Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:20](B1OC(C)(C)C(C)(C)O1)=[CH2:21].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>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.C(OCC)(=O)C.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[C:16]([CH:20]=[CH2:21])[CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1cnn(-c2cc(Br)cnc2Cl)c1C
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: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cnc(Cl)c(-n2ncc(C(=O)OCC)c2C)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
Tetrahydrofuran (75 ml) was added to 1-(5-bromo-2-chloropyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3 g) described in Reference Example 29, vinylboronic acid pinacol ester (2.01 g), tetrakis(triphenylphosphine)palladium (504 mg) and 2M aqueous solution of sodium carbonate (15.2 ml) and stirred at 90° C. for 4 hours. The reaction solution was cooled to 0° C., and a saturated aqueous solution of ammonium chloride and ethyl acetate were added therein. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with column chromatography (n-hexane/ethyl acetate) to give 1-(2-chloro-5-vinylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.84 g).
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:19][C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.Cl.Cl.[NH2:32][CH2:33][CH2:34][NH:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([NH2:42])[N:37]=1>>[NH2:42][C:38]1[N:37]=[C:36]([NH:35][CH2:34][CH2:33][NH:32][C:14]2[C:13]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:19][C:12]=3[N:17]=[C:16]([NH2:18])[N:15]=2)[CH:41]=[CH:40][N:39]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC(c2ccccc2)C3)cc1
Reactant: NCCNc1ccnc(N)n1
Agent: Cl
Product: Nc1nccc(NCCNc2nc(N)nc3c2CCCC(c2ccccc2)C3)n1

Procedure:
The product from Example 11C (102 mg, 0.248 mmol) and the product from Example 1E (73 mg, 0.323 mmol) were treated under the conditions of Example 1F to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.09-1.29 (m, 2H) 1.70-2.02 (m, 3H) 2.22-2.63 (m, 2H) 2.71 (dd, J=15.47, 5.16 Hz, 1H) 3.06-3.27 (m, 2H) 3.34-3.50 (m, 3H) 5.56-5.65 (m, 2H) 5.70-5.78 (m, 1H) 5.87 (s, 2H) 6.52 (s, 1H) 6.90 (s, 1H) 7.10-7.34 (m, 5H) 7.61 (d, J=5.55 Hz, 1H); MS (ESI+) m/z 391.1 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH3:11])=[O:2].[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Cl)[CH3:13].CC[O-].[Na+].O>C1C=CC=CC=1.C(O)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[O:2][CH:16]2[C:15]([O:14][CH2:12][CH3:13])=[O:18])=[C:4]([CH3:11])[CH:5]=1)#[N:8]
Reactant: CCOC(=O)CCl
Reactant: Cc1cc(C#N)ccc1C=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1OC1c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A mixture of 4-formyl-3-methylbenzonitrile (1.5 g, 10.3 mmol) and chloroacetic acid ethyl ester (1.2 g, 10 mmol) were dissolved in 60 mL of dry benzene. Freshly prepared EtONa (12.4 mmol) in 8 mL of ethanol was added, and the mixture were stirred at room temperature for 2 hours. The mixture was added water, then extracted with EA, dried over Na2SO4 and distilled off solvent to afford 1.7 g of crude ethyl 3-(4-cyano-2-methylphenyl)oxirane-2-carboxylate. MS m/z: 232 (M+1)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[C:13]([O-:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>CN(C=O)C>[C:13]([O:21][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])c1ccccc1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Oc1ccc2c(c1)C(=O)OC2=O)c1ccccc1
Yield: 50.7 %

Procedure:
4-Fluorophthalic anhydride (16.7 g, 100 mmol) and sodium benzoate (14.5 g, 101 mmol) were heated to about 145° C. in DMF (70 ml). After heating for 5 hours, the solvent was distilled off under reduced pressure (the temperature was kept at less than 100° C.). Ethyl acetate (50 ml) was added and the suspension refluxed for 30 minutes. The suspension was filtered and the ethyl acetate allowed to cool to give 4-benzoyloxyphthalic anhydride (13.6 g, 86% pure) as a whitish solid. Ethyl acetate (8 mls) was distilled from the mother liquor and hexane added to the hot solution. The solution was allowed to cool and stand for several days upon which a solid benzoyloxyphthalic anhydride precipitated (4.7 g, 79% pure).
Reaction SMILES: [C:1]([NH:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16](S(C2C=CC(C)=CC=2)(=O)=O)[CH:15]=[C:14]3B2OC(C)(C)C(C)(C)O2)=[N:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:40]1[S:41][C:42]([C:45]([NH2:47])=[O:46])=[CH:43][N:44]=1.ClC1SC(C(N)=O)=CN=1>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>[C:1]([NH:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:40]2[S:41][C:42]([C:45]([NH2:47])=[O:46])=[CH:43][N:44]=2)=[N:9][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)c1cnc(Br)s1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)(C)C)o4)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: NC(=O)c1cnc(Cl)s1
Product: CC(C)(C)Nc1nnc(-c2ccc3[nH]cc(-c4ncc(C(N)=O)s4)c3c2)o1
Yield: 52 %

