Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.CN(C)C1C=CC=CC=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].O>O1CCOCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:29]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)(=[O:32])[CH:30]=[CH2:31]
Reactant: CC(C(=O)O)c1ccc(OCCCCCCO)cc1
Reactant: C=CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CN(C)c1ccccc1
Product: C=CC(=O)OCCCCCCOc1ccc(C(C)C(=O)O)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
(4-(6-Hydroxyhexyloxy)phenyl)propionic acid (200 g), N,N-dimethylaniline (100 g) and BHT (0.3 g) were dissolved in dioxane (1,000 mL). Acrylic acid chloride (74.3 g) was added dropwise thereto over 10 minutes, followed by agitating at 60° C. for 5 hours. The reaction solution was poured into water, to which ethyl acetate was added, followed by agitating. The ethyl acetate layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the ethyl acetate layer to obtain a solid product. The solid product was dissolved in toluene and reprecipitated by pouring into a large amount of heptane to obtain 213 g of (4-(6-acryloyloxyhexyloxy)phenyl)propionic acid. (Melting point: 64 to 68° C.)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:21][NH2:22]>>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH:9]=1)[C:3]([NH:21][NH2:22])=[O:2])([O-:12])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccccc1
Reactant: NN
Product: NNC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccccc1
Yield: 74 %

Procedure:
A mixture of 5-nitro-2-phenoxy-benzoic acid methyl ester (4.0 g, 14.7 mmol) and hydrazine (5 mL, 80%) was refluxed for 4 h to yield 5-nitro-2-phenoxy-benzoic acid hydrazide (2.97 g, 74%). The title compound was prepared from 5-nitro-2-phenoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 12.20 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.17 (s, 1H), 8.10 (d, J=6.6 Hz, 1H), 7.81 (m, 1H), 7.75 (t, J=6.6 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 7.35 (m, 2H), 7.27 (d, J=7.2 Hz, 1H), 7.03 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[C:27](=[O:28])[C:26](OC)=[C:25]([C:31]3[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][CH:32]=3)[CH:24]=[N:23]2)[CH:19]=[CH:20][CH:21]=1>O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[C:27](=[O:28])[C:26]([N:2]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH3:1])=[C:25]([C:31]3[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][CH:32]=3)[CH:24]=[N:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1c(-c2ccc(SC)cc2)cnn(-c2cccc(Cl)c2)c1=O
Reactant: CNCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2N(C)Cc2ccccc2)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a rapidly stirred 0° C. mixture of N-methylbenzylamine (67.5 mg, 0.56 mmol) and tetrahydrofuran (3.7 mL) was slowly added dropwise an n-BuLi solution (0.235 mL, 0.59 mmol, 2.5 M in hexanes). The reaction mixture was stirred for 10 minutes at 0° C. and 1 hour at 23° C. The solution was cooled to −78° C., and a tetrahydrofuran (10-15 mL) solution of the 2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (200 mg, 0.56 mmol) slowly added along the interior wall of the reaction vessel. This reaction mixture was stirred overnight, slowly warming to 23° C. as the cooling bath evaporated. The reaction was quenched with water and diluted with a large excess of ethyl acetate. The layers were separated, and the ethyl acetate layer washed with additional water and brine and dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:9) to provide 2-(3-chlorophenyl)-4-(N-methyl benzylamino)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 145 mg, 58%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1.C(N(CC)CC)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([NH:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CNCc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 4-(bromomethyl)-2-methoxy-1-nitrobenzene (1.0 g, 4.06 mmol) in THF (15 ml), triethylamine (1.23 g, 12.19 mmol) and benzyl amine (1.3 g, 12.19 mmol) were added at RT and the reaction was stirred for 2 hours. The reaction mixture was partitioned between water (50 ml) and EtOAc (25 ml) and the separated aqueous layer was extracted with EtOAc (15 ml). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on neutral silica gel using 15-25% EtOAc in hexane to give the title compound (1.0 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](C4C=CC=C(B5OC(C)(C)C(C)(C)O5)C=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Cl[C:43]1[CH:44]=[CH:45][C:46]2[O:51][CH2:50][N:49]3[C:52]4[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=4[N:54]=[C:48]3[C:47]=2[CH:59]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[CH:59]1[C:47]2[C:48]3[N:49]([C:52]4[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=4[N:54]=3)[CH2:50][O:51][C:46]=2[CH:45]=[CH:44][C:43]=1[C:18]1[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:10]2[O:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=2[CH:17]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cc12
Reactant: Clc1ccc2c(c1)-c1nc3ccccc3n1CO2
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: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(c3)-c3nc5ccccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 15 h
Yield: 21.9 %

