Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].FC1C(F)=C(C=CC=1)C=O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[N:13]([CH2:14][CH3:15])[CH2:11][CH3:12]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CCNCC
Agent: O=Cc1cccc(F)c1F
Solvent: CS(C)=O
Product: CCN(CC)c1ccc(C=O)cc1F
Reaction time: 6 h
Yield: 93 %

Procedure:
In a 250 mL round bottom flask equipped with stirbar, condenser and nitrogen inlet was placed 3,4-difluorobenzaldehyde (25.0 g, 176 mmol), dimethylsulfoxide (50 mL) and diethylamine (38.6 g, 528 mmol). The resulting solution was boiled gently for 6 hr at which time thin layer chromatography indicated all the difluorobenzaldehyde was consumed. The solution was cooled and transferred to a separatory funnel with ethyl acetate and water. The phases were separated, the organic phase washed well with water, dried (MgSO4) and filtered through a short pad of silica gel. Silica gel (50 g) was added to the filtrate and the mixture concentrated to dryness. This material was placed at the top of a column of silica gel and eluded with a gradient of ethylacetate in hexane (0→4%). Concentration of the pure fractions by rotary evaporation afforded a light brown oil (31.97 g, 92%) of sufficient purity for subsequent transformations: IR (CCl4)1695 cm-1 ; 1H NMR (CDCl3)δ9.70 (s, 1H), 7.41-7.50 (m, 2H), 6.78 (t, J= 8Hz, 1H), 3.39 (q, J=7 Hz, 4H), 1.20 (t, J=7 Hz, 6H); 13C NMR (CDCl3) ppm 189.048, 151.901 (d, J=244 Hz), 142.844 (d, J=8 Hz), 127.880. 126.244 (d, 6 Hz), 116.433 (d, J=23Hz), 115.316 (d, 5 Hz), 45.845 (d, J=6Hz), 12.858 d,J=1 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][N:12]=1.[Mn]([O-])(=O)(=O)=[O:20].[K+].[Mn]([O-])(=O)(=O)=O.[OH2:30]>>[C:13]1([C:10]2[S:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:1]([OH:20])=[O:30])=[N:12][N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccccc1-c1nnc(-c2ccccc2)s1
Agent: [K+]
Product: O=C(O)c1ccccc1-c1nnc(-c2ccccc2)s1

Procedure:
2-o-Methylphenyl-5-phenyl-1,3,4-thiadiazole (25 g.) was suspended in a solution of potassium permanganate (40 g.) in water (475 ml.). The reaction mixture was stirred and refluxed until the color of permanganate had discharged, then filtered and cooled. Unreacted 2-o-methylphenyl-5-phenyl-1,3,4-thiadiazole which separated was removed by filtration. When this filtrate was acidified, 2-(5-phenyl-1,3,4-thiadiazol-2-yl)benzoic acid was obtained and recrystallized from ethanol to give white crystals, M.P. 178°-180°. Analysis gave C, 63.37; H, 3.74; N, 9.74. C15H10N2O2S requires C, 63.83; H, 3.51; N, 9.93.
Reaction SMILES: C([Li])(CC)C.Br[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.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:27])[CH2:20]2.Cl>C1CCCCC1.O1CCCC1>[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]([C:21]2([OH:27])[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]2)=[CH:8][CH:9]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: OC1(c2ccc(-c3ccccc3)cc2)CN2CCC1CC2
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 41.1 %