Procedure:
The title compound (49 mg, 52% yield) as a yellow crystalline solid was prepared similar to that described in Example 275, using N-tert-butyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (131 mg, 0.244 mmol), 106 mg of the 1:1 mixture of 2-bromothiazole-5-carboxamide and 2-chlorothiazole-5-carboxamide, and Pd(PPh3)4 (Strem Chemicals, 14 mg) as the starting materials and reagent. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.21 (1H, br.), 8.63 (1H, s), 8.38 (s, 1H), 8.28 (1H, s), 8.14 (1H, br.), 7.75 (1H, d, J=8.80 Hz), 7.66 (2H, m), 7.53 (1H, br.), 1.40 (9H, s). MS (ESI, pos. ion) m/z: 383.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)(O)[O-].[Na+].[C:20](OC(=O)C)(=O)[CH3:21]>>[CH3:14][N:13]1[C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[N:1]=[C:20]1[CH3:21]
Reactant: CCOC(=O)c1ccc(NC)c(N)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1ccc2c(c1)nc(C)n2C

Procedure:
Ethyl 3-amino-4-methylaminobenzoate (1.00 g, 5.15 mmol) prepared in the Step 1-1-3 was dissolved in acetic anhydride (4 ml), and the mixture was heated under reflux for 19 hours. After being allowed to cool, the mixture was neutralized with a saturated sodium bicarbonate solution and subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (1.15 g, quantitative) as a light-brown oily substance.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][N:55]=1.[NH2:61][CH2:62][CH2:63][N:64]1[CH2:68][CH2:67][CH2:66][CH2:65]1>C1(C)C=CC=CC=1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:60][C:57]1[CH:58]=[CH:59][C:54]([NH:61][CH2:62][CH2:63][N:64]2[CH2:68][CH2:67][CH2:66][CH2:65]2)=[N:55][CH:56]=1
Reactant: Brc1ccc(Br)nc1
Reactant: NCCN1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc(NCCN2CCCC2)nc1

Procedure:
13.8 g (100.0 mmol) K2CO3, 79 mg (0.12 mmol) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 28 mg (0.12 mmol) Pd(OAc)2 are added successively to a solution of 1.5 g (6.33 mmol) 2,5-dibromopyridine and 0.98 mL (7.60 mmol) 1-(2-aminoethyl)-pyrrolidine in 60 mL toluene. The reaction is refluxed for 40 h. The solvent is eliminated i.vac. and the residue is taken up in 150 mL EtOAc and 100 mL water. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Purification is carried out by column chromatography on silica gel (gradient: EtOAc/MeOH/NH3 19:1:0.1 to EtOAc/MeOH/NH3 9:1:0.1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH2:11][N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1)[CH2:8]2.[C:17]1(C)C=CC=CC=1.C([Li])CCC.CI>O1CCCC1>[CH3:17][C:16]1[N:12]([CH2:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)[N:13]=[CH:14][CH:15]=1
Reactant: c1cnn(CC2C3CC4CC(C3)CC2C4)c1
Reactant: Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccnn1CC1C2CC3CC(C2)CC1C3
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 62A (0.192 g, 0.888 mmol) in tetrahydrofuran (1 mL)/toluene (1 mL) was added n-butyllithium (1.6 M, 0.721 mL) at 0° C. The reaction mixture was stirred for 60 minutes. Then CH3I (0.166 mL) was added and stirring continued for 3 hours at 0° C. The reaction mixture was quenched with water, extracted with diethyl ether, dried over Na2SO4, filtered, and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:5](=[C:10]([CH3:26])[C:11]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:12][C:13]=1[O:14]CC=C)[C:6]([O:8][CH3:9])=[O:7].C(NCC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:5](=[C:10]([CH3:26])[C:11]([O:18][S:19]([C:22]([F:23])([F:25])[F:24])(=[O:21])=[O:20])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=CCOc1cc(OS(=O)(=O)C(F)(F)F)c(C)c(C(=O)OC)c1C(=O)OC
Solvent: CCNCC
Solvent: Cc1ccccc1
Product: COC(=O)c1c(O)cc(OS(=O)(=O)C(F)(F)F)c(C)c1C(=O)OC
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of 6-allyloxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethyl ester (8.39 g, 20.3 mmol) in toluene (20 mL) was added tetrakistriphenylphosphine palladium (0.47 g, 0.40 mmol) and diethylamine (2.97 g, 40.86 mmol) at room temperature under an atmosphere of nitrogen. Stirring at room temperature was continued until all starting material was consumed. The crude reaction mixture was partitioned between diethyl ether and HCl (0.1 N). The organic layer was washed with brine and dried over sodium sulfate. Filtration and evaporation of solvents in vacuo yielded a crude material, which was purified by silica gel chromatography to provide 4.16 g (55%) of the desired product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ=2.20 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 7.01 (s, 1H) ppm; 19F NMR (282 MHz, CDCl3): δ=−74 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[Na+].Br[CH:12]([CH3:14])[CH3:13]>C(O)C>[CH3:13][CH:12]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])[CH3:14]
Reactant: CC(C)Br
Reactant: Nc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Sc1ccccc1N
Temperature: 25 °C

