about 2 hours at the same temperature (˜5° C.). The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.6 g, 64%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.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]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Reactant: CC(=O)N1c2cc([N+](=O)[O-])c(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2cc([N+](=O)[O-])c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C
Yield: 83.3 %

Procedure:
A mixture of isopropyl (S)-4-acetyl-7-bromo-3-methyl-6-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.870 g, 2.17 mmol), 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane (0.920 g, 3.26 mmol), cesium carbonate (2.1 g, 6.52 mmol), XPhos (0.104 g, 0.22 mmol) and tris(dibenzylideneacetone)dipalladium (0.100 g, 0.11 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was heated for 16 h at 90° C. The reaction was cooled to rt and concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was concentrated and the residue was purified by column chromatography on silica gel (eluting with 50% ethyl acetate-hexane) to afford isopropyl (S)-4-acetyl-3-methyl-7-(4-(methylsulfonyl)phenyl)-6-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.860 g, 83%). MS (ESI, pos. ion) m/z 498 [M+Na]+.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[N:31]=[CH:30][C:29]([NH:32][C:33](=[O:38])[CH2:34][C:35]([OH:37])=O)=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)=[O:60]>CN(C=O)C.O>[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]([N:61]1[CH2:62][CH2:63][N:64]([C:35](=[O:37])[CH2:34][C:33]([NH:32][C:29]2[CH:30]=[N:31][C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:27][CH:28]=2)=[O:38])[CH2:65][CH2:66]1)=[O:60]
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Reactant: O=C(c1ccccc1Br)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)nc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
HOBt (41 mg, 0.3 mmol) and DIEA (98 mg, 0.76 mmol) were added to a stirred solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid (65 mg, 0.25 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (58 mg, 0.3 mmol) followed by (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride (93 mg, 0.3 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 58.5 mg (46%) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(6-phenyl-pyridin-3-yl)-propionamide. LCMS: 507.1 (M+1)+ 98.54%, 1H NMR: (DMSO-d6): δ 10.5 (d, 1H), 8.8 (dd, 1H), 8.2-7.86 (m, 4H), 7.5 (d, 1H), 7.34 (m, 6H), 3.8-3.4 (m, 8H), 3.2-3.1 (m. 2H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:7]([F:9])[F:8])[CH:6]=1.[Si:10]([C:14]#[CH:15])([CH3:13])([CH3:12])[CH3:11].C(NC(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I.C1CCCCC1>[F:8][CH:7]([F:9])[N:5]1[CH:6]=[C:2]([C:15]#[C:14][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=[N:4]1
Reactant: FC(F)n1cc(I)cn1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cnn(C(F)F)c1
Temperature: 60 °C

Procedure:
4-Iodo-1-difluoromethylpyrazole (521 mg, 1.81 mmole) was dissolved in DMF (3 mL). TMS-acetylene (0.43 ml) was added followed by di-isopropylamine (395 uL), copper(I) iodide (27 mg) and triphenylphosphine (112 mg). The reaction was flushed with nitrogen. Palladium acetate (32 mg) was added and the reaction flushed again with nitrogen (×3) and was heated at 60° C. for 65 minutes. The reaction was cooled and diluted with ethyl acetate (20 mL). The solution was washed with water (3×10 mL) and with brine then dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with 1:1 dichloromethane:cyclohexane to afford the title compound (413 mg 1.92 mmole). 1H-NMR (CDCl3, 500 MHz): δ 0.25 (s, 9H), 7.15 (t, J=60.2 Hz, 1H), 7.71 (s, 1H), 7.94 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]([O:10][C:11]([N:13]([CH3:25])[C@@H:14]([C:22](O)=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.S([O-])(O)(=O)=O.[Na+]>[C:6]([O:10][C:11](=[O:12])[N:13]([C@@H:14]([C:22](=[O:23])[NH:1][CH2:2][CH2:3][CH2:4][OH:5])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:25])([CH3:7])([CH3:9])[CH3:8]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Reactant: NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)NCCCO
Temperature: 25 °C
Reaction time: 22 h
Yield: 64.6 %