Procedure:
A solution of sec-butyllithium in cyclohexane (100 ml, 1.3M) was added dropwise with stirring to a solution of 4-bromobiphenyl (25 g) in dry tetrahydrofuran (240 ml) under an argon atmosphere at -78° C. The mixture was stirred for 5 minutes and a solution of quinuclidin-3-one (12 g) in dry tetrahydrofuran (100 ml) added during 20 minutes. Stirring was continued at -78° C. for 30 minutes and the mixture allowed to reach room temperature over 2 hours. 2M Hydrochloric acid (225 ml) was added keeping the reaction temperature below 10° C. The aqueous layer was separated and washed with diethyl ether (2×300 ml) before the addition of excess sodium hydroxide solution (density 1.35 g/cm3) to pH14. The mixture was extracted with ethyl acetate which had been heated to 50° C. and the ethyl acetate phase separated, dried (Na2SO4) and evaporated to yield a colourless solid which crystallised from ethyl acetate to give 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (11.0 g) m.p. 165°-166° C.; microanalysis, found: C, 81.1; H, 7.5; N, 5.2%; C19H21NO 0.1H2O requires: C, 81.1; H, 7.5; N, 5.0%; NMR (CDCl3 /CD3CO2D): 1.7-1.9(3H, m,), 2.5(1H, m), 2.5-2.7(1H, m), 3.2-3.5(4H, m), 3.7(1H, dd), 4.0(1H, dd) and 7.3-7.7(9H, m); m/z 279 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C=O)C>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1

Procedure:
trans-Methyl 4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)-cyclohexanecarboxylate (29.00 g, 93.02 mmol) was dissolved in anhydrous acetonitrile (930 mL) and anhydrous DMF (9 mL) and heated at 55° C. under nitrogen for 3 h. The reaction mixture was concentrated in vacuo, then, the solid residue was taken up in DCM, then, basified to pH 10 with 2M ammonia in isopropanol. The mixture was concentrated in vacuo, re-dissolved in DCM, and then loaded onto TEA-basified silica gel. The crude product was purified by a silica gel column chromatography (eluted with 2:3 EtOAc/DCM) to obtain the title compound as a yellow powder; 1H NMR (CDCl3, 400 MHz) δ 1.63 (ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.85 (ddd, J=13.2, 13.2, 13.2, 2.8 Hz, 2H), 2.10 (dd, J=14.4, 3.2 Hz, 2H), 2.19 (dd, J=14.0, 3.2 Hz, 2H), 2.46 (tt, J=12.4, 3.6 Hz, 1H), 2.96 (tt, J=11.6, 3.2 Hz, 1H), 3.70 (s, 3H), 7.33 (dd, J=5.2, 1.2 Hz, 1H), 7.61 (d, J=4.8 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z 294.17/296.14 (100/86) [MH+]. HPLC: tR=2.85 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[NH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:11][C:8]([F:9])([F:10])[C:6]1[CH:7]=[C:3]([C:2]([F:1])([F:12])[F:13])[N:4]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:5]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Cn1nc(C(F)(F)F)cc1C(F)(F)F)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3,5-Bis-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 6.94-7.0 (m, 2H), 6.92 (s, 1H), 6.82-7.90 (dd, 2H), 5.2 (s, 2H), 3.72-3.8 (t, 2H), 3.58-3.66 (t, 2H), 3.12-3.18 (t, 2H), 3.02-3.12 (t, 2H). 13C NMR (400 MHz, CDCl3): 162.2, 158.2, 156.4, 146.5, 118.4, 116.2, 115.8, 113.2, 60.4, 53.2, 50.6, 50.2, 45.2, 42.2, 21.2, 14.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29]N)=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:33]=1.C=O.[C:36]([BH3-])#[N:37].[Na+].[C:40](=O)([O-])[O-].[K+].[K+]>CO.C(O)(=O)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][N:37]([CH3:36])[CH3:40])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:33]=1
Reactant: NCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Reactant: O=C([O-])[O-]
Reactant: [BH3-]C#N
Agent: C=O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloro-1-{6-[2-(2-aminoethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.11 g) in methanol (3 ml) is added 37% formalin (0.24 ml), and thereto is added sodium cyanoborohydride (0.044 g), and thereto is added with stirring acetic acid (0.18 ml) at 10° C. The mixture is stirred at room temperature for one hour, and poured into ice-water, and the mixture is made basic with potassium carbonate, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and the resultant is dissolved in ethanol (5 ml), and thereto is added conc. hydrochloric acid, and the mixture is stirred at room temperature for one hour. The mixture is evaporated under reduced pressure to remove the solvent, and crystallized from diethyl ether to give 7-chloro-1-{6-[2-(2-dimethylaminoethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine dihydrochloride (53 mg) as white powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[OH-].[Li+]>C1COCC1.CO.O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a stirred solution of methyl 4-bromo-3-methoxybenzoate (11.2 g) in THF (130 mL), methanol (45 mL) and water (45 mL) was added a 1 M solution of lithium hydroxide in water (140 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuum. Water was added and 1 N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by filtration, washed with water and dried in vacuum to give 10.1 g of the title compound, that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([O:14][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Yield: 54.6 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 12.55 mmol) in anhydrous DMF (5 mL) were added chlorotrimethylsilane (1.95 mL, 15.37 mmol) and triethylamine (4.18 mL, 30.0 mmol). The resulting milky mixture was heated at 80° C. for 17 h, then cooled to RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a pale yellow oil (1.86 g, 55%). To a solution of 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.86 g, 6.852 mmol) in acetonitrile (80 mL) was added Selectfluor™ (2.7 g, 7.622 mmol) and the mixture was stirred at RT for 2 h. The resulting solution was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a colourless oil (1.13 g, 76%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>ClCCl>[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[S:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=1)(=[O:34])=[O:33])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
To a mixture of (S)-piperidine-2-carboxylic acid benzyl ester hydrochloride (5.00 g, 19.5 mmol) and triethylamine (5.50 mL, 39.1 mmol) in dichloromethane (150 mL) was added 3-fluorobenzenesulfonyl chloride (3.80 g, 19.5 mmol). The mixture was stirred at room temperature for 5 h as it turned to a white suspension. The suspension was washed twice with distilled water. The organic layer was then dried over magnesium sulfate and concentrated to afford 9 g of crude oil. Flash column chromatography on silica gel (ethyl acetate/n-heptane) provided 6.51 g (88.3%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[N:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1nccc(Cl)n1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccnc(C)n5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-chloro-2-methyl-pyrimidine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.00 min; Mass spectrum (ESI+): m/z=451 [M+H]+.
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][CH2:28][NH:29][C@H:4]2[CH2:5][CH2:6][C@H:1]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[O:14][C:10]=4[CH:9]=3)[CH2:2][CH2:3]2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: NCCCc1ccc(F)c(F)c1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)c(F)c4)CC3)cc2o1