Procedure:
To a solution of 2-aminothiophenol (90%, 100 g, 0.72 mol) and sodium hydroxide (31.7 g, 0.792 mol) in 90% aqueous ethanol (500 ml) was added dropwise 2-bromopropane (89 g, 0.72 mol) at room temperature. When the addition was complete, the reaction mixture was refluxed for 3 hours, cooled to room temperature, and then concentrated in vacuo. The residue was diluted with water (300 ml) and extracted with ether (3×500 ml). The ether extracts were washed with water and brine, dried with MgSO4 and concentrated in vacuo to yield the crude product. Distillation through a Vigreaux column gave 2-(1-methylethylthio)benzenamine: bp 94° (2.2-2.4 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][P:25]([O:29][CH3:30])([O:27][CH3:28])=[O:26])[CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][P:25](=[O:26])([O:29][CH3:30])[O:27][CH3:28])[CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COP(=O)(CN1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COP(=O)(CN1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-N-[(3S)-1-(dimethoxyphosphorylmethyl)-3-piperidyl]-5-fluoro-pyrimidin-4-amine, 56a, (1.00 g, 1.61 mmol) in MeOH (40 mL) was added sodium methanolate (20 mL of 25% w/v, 92.55 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. All volatiles were removed at reduced pressure and the resulting residue was diluted with aqueous saturated NH4Cl solution and extracted twice with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography using 0-10% MeOH:CH2Cl2 gradient to provide 270 mg of a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:6]=1.[CH3:20][CH:21]([O:23][C:24](=[O:49])[NH:25][CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[N:29]([C:45](=[O:47])[CH3:46])[CH:28]([CH3:48])[CH2:27]1)[CH3:22].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C.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>[CH3:22][CH:21]([O:23][C:24](=[O:49])[NH:25][C@H:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:2]3[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:9]4[C:17](=[O:18])[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[C:10]4=[O:19])[CH:6]=3)[CH:34]=2)[N:29]([C:45](=[O:47])[CH3:46])[C@@H:28]([CH3:48])[CH2:27]1)[CH3:20]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C(NC(=O)OC(C)C)CC1C
Reactant: O=C1c2ccccc2C(=O)N1CCn1cc(Br)cn1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3cnn(CCN4C(=O)c5ccccc5C4=O)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C

Procedure:
2-[2-(4-bromo-1H-pyrazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione (for a preparation see Intermediate 28) (80 mg, 0.250 mmol) and 1-methylethyl[1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (Intermediate 12, 150 mg, 0.360 mmol) were mixed with potassium carbonate (69.1 mg, 0.500 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.44 mg, 0.012 mmol), dissolved in ethanol (1 mL) and toluene (1 mL) and stirred under nitrogen at 90° C. for 1 hour. The mixture was partitioned between distilled water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL) and the organic fractions were combined, washed (brine, 30 mL), dried (MgSO4), filtered and evaporated to dryness to give a yellow solid which was loaded on to a 12+M Biotage silica column and eluted with cyclohexane:ethyl acetate (3:1 to 1:2). Product-containing fractions were evaporated to dryness to give a solid (39 mg). LCMS (Method C): Rt=0.95, MH+=530
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[CH2:14]([CH:16]1[O:18][CH2:17]1)Br>CN(C)C=O.C(OCC)(=O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][N:9]([CH2:14][CH:16]1[CH2:17][O:18]1)[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: BrCC1CO1
Reactant: CS(=O)(=O)NCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(Cc1ccco1)CC1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
Sodium hydride (60% mineral oil dispersion, 0.524 g, 13.1 mmol) was added in portions to a 0° C. solution of N-(furan-2-ylmethyl)methanesulfonamide (2.0 g, 11.4 mmol) in 38 ml anhydrous N,N-dimethylformamide (38 mL), and the resultant mixture was allowed to warm to room temperature and stirred for 1 hour. Epibromohydrin (1.2 mL, 14.3 mmol) was added slowly, and the reaction was stirred for 3 hours at room temperature and 16 hours at 70° C. The reaction was cooled, diluted with ethyl acetate, and successively washed twice with water and once with saturated aqueous sodium chloride solutions. The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (25-60% ethyl acetate in hexanes) to give a pale yellow liquid (2.2 g, 84%). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.39 (m, 1H), 6.37-6.35 (m, 2H), 4.64-4.50 (br dd, 2H, J=25.8, 16.5 Hz), 3.61-3.55 (m, 1H), 3.22-3.12 (m, 2H), 2.82 (s, 3H), 2.82-2.79 (m, 1H), 2.62-2.60 (m, 1H). ESI (m/z): 232.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(OO)(=[O:14])C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[N+:4]([O-:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(=O)OO
Reactant: Brc1cnc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cc(Br)cc2ccccc21
Reaction time: 12 h