Procedure:
3-Aminopropan-1-ol (0.39 mL, 5.12 mmol) was added at room temperature to a solution of N-tert-butoxycarbonyl-N-methyl-D-phenylalanine (1.30 g, 4.65 mmol) in N,N-dimethylformamide (40 mL). 1-Hydroxybenzotriazole monohydrate (0.63 g, 4.65 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.89 g, 4.65 mmol) were added successively. The reaction mixture was stirred for 22 h at room temperature. It was diluted with 10% sodium hydrogensulfate solution (300 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica (45 g) with dichloromethane/methanol (10:1) to give 1.01 g of N-((1R)-1-(3-hydroxypropylcarbamoyl)-2-phenylethyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: [CH2:1]([N:7]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:8]([CH:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].CI.[C:37](OCC)(=O)C>CN(C)C=O>[CH2:27]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([CH:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:37])[C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1)=[O:9])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCN(CCCCCC)C(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCCCN(CCCCCC)C(=O)C1Sc2ccccc2-c2c1c1ccccc1n2C
Temperature: 25 °C

Procedure:
To a solution of 200 mg of N,N-dihexyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-6-carboxamide in 10 ml of N,N-dimethylformamide was added 21 mg of 60% sodium hydride/oil, followed by stirring at room temperature for an hour. To the solution was added 33 μl of methyl iodide, followed by stirring at room temperature for 5 hours. The reaction solution, after addition of ethyl acetate, was washed with water, 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane to give 155 mg of N,N-dihexyl-6,11-dihydro-11-methyl-5-thia-11-aza-benzo[a]fluoren-6-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[N:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[N:17][CH:18]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)c([N+](=O)[O-])c2)cn1
Yield: 52.4 %

Procedure:
In the same manner as in Reference Example 1 and using 4-chloro-3-nitrophenol (4.70 g, 27.1 mmol), 5-bromo-2-nitropyridine (5.00 g, 24.6 mmol), cesium carbonate (12.0 g, 36.9 mmol) and N,N-dimethylformamide (50 mL) as starting materials, the title compound (3.81 g, 52%) was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:17]1N2CN3CN(C2)C[N:18]1C3.Cl.[C-]#N.[Na+]>C(O)(=O)C.C(Cl)Cl>[C:17]([CH:6]([OH:7])[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1)#[N:18]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1

Procedure:
For example, 4-fluoro-3-phenoxy-toluene, when reacted with N-bromosuccinimide in the presence of a radical initiator, for example azodiisobutyronitrile, optionally using a diluent, for example carbon tetrachloride, optionally using a diluent, and 100° C., gives 4-fluoro-3-phenoxy-benzyl bromide. From this, 4-fluoro-3-phenoxy-benzaldehyde can be prepared in a Sommelet reaction, that is to say by reaction with hexamethylenetetramine in the presence of a diluent, for example methylene chloride, at temperatures between 0° and 50° C., followed by reaction with aqueous acetic acid and thereafter with hydrochloric acid, at temperatures between 80° and 120° C. The reaction of 4-fluoro-3-phenoxy-benzaldehyde with sodium cyanide in aqueous acetic acid at 20° C. gives α-cyano-4-fluoro-3-phenoxy-benzyl alcohol. The reaction sequence described above is outlined in the following equations: ##STR11##
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:36][CH3:37])[CH2:25][NH:26]CC2C=CC(OC)=CC=2)[C:5]1=[O:38])[CH:2]=[CH2:3]>C(#N)C.O.[OH-].[Na+].CCOC(C)=O>[CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:36][CH3:37])[CH2:25][NH2:26])[C:5]1=[O:38])[CH:2]=[CH2:3]
Reactant: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CNCc2ccc(OC)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CN)C1=O