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzofuran-3-carboxamide (117 mg, 0.23 mmol) and 2-chloro-6H-benzo[e]benzo[4,5]imidazo[1,2-c][1,3]oxazine (60 mg, 0.23 mmol) in dioxane:H2O (2 mL:0.5 mL) was added Pd2(dba)3 (21 mg, 0.02 mmol), X-Phos (22 mg, 0.05 mmol) and K3PO4 (184 mg, 0.69 mmol) under N2. The mixture was heated to 100° C. and stirred for about 15 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with H2O, brine, dried over Na2SO4. After being concentrated in vacuo, the resulting resulting residue was purified using prep-HPLC to provide the product of Compound 133 (30 mg, yield: 22%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.59 (d, J=4.4 Hz, 1H), 8.14 (d, J=1.9 Hz, 1H), 8.08˜8.05 (m, 3H), 7.77˜7.72 (m, 2H), 7.69 (s, 1H), 7.63 (dd, J=8.7, 2.0 Hz, 1H), 7.46 (t, J=8.7 Hz, 2H), 7.37˜7.30 (m, 3H), 6.38 (s, 2H), 3.21 (s, 3H), 3.05 (s, 3H), 2.87 (d, J=4.4 Hz, 3H). MS (M+H)+: 597.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH3:16])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]1[CH:11]=[C:10]([CH3:16])[CH:9]=[C:8]([O:7][CH3:6])[C:13]=1[CH2:26][CH2:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(C)cc(OC)c1
Reactant: BrCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(C)cc(OC)c1CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 1347.9 %

Procedure:
A solution of nBuLi in hexanes (1.7 M, 14 mL, 24 mmol) was added over 15 min to a solution of 3,5-dimethoxytoluene (2.93 mL, 20 mmol) in THF (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h then at room temperature for 3 h. The reaction was cooled to 0° C. and a solution of the 4-phenylbutylbromide (4.13 mL, 1.2 mmol) in toluene (15 mL) was added over 5 min. The reaction mixture was allowed to warm to room temperature and heated to 80° C. for 3-4 h. The reaction was quenched slowly with water and partitioned over Et2O (100 mL) and water (100 mL). The phases were separated and the aqueous phase was extracted with Et2O (3×100 mL). The pooled organics were washed with brine (120 mL), dried over Na2SO4, and concentrated under vacuum and the crude product was purified by flash chromatography (silica-gel, petroleum ether/EtOAc 200:1) to afford the product as a clear oil (4.6 g, 81%). 1H NMR (CDCl3): δ 1.53-1.67 (m, 4H), 2.31 (s, 3H), 2.60-2.64 (m, 4H), 3.76 (s, 6H), 6.34 (s, 2H), 7.13-7.22 (m, 5H).
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.CN(C)C(=O)C(C)C.[Cl:16][C:17]([Cl:22])=[C:18]([Cl:21])[CH:19]=[CH2:20].O>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[Cl:16][C:17]([Cl:22])=[C:18]([Cl:21])[CH:19]=[CH2:20].[CH3:1][NH:3][CH3:4]
Reactant: CCN(CC)CC
Agent: C=CC(Cl)=C(Cl)Cl
Agent: CC(C)C(=O)N(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CNC