Procedure:
Coupling of ketone 5 and 3-(3,4-difluorophenyl)-1-propylamine, using the method given in Example 1, gave 6-(trans-4-[3-(3,4-difluorophenyl)-propylamino]cyclohexyl}-3H-benzoxazol-2-one (690 mg, 37%): 1H NMR (500 MHz, DMSO-d6): δ 7.33-7.24 (m, 2H), 7.12 (d, J=1 Hz, 1H), 7.06-7.02 (m, 1H), 6.98-6.93 (m, 2H), 3.51-3.10 (br s, 2H), 2.62 (dd, J=8, 8 Hz, 2H), 2.55 (dd, J=7, 7 Hz, 2H), 2.48-2.38 (m, 2H), 1.98-1.91 (m, 2H), 1.80-1.73 (m, 2H), 1.71-1.65 (m, 2H), 1.44 (dddd, J=10, 10, 10, 3 Hz, 2H), 1.13 (dddd, J=10, 10, 10, 3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:12]=1[C:13]([N:15]([CH3:17])[CH3:16])=[O:14].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:19]2[CH:20]=[CH:21][C:11]([F:10])=[C:12]([CH:18]=2)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cncc(Cl)c1
Reactant: CN(C)C(=O)c1cc(I)ccc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1cc(C#Cc2cncc(Cl)c2)ccc1F
Product: Cl