Procedure:
To a solution of (3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((SR)-1-(4-methoxybenzylamino)butan-2-yl)piperidin-2-one (88 mg, 0.160 mmol) in acetonitrile (1899 μL) and water (380 μL) was added ceric ammonium nitrate (350 mg, 0.638 mmol) at 25° C. The reaction was monitored by LCMS and HPLC and on completion was diluted with 0.5 M aq. NaOH and EtOAc and the resulting emulsion was filtered through a pad of Celite® (J. T. Baker, Phillipsberg, N.J., J. T. Baker, Phillipsberg, N.J., diatomaceous earth). The filtrate was extracted with ethyl acetate and the combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to provide the crude product which was used n subsequent steps without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1B(O)O>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][C:28]=2[O:30][CH3:31])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: COc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)c(OC)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2,4-Dimethoxybenzene boronic acid. MS (M+H) 413.2
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:36])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N:18](C(=O)C)[CH2:19][CH2:20][CH2:21][N:22]4[C:26](=[O:27])[C:25]5=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]5[C:23]4=[O:32])=[CH:14][CH:13]=3)[O:11][C:6]=2[C:5]([F:37])=[CH:4][C:3]=1[F:38].Cl.[OH-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:7]2[C:8](=[O:36])[CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]4[C:23](=[O:32])[C:24]5=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]5[C:26]4=[O:27])=[CH:16][CH:17]=3)[O:11][C:6]=2[C:5]([F:37])=[CH:4][C:3]=1[F:38]
Reactant: CC(=O)N(CCCN1C(=O)c2ccccc2C1=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)cc3)cc(=O)c12
Yield: 79.3 %

Procedure:
0.83 g of Compound 22 was dissolved in 12 ml of dioxane, 8 ml of concentrated hydrochloric acid was added and the mixture was heated at reflux for 4 hours. The reaction solution was cooled on ice and adjusted to pH 8 by addition of a 10N aqueous solution of sodium hydroxide thereto, and the precipitated crystals were collected by filtration to give 605 mg (79%) of Compound 23.
Reaction SMILES: O.Cl.C(=[N:16][CH:17]([CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=1)[C:18]#[N:19])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)C.CO>[NH2:16][CH:17]([CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=1)[C:18]#[N:19]
Reactant: N#CC(Cc1ccnc(Cl)c1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: O
Product: N#CC(N)Cc1ccnc(Cl)c1
Reaction time: 0.33 h

Procedure:
To a solution of ethanol (20 mL), water (0.08 mL, 4 mmol), hydrogen chloride (10.8 mL, 1M in diethylether) was added a solution of 2-(benzhydrylidene-amino)-3-(2-chloro-pyridin-4-yl)-propionitrile (1.50 g, 4 mmol) in ethanol (15 mL) and methanol (5 mL). The reaction was stirred for 20 minutes, then concentrated to one third volume. The crude residue was triturated with hexane (20 mL), ethanol (10 mL), three 30 mL portions of hexane:ether (4:1 vol:vol) and three 30 mL portions of hexane. The precipitate was dried in vacuo to give 2-amino-3-(2-chloro-pyridin-4-yl)-propionitrile as an off white powder (0.90 g, 82%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23](F)[CH:22]=1)[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH2:17][F:18])([CH2:15][F:16])[CH3:14])[C@H:7]([CH3:19])[NH:6]1)[OH:4].[CH3:29][CH:30]([S-:32])[CH3:31].[Na+].[Cl-].[NH4+]>CN1CCCC1=O.CO>[NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([S:32][CH:30]([CH3:31])[CH3:29])[CH:22]=1)[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH2:17][F:18])([CH2:15][F:16])[CH3:14])[C@H:7]([CH3:19])[NH:6]1)[OH:4]
Reactant: CC(C)[S-]
Reactant: C[C@@H]1N[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO[C@H]1OCC(C)(CF)CF
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(C)Sc1cc(F)cc(C[C@H](N)[C@H](O)[C@H]2CO[C@@H](OCC(C)(CF)CF)[C@H](C)N2)c1
Temperature: 25 °C
Yield: 3.9 %