Procedure:
To a solution of 3-bromo-quinoline (1.0 eq.) in CH2Cl2 (0.2M) was added peracetic acid (2.0 eq.). The mixture was stirred for 12 h, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Crystallization from CH2Cl2:Hex afforded the title compound as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1([CH2:28][OH:29])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.Br[CH2:31][C:32]1[CH:33]=[C:34]([C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=2)[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>C1COCC1>[Br:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1([CH2:28][O:29][CH2:31][C:32]2[CH:33]=[C:34]([C:42]3[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=3)[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]1
Reactant: N#Cc1ccc(-c2cc(CBr)cc(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2Br)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccc(F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.1 %

Procedure:
Potassium tert-butoxide (266 mg, 2.37 mmol) was added to a 0° C. solution of tert-butyl 4-(2-bromo-4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (460 mg, 1.18 mmol) and 3′-(bromomethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (524 mg, 1.54 mmol) in THF (10 mL) and was allowed to warm to ambient temperature and stir for 24 hours. The solvent was evaporated and the residue was purified by chromatography on SiO2 with a gradient of ethyl acetate/hexanes from 5% to 40%. The product tert-butyl 4-(2-bromo-4-fluorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate (520 mg, 68%) was isolated as a clear syrup. 1H-NMR (CDCl3, 400 MHz) δ 7.75 (d, J=8.3 Hz, 2H), 7.67 (s, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.36 (m, 3H), 7.22 (m, 1H), 6.99 (m, 1H), 4.49 (s, 2H), 3.94 (s, 2H), 3.57 (m, 1H), 3.24 (m 1H), 2.48 (m, 2H), 2.05 (m, 2H), 1.42 (s, 9H). Mass spec.: 647.2 (M+H).
Reaction SMILES: N.[CH2:2]([C@@H:8]1[C:11](=[O:12])[O:10][C@H:9]1[CH2:13][C@@H:14]([O:26][CH2:27][CH2:28][C:29]([OH:31])=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C[N:33](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:29]([CH2:28][CH2:27][O:26][C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][C@@H:9]1[O:10][C:11](=[O:12])[C@H:8]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])(=[O:31])[NH2:33]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OCCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CC#N
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OCCC(N)=O
Yield: 81.4 %

Procedure:
Ammonia gas was blown into a solution of 40 mg of 3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]propionic acid (Example L) in 2.5 ml of acetonitrile until the solution is saturated and subsequently 50 mg of HBTU were added. Then, the mixture was filtered and evaporated and the residue was chromato- graphed on silica gel with 5 percent methanol in methylene chloride. There were obtained 32.5 mg of (3S,4S)-4-[(S)-2-(2-carbamoylethoxy)tridecyl]-3-hexyl-2-oxetanone, m.p. 35°.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](Cl)=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:7][C:6]=1[O:18]C(=O)C)(=O)C.O.[SH2:23].[Na]>CO>[OH:18][C:6]1[CH:7]=[C:8]([C:11]2[C:12](=[S:23])[NH:13][CH:14]=[N:15][CH:16]=2)[CH:9]=[CH:10][C:5]=1[OH:4]
Reactant: S
Reactant: CC(=O)Oc1ccc(-c2cncnc2Cl)cc1OC(C)=O
Agent: [Na]
Solvent: CO
Solvent: O
Product: Oc1ccc(-c2cnc[nH]c2=S)cc1O
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 97.1 %

Procedure:
4-(4-Chloro-5-pyrimidinyl)-o-phenylene diacetate (1.1 g) (3.6 mmol) are dissolved in 30 ml of methanol. 1.56 g of sodium hydrogen sulphide hydrate are added thereto and the mixture is stirred at 60° C. for 4.5 hours. The solvent is distilled off in a vacuum and the residue is dissolved in 20 ml of water. The solution is acidified with dilute aqueous hydrochloric acid to pH 5, the precipitated product is filtered off under suction and washed with water and diethyl ether. After drying in a high vacuum there are obtained 770 mg of 5-(3,4-dihydroxyphenyl)-4(3H)-pyrimidinethione as yellow crystals of m.p. 235° C. (dec.).