Procedure:
50.0 g (0.5 mol) of triethylamine in 100 ml of methylene chloride was added dropwise to 350 ml of the solution, prepared according to Example 7a, of the amide chloride of isobutyric acid dimethylamide in methylene chloride at 20° C., while cooling and stirring, and the mixture was then heated and refluxed for 1 hour. Thereafter, 75.0 g (0.55 mol) of zinc chloride were added at 10° C. and 79.0 g (0.5 mol) of 1,1,2-trichlorobutadiene were added dropwise to the reaction solution in the course of 60 minutes. After heating under reflux for 5 hours, 400 ml of water were added to the reaction solution and the mixture was stirred overnight (15 hours). Separating the phases and drying the organic phase over sodium sulphate and subjecting it to fractional distillation gave 10.5 g of 1,1,2-trichlorobutadiene, 11.5 g of isobutryic acid dimethylamine and 66.8 g (59%, relative to isobutyric acid dimethylamine employed) of the ketone of boiling point 112°-117° C./10 mm Hg and refractive index nD20 of 1.509.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:23][C:24]1[NH:28][N:27]=[N:26][N:25]=1>>[NH:25]1[C:24]([NH:23][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])=[N:28][N:27]=[N:26]1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(Nc1nnn[nH]1)c1cccc(Br)n1
Yield: 56.5 %

Procedure:
0.89 g of 6-bromo-2-pyridinecarboxylic acid, 0.71 g of N,N-carbonyldiimidazole and 0.41 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and water, whereby 0.67 g of N-(5-tetrazolyl)-6-bromo-2-pyridinecarboxamide is obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH:20]([O:23][CH3:24])[O:21][CH3:22])=[CH:4][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[N:6][CH:7]=1.C([Li])CCC.CN([CH:33]=[O:34])C.[BH4-].[Na+]>C1COCC1>[CH3:22][O:21][CH:20]([O:23][CH3:24])[C:3]1[CH:4]=[C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:6]=[CH:7][C:2]=1[CH2:33][OH:34]
Reactant: CN(C)C=O
Reactant: COC(OC)c1cc(OCCCCC2CCN(C)CC2)ncc1Br
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(OC)c1cc(OCCCCC2CCN(C)CC2)ncc1CO
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
5-Bromo-4-dimethoxymethyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine (0.5 g, 1.25 mmol, 1.0 equiv) was dissolved in THF (6 mL) and cooled to −78° C. A 2.5 M solution of n-butyllithium in hexanes (0.6 mL, 1.5 mmol, 1.2 equiv) was added dropwise. The solution was stirred for 45 min, and then DMF (0.55 mL, 1.25 mmol, 1.0 equiv) was added. After 1 h, sodium borohydride (38 mg, 1.36 mmol, 1.1 equiv) was added. The mixture was allowed to warm to −40° C. for 30 min, then was quenched with satd. aq. NaHCO3 (10 mL). The mixture was extracted with chloroform (3×30 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated to afford {4-dimethoxymethyl-6-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-3-yl}-methanol as a crude mixture. This crude material (88 mg) was dissolved in THF (3 mL) and 1.0 M HCl (3 mL) was added portionwise over 3 h at 60° C. The mixture was cooled, satd. aq. NaHCO3 was added, and the mixture was extracted with chloroform (3×30 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated. A portion of the resulting crude 5-hydroxymethyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbaldehyde (33 mg), 3,5-dimethyl-benzene-1,2-diamine (22 mg), and Na2S2O5 (36 mg) were stirred in DMF (2 mL) at 90° C. for 36 h. The reaction mixture was purified by Method 2 to afford 5.3 mg of the title compound. MS (electrospray): mass calculated for C25H34N4O2, 422.27; m/z found, 423.5 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.21 (s, 1H), 7.30 (s, 1H), 7.23 (br s, 1H), 6.95 (br s, 1H), 4.68 (s, 2H), 4.34 (t, J=6.4 Hz, 2H), 2.95-2.82 (m, 2H), 2.57 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H), 2.11-1.98 (m, 2H), 1.86-1.68 (m, 4H), 1.57-1.44 (m, 2H), 1.39-1.15 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:6]1[CH:5]=[C:4]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=2)[N:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Cl)nc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Yield: 65.2 %