Procedure:
Heat a mixture of (1S,2S)-2-Amino-3-(3,5-difluorophenyl)-1-[(3R,5S,6R)-6-(2,2-di-(fluoromethyl)propoxy)-5-methylmorpholin-3-yl]-propan-1-ol (91 mg, 0.22 mol) and sodium 2-propanethiolate (328 mg, 3.34 mmol) in N-methylpyrrolidin-2-one (2.0 mL) at 90° C. in a sealed tube for 1 hour. Cool the reaction mixture to room temperature, dilute with methanol, add ammonium chloride (192 mg, 3.34 mmol), and mix well. Load mixture on SCX™ column and elute with 2.0 M ammonia in methanol to provide the desired compound (60 mg, 58%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl[CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22]>O1CCCC1>[CH3:22][O:21][CH:20]([O:23][CH3:24])[CH2:19][CH:1]([N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cn2cccn2)cc1
Reactant: COC(CCl)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(CC(c1ccccc1)n1cccn1)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-1H-pyrazole (0.653 g) in tetrahydrofuran (5 mL) cooled to −78° C. was dropwise added 1.6M n-butyllithium (2.84 mL). The reaction mixture was stirred for 60 minutes, and 2-chloro-1,1-dimethoxyethane (0.517 mL) was added, and stirring continued for 3 hours. The reaction mixture was allowed to slowly warm up to room temperature, and was quenched with water, extracted with ether, dried over Na2SO4, filtered, and concentrated. The product was purified by chromatography on silica gel using 0-20% ethyl acetate/hexanes as the eluent to provide the title compound.
Reaction SMILES: BrC[C:3]1C=CC=C[C:4]=1[CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([CH:17]2[CH2:22][CH2:21][CH:20](C3C=CC=CC=3CBr)[CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[C-]#[N:32].[Na+].O1CCOCC1>O>[CH:17]1([C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:4][C:3]#[N:32])=[CH:10][CH:11]=2)=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: [C-]#N
Reactant: O=C(C1CCC(c2ccccc2CBr)CC1)C1CCC(c2ccccc2CBr)CC1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCc1ccc(C(=O)C2CCCCC2)cc1

Procedure:
Crude α-bromo-p-tolylcyclohexyl ketone (17 g.), sodium cyanide (3 g.), dioxan (80 ml.) and water (20 ml.) were heated under reflux for 4 hours. The mixture when cold was poured into water and extracted with ether. Evaporation of the extracts followed by chromatography on silica gave a solid (1.5 g.) which was crystallised from light petroleum (b.p. 60°-80°) m.p. 102°-103°.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][CH:12]1[S:16](=[O:18])(=[O:17])[O:15][CH2:14][CH2:13]1>O1CCOCC1.O>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH2:13][CH:12]([S:16]([OH:18])(=[O:17])=[O:15])[CH3:11]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CC1CCOS1(=O)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(CCSc1nc2ccccc2[nH]1)S(=O)(=O)O
Yield: 86 %

Procedure:
To a hot solution of 2-mercaptobenzimidazole (2.0 g, 13.3 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added via syringe pump (1 hour addition) a solution of 2,4-butane sultone (1.80 g, 12.7 mmol in 1,4-dioxane (total of 3 mL)). The solution was stirred at reflux for an additional 3 hours. The solid was collected by filtration. It was washed with acetone (2×20 mL) and dried in vacuo. Yield: 86%. 1H NMR (DMSO, 500 MHz) δ ppm 7.64(m, 2H), 7.44 (m, 2H), 3.63 (t, 2H, J=7.3 Hz), 2.68 (m, 1H), 2.10 (m, 1H), 1.90 (m, 1H), 1.15 (d, 3H, J=6.8 Hz). 13C (DMSO, 125 MHz) δ ppm 152.64, 133.32, 125.66, 113.67, 53, 10, 39.72, 33.48, 30.14, 16.85. ES-MS 287 (M+1).