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (46 mg, 0.07 mmol), copper (I) iodide (25 mg, 0.13 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (200 mg, 1.45 μmmol) to a solution of 2-fluoro-5-iodo-N,N-dimethylbenzamide, (prepared as described in PREPARATION 45), (0.600 g, 2.1 mmol) in triethylamine (4.3 mL, 31 mmol) and place in an oil bath at 70° C. Add toluene (10 mL) and heat for 2 h. Concentrate and purify by silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes, to give the free base of the title compound as a colorless oil. Dissolve the free base in diethyl ether (50 mL) and add 2 M hydrogen chloride in diethyl ether (2.6 mL, 5.2 mmol). Stir for 10 min, concentrate, triturate with diethyl ether and dry to give the title compound as a light yellow solid (350 mg, >99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C@@H:19]([NH:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1)[CH3:20])=[CH:7]2.O.[OH-].[NH4+:31]>O1CCOCC1.[Cl-].[Na+].O>[NH2:31][C:26]1[N:25]=[CH:24][N:23]=[C:22]([NH:21][C@H:19]([C:8]2[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[CH3:20])[CH:27]=1
Reactant: [NH4+]
Reactant: C[C@H](Nc1cc(Cl)ncn1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(N)ncn1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A heavy-wall glass tube with stir bar and FEP-encapsulated-silicone O-ring seal was charged with 77 (ca. 300 mg, 0.73 mmol) in 1,4-dioxane (12 mL) and concentrated ammonium hydroxide solution (10 mL), then sealed tightly and heated at 120° C. After 16 h, more ammonium hydroxide (6 mL) was added and heating continued at 150° C. during 6 h, then 160° C. during 24 h. A third portion of ammonium hydroxide (8 mL) was added and heating continued at 150° C. during 3 days. The reaction mixture was poured into a mixture of water and brine (35 mL each), stirred about 1 h at 0° C., and the resulting precipitate collected by filtration and washed with ice-water. This material was dried in vacuo to give (S)-3-(1-(6-aminopyrimidin-4-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one 78. ESI-MS m/z: 392.15 [M+H]+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.O>C(Cl)Cl>[N:10]1([CH2:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: c1cc(CN2CCOCC2)ccn1
Reaction time: 50 h
Yield: 84.4 %

Procedure:
A suspension of 4-picolyl chloride hydrochloride (10.0 g, 60.98 mmol) in 100 ml of methylene chloride at room temperature is treated with morpholine (26.52 g, 304.9 mmol, 5.0 equiv.) at once. After stirring for 50 h, the reaction mixture is poured into 250 ml of water, extracted six times with ethylacetate, three times with ethylacetate-methanol (9:1) and the combined organic extracts are dried over Na2SO4. The concentrated filtrate is chromatographed with 350 g of silica gel, packed and eluted with acetone-methylene chloride (1:2), to give 9.17 g (84%) of 4-(4-morpholinyl)methylpyridine as a yellow liquid.
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[CH3:7][NH:8][CH2:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11].[OH:20]CCCC(O)=O>O>[OH:20][CH:2]([CH2:3][CH3:4])[C:1]([O:15][C@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[C@H:12]([OH:13])[C@@H:10]([OH:11])[CH2:9][NH:8][CH3:7])=[O:6]
Reactant: O=C(O)CCCO
Reactant: O=C1CCCO1
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: CCC(O)C(=O)O[C@@H]([C@H](O)[C@@H](O)CNC)[C@H](O)CO
Temperature: 60 °C

Procedure:
500 ml (565 g, 6.56 mol) of gamma-butyrolactone are placed in 1.8 l of water. 1.28 kg (6.56 mol) of methylglucamine are added to the solution obtained. The mixture is then heated to 60° C. for 8 hours. The pH value falls over this period from an initial value of 11 to 7.5. The volume of the solution obtained is then adjusted to 3.4 l by the addition of water (approximately 200 ml) in order to achieve a concentration of 2 g of gamma-hydroxybutyric acid in 10 ml of solution.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])([NH:8][S:9](=[O:26])(=[O:25])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.[CH3:33][I:34]>>[I-:34].[CH2:31]([O:30][C:28](=[O:29])[CH2:27][C:5]1([NH:8][S:9](=[O:25])(=[O:26])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=2)[CH2:6][CH2:7][N+:2]([CH3:33])([CH3:1])[CH2:3][CH2:4]1)[CH3:32]
Reactant: CCCCCCCCc1ccc(NS(=O)(=O)NC2(CC(=O)OCC)CCN(C)CC2)cc1
Reactant: CI
Product: CCCCCCCCc1ccc(NS(=O)(=O)NC2(CC(=O)OCC)CC[N+](C)(C)CC2)cc1
Product: [I-]