Procedure:
To a degassed solution of 2-bromo-6-chloro-4-methyl-pyridine (1.45 g, 7.04 mmol), 4-trifluoromethylbenzeneboronic acid (3.8 g, 20 mmol), 2N Na2CO3 (10 mL) in DME (80 mL) was added tetrakis(triphenylphosphine)palladium (690 mg, 0.6 mmol) under argon. The mixture was heated to 85° C. for 4 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (0-20% methylene chloride in heptane) to give the product as an off white solid (1.75 g, 65%). 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=7.91 Hz, 26H), 7.75 (d, J=8.29 Hz, 26H), 7.61 (s, 13H), 2.53 (s, 19H). MS m/e 382.2 (M+H)
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>O1CCOCC1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=[S:29])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Yield: 98 %

Procedure:
A mixture of 5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazoli-dine-2-one. (0.100 g, 0.374 mmol) and Lawesson's reagent (0.151 g, 0.374 mol) in dioxane (2 ml) was stirred at 65° C. for 2 h. The solution was concentrated under vacuum and the residue purified by PTLC (10% methanol/dichloromethane) to give a tan solid (0.104 g, 98%); mp 137-88° C.; MS: (M+H)+=284.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1C=CC(C)=CC=1CC=O.[CH3:15][O:16][C:17](=[O:30])[C:18]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:15][O:16][C:17](=[O:30])[C:18]1[CH:23]=[C:22]([CH2:4][CH:3]=[O:2])[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)c1ccc(C)cc1CC=O
Reactant: CCCCOc1ccc(Br)cc1C(=O)OC
Product: CCCCOc1ccc(CC=O)cc1C(=O)OC
Yield: 30 %

Procedure:
The title compound (30%) is prepared essentially according to the preparation of 4-Methyl-2-(2-oxo-ethyl)-benzoic acid methyl ester using 5-bromo-2-butoxy-benzoic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.61 (d, 1H), 7.26-7.23 (dd, 1H), 6.94-6.92 (d, 1H), 4.02-3.99 (t, 2H), 3.85 (s, 3H), 3.62 (d, 2H), 1.80-1.76 (m, 2H), 1.52-1.47 (m, 2H), 0.96-0.93 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:47]1[CH:52]=[CH:51][C:50]([CH2:53]Br)=[CH:49][CH:48]=1>CN(C=O)C>[C:50]1([CH2:53][N:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:23][CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:11][CH2:10][CH2:9][N:8]([CH2:53][C:50]2[CH:51]=[CH:52][CH:47]=[CH:48][CH:49]=2)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:51]=[CH:52][CH:47]=[CH:48][CH:49]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCCCCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCCCCCN(CCCN(Cc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCN(Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
Dissolve 20.0 gm (0.03 mol) of the product from Step C in 30 ml DMF and treat with 7.5 gm (0.067 mol) KtBuO and 7.96 ml (0.067 mol) BnBr, with stirring for 18 hours. Evaporate the volatiles (0.5 mm and 45° C.) and take up the resulting residue in 1400 ml of EtOAc and water-wash (2×, 500 ml). The organic layer is then dried (MgSO4) and the solvent is evaporated (in vacuo). Flash chromatography on silica gel eluted with 20% EtOAc/hexane yields 12.4 gm (50%) of desired product as a clear viscous oil. Rf is 0.42 (silica gel plates eluted with 25% EtOAc/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([O:28][CH2:36][C:35]5[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=5)[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1CCCCC(OCc2ccc(F)cc2)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 138, 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide (50 mg, 0.124 mmol), NaH (8.9 mg, 0.37 mmol), and 4-fluorobenzyl bromide (28.2 mg, 0.15 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH. LC-MS: 511 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.45 (d, 1H), 7.35 (m, 2H), 7.00 (m, 2H), 6.85 (d, 1H), 4.50 (m, 2H), 4.40 (m, 1H), 4.10 (m, 1H), 3.65 (m, 4H), 3.20 (m, 4H), 2.20 (m, 1H), 2.10 (m, 1H), 1.50–1.90 (m, 6H), 1.40 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[S:10]([NH2:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].Cl>O1CCOCC1>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23]([NH:13][S:10](/[CH:9]=[CH:8]/[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:11])=[O:12])=[O:24]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: NS(=O)(=O)/C=C/c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)/C=C/c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Yield: 28.7 %

Procedure:
To a solution of (E)-2-(4-chloro-phenyl)-ethenesulfonic acid amide (65 mg, 0.3 mmol) in 1,4-dioxane (1.5 ml) was added potassium carbonate (83 mg, 0.6 mmol) followed by 2,4-dichlorobenzoyl chloride (63 μL, 0.45 mmol). The reaction was heated at 80° C. for 16 hours then allowed to cool to room temperature whereupon 1N HCl (2 ml) was added. The mixture was extracted with ethyl acetate (2 ml), the organics were dried with MgSO4 and washed with ethyl acetate (0.4 ml). The mixture was concentrated in vacuo and the resultant residue was purified by preparative HPLC to afford (E)-2-(4-chloro-phenyl)-ethenesulfonic acid 2,4-dichloro-benzoylamide (33.6 mg, 29%).
Reaction SMILES: O1CCCCC1O[C@H]1CC[C@H](CO)CC1.BrC1C=CC(O)=CC=1.[Br:24][C:25]1[CH:45]=[CH:44][C:28]([O:29][CH2:30][C@@H:31]2[CH2:36][CH2:35][C@H:34]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([O:29][CH2:30][C@H:31]2[CH2:32][CH2:33][C@H:34]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[CH2:35][CH2:36]2)=[CH:44][CH:45]=1
Reactant: Brc1ccc(OC[C@H]2CC[C@@H](OC3CCCCO3)CC2)cc1
Agent: OC[C@H]1CC[C@H](OC2CCCCO2)CC1
Agent: Oc1ccc(Br)cc1
Product: Brc1ccc(OC[C@H]2CC[C@H](OC3CCCCO3)CC2)cc1

Procedure:
The title compound (987 mg, 70.3%) was prepared from (+/−)-[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol (815 mg, 3.80 mmol) and 4-bromophenol (0.724 g, 4.18 mmol) by a procedure analogous to that described for (+/−)-2-({cis-4-[(4-bromophenoxy)methyl]cyclohexyl}oxy)tetrahydro-2H-pyran, Example 8, Step C. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02-1.35 (m, 3H) 1.36-1.64 (m, 5H) 1.66-1.90 (m, 3H) 1.90-2.01 (m, 2H) 2.02-2.18 (m, 2H) 3.51 (dt, J=11.02, 5.22 Hz, 1H) 3.61 (tt, J=10.98, 4.24 Hz, 1H) 3.68-3.78 (m, 2H) 3.88-4.00 (m, 1H) 4.68-4.79 (m, 1H) 6.71-6.82 (m, 2H) 7.31-7.42 (m, 2H)
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:19]([C:21]1([OH:29])[CH2:26][CH2:25][CH2:24][N:23]([CH3:27])[C:22]1=[O:28])#[CH:20]>>[OH:29][C:21]1([C:19]#[C:20][C:2]2[CH:18]=[CH:17][C:5]3[O:6][CH2:7][CH2:8][C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=3[CH:3]=2)[CH2:26][CH2:25][CH2:24][N:23]([CH3:27])[C:22]1=[O:28]
Reactant: C#CC1(O)CCCN(C)C1=O
Reactant: NC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CN1CCCC(O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)sc2CCO3)C1=O
Yield: 8 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 3-ethynyl-3-hydroxy-1-methylpiperidin-2-one to give the titled compound as a white solid (10 mg, 8%).