Procedure:
Ethyl 2-(1-methyl-4-(N-(4-octylphenyl)sulfamoylamino)piperidin-4-yl)acetate (39 mg, 0.084 mmol), was treated with MeI (0.2 mL, 3.2 mmol) as described in example 2a to yield crude 4-(2-ethoxy-2-oxoethyl)-1,1-dimethyl-4-(N-(4-octylphenyl)sulfamoyl-amino)piperidinium iodide which was used without further purification. Subsequent saponification and preparative HPLC purification gave the title compound (8 mg, 17%) as white solid. 1H NMR (400 MHz, CD3OD) δ 7.20 (d, 2H, J=8.4 Hz), 7.15 (d, 2H, J=8.8 Hz), 3.27-3.15 (m, 4H), 3.08 (s, 3H), 2.88 (s, 2H), 2.81 (s, 3H), 2.59 (t, 2H, J=15.6 Hz), 2.39 (d, 2H, J=15.6 Hz), 2.26-2.18 (m, 2H), 1.65-1.55 (m, 2H), 1.48-1.25 (m, 10H), 0.91 (t, 3H, J=6.8 Hz); MS ESI 454.3 [M+H]+, calcd for [C23H39N3O4S+H]+ 454.27.
Reaction SMILES: [C:1]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[C:2]([O:4]CC1C=CC=CC=1)=O.[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1.[CH3:26][CH2:27]OCC>>[CH2:14]([O:13][C:1](=[O:12])[C:2](=[O:4])[CH2:23][CH2:22][CH2:21][CH2:25][CH2:26][CH3:27])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1CCOC1
Reactant: O=C(OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCOCC
Product: CCCCCCC(=O)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 73 %

Procedure:
Magnesium turnings (720 mg, 30 mmol) were suspended in THF (30 mL) in a 250 mL round bottom flask fitted with a thermometer. A solution of 1-bromohexane (3.2 mL, 23 mmol) in THF (10 mL) was prepared after first drying the 1-bromohexane by passing it through a pad of activated basic alumina. About 10% of the halide solution was added to the Mg suspension, followed by a small pellet of iodine. The addition of the iodine led to an increase in the reaction temperature indicating the initiation of the Grignard reagent formation. The remaining halide solution was added dropwise over ˜15 minutes. After the completion of the addition of the halide, the suspension was held at ˜55° C. to complete the formation of the Grignard reagent. While the Grignard reagent was forming, a suspension of dibenzyl oxalate (5.1 g, 19 mmol) was prepared in a mixture of ether (50 mL), and THF (15 mL). This suspension was cooled to <−70° C. (internal monitoring) and then treated with the Grignard solution prepared previously at a rate sufficient to keep the internal temperature below −70° C. After stirring for 3 hours at <−70° C., the reaction was quenched by the addition of saturated aqueous NH4Cl, followed by addition of 1 N HCl (25 mL). The cold solution was then allowed to come to ambient temperature. After ˜64 hours the reaction mixture was diluted with ether and the layers were separated. The acidic aqueous layer was extracted with ether (2×50 mL). The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a pale brown oil. The crude material was purified by flash chromatography eluting with a gradient from 0% to 30% ethyl acetate/hexane to afford 2-oxo-octanoic acid benzyl ester (3.43 g, 73% yield) as a pale yellow oil. The material was not completely pure by NMR analysis. 1H-NMR (400 MHz, CDCl3): δ 7.42-7.33 (5H, m), 5.27 (2H, m), 2.82 (2H, t, J=7.3 Hz), 1.66-1.56 (2H, m), 1.35-1.23 (6H, m), 0.89-0.85 (3H